Differential expression of largemouth bass (Micropterus salmoides) estrogen receptor isotypes alpha, beta, and gamma by estradiol.

PubMed

Sabo-Attwood, Tara; Kroll, Kevin J; Denslow, Nancy D

2004-04-15

The expression levels of three estrogen receptor (ER) isotypes alpha, beta, and gamma were quantified in female largemouth bass (Micropterus salmoides) (LMB) liver, ovary, brain, and pituitary tissues. ER alpha and beta expression predominated in the liver, while ERs beta and gamma predominated in the other tissues. Temporally in females, ER alpha was highly up-regulated, ER gamma was slightly up-regulated, and ER beta levels remained unchanged in the liver when plasma 17-beta estradiol (E2) and vitellogenin (Vtg) levels were elevated in the spring. In ovarian tissue from these same fish, all three ERs were maximally expressed in the fall, during early oocyte development and prior to peak plasma E2 levels. When males were injected with E2, ER alpha was highly inducible, ER gamma was moderately up-regulated, and ER beta levels were not affected. None of the ER isotypes were induced by E2 in gonadal tissues. These results combined suggest that the ERs themselves are not regulated in the same manner by E2, and furthermore, do not contribute equally to the transcriptional regulation of genes involved in fish reproduction such as Vtg.

Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia.

PubMed

Schaefer, Natascha; Kluck, Christoph J; Price, Kerry L; Meiselbach, Heike; Vornberger, Nadine; Schwarzinger, Stephan; Hartmann, Stephanie; Langlhofer, Georg; Schulz, Solveig; Schlegel, Nadja; Brockmann, Knut; Lynch, Bryan; Becker, Cord-Michael; Lummis, Sarah C R; Villmann, Carmen

2015-01-07

Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) α1 biogenesis. Here, we examine the properties of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel mutants localized in the large extracellular domain of the GlyR α1 have reduced cell surface expression with a high proportion of receptors being retained in the ER, although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but none of those in loop D/β2-3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that a proportion of GlyR α1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/β2-3 is an important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in ligand binding. Copyright © 2015 the authors 0270-6474/15/350422-16$15.00/0.

Neurotrophins regulate ApoER2 proteolysis through activation of the Trk signaling pathway.

PubMed

Larios, Jorge A; Jausoro, Ignacio; Benitez, Maria-Luisa; Bronfman, Francisca C; Marzolo, Maria-Paz

2014-09-19

ApoER2 and the neurotrophin receptors Trk and p75(NTR) are expressed in the CNS and regulate key functional aspects of neurons, including development, survival, and neuronal function. It is known that both ApoER2 and p75(NTR) are processed by metalloproteinases, followed by regulated intramembrane proteolysis. TrkA activation by nerve growth factor (NGF) increases the proteolytic processing of p75(NTR) mediated by ADAM17. Reelin induces the sheeding of ApoER2 ectodomain depending on metalloproteinase activity. However, it is not known if there is a common regulation mechanism for processing these receptors. We found that TrkA activation by NGF in PC12 cells induced ApoER2 processing, which was dependent on TrkA activation and metalloproteinases. NGF-induced ApoER2 proteolysis was independent of mitogen activated protein kinase activity and of phosphatidylinositol-3 kinase activity. In contrast, the basal proteolysis of ApoER2 increased when both kinases were pharmacologically inhibited. The ApoER2 ligand reelin regulated the proteolytic processing of its own receptor but not of p75(NTR). Finally, in primary cortical neurons, which express both ApoER2 and TrkB, we found that the proteolysis of ApoER2 was also regulated by brain-derived growth factor (BDNF). Our results highlight a novel relationship between neurotrophins and the reelin-ApoER2 system, suggesting that these two pathways might be linked to regulate brain development, neuronal survival, and some pathological conditions.

The Role of Hypothalamic Estrogen Receptors in Metabolic Regulation

PubMed Central

Frank, Aaron; Brown, Lynda M.; Clegg, Deborah J.

2014-01-01

Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two ”classical“ estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1−/−); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism. PMID:24882636

The role of hypothalamic estrogen receptors in metabolic regulation.

PubMed

Frank, Aaron; Brown, Lynda M; Clegg, Deborah J

2014-10-01

Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two 'classical' estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1(-/-)); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism. Copyright © 2014 Elsevier Inc. All rights reserved.

The sigma-1 receptor chaperone as an inter-organelle signaling modulator

PubMed Central

Su, Tsung-Ping; Hayashi, Teruo; Maurice, Tangui; Buch, Shilpa; Ruoho, Arnold E.

2010-01-01

Inter-organelle signaling plays important roles in many physiological functions. Endoplasmic reticulum (ER)-mitochondrion signaling affects intra-mitochondrial calcium (Ca2+) homeostasis and cellular bioenergetics. ER-nucleus signaling attenuates ER stress. ER-plasma membrane signaling regulates cytosolic Ca2+ homeostasis, and ER-mitochondrion-plasma membrane signaling regulates hippocampal dendritic spine formation. Here we propose that the sigma-1 receptor (Sig-1R), an ER chaperone protein, acts as an inter-organelle signaling modulator. Sig-1Rs normally reside at the ER-mitochondrion contact called the MAM (mitochondrion-associated ER membrane), where Sig-1Rs regulate ER-mitochondrion signaling and the ER-nucleus cross-talk. When cells are stimulated by ligands or undergo prolonged stress, Sig-1Rs translocate from the MAM to the ER reticular network and plasmalemma/plasma membrane to regulate a variety of functional proteins, including ion channels, receptors, and kinases. Thus, the Sig-1R serves as an inter-organelle signaling modulator locally at the MAM and remotely at the plasmalemma/plasma membrane. Many pharmacological/physiological effects of Sig-1Rs may relate to this unique action of Sig-1Rs. PMID:20869780

Automatic control of negative emotions: evidence that structured practice increases the efficiency of emotion regulation.

PubMed

Christou-Champi, Spyros; Farrow, Tom F D; Webb, Thomas L

2015-01-01

Emotion regulation (ER) is vital to everyday functioning. However, the effortful nature of many forms of ER may lead to regulation being inefficient and potentially ineffective. The present research examined whether structured practice could increase the efficiency of ER. During three training sessions, comprising a total of 150 training trials, participants were presented with negatively valenced images and asked either to "attend" (control condition) or "reappraise" (ER condition). A further group of participants did not participate in training but only completed follow-up measures. Practice increased the efficiency of ER as indexed by decreased time required to regulate emotions and increased heart rate variability (HRV). Furthermore, participants in the ER condition spontaneously regulated their negative emotions two weeks later and reported being more habitual in their use of ER. These findings indicate that structured practice can facilitate the automatic control of negative emotions and that these effects persist beyond training.

Spaceborne Sensors Track Marine Debris Circulation in the Gulf of Mexico

NASA Technical Reports Server (NTRS)

Reahard, Ross; Mitchell, Brandie; Lee, Lucas; Pezold, Blaise; Brook, Chris; Mallett, Candis; Barrett, Shelby; Albin, Aaron

2011-01-01

Marine debris is a problem for coastal areas throughout the world, including the Gulf of Mexico. To aid the NOAA Marine Debris Program in monitoring marine debris dispersal and regulating marine debris practices, sea surface height and height anomaly data provided by the Colorado Center for Astrodynamics Research at the University of Colorado, Boulder, were utilized to help assess trash and other discarded items that routinely wash ashore in southeastern Texas, at Padre Island National Seashore. These data were generated from the NASA radar altimeter satellites TOPEX/Poseidon, Jason 1, and Jason 2, as well as the European altimeter satellites ERS-1, ERS-2 (European Remote Sensing Satellite), and ENVISAT (Environmental Satellite). Sea surface temperature data from MODIS were used to study of the dynamics of the Loop Current. Sea surface height and MODIS data analysis were used to show that warm water in the core of eddies, which periodically separate from the Loop Current, can be as high as 30 cm above the surrounding water. These eddies are known to directly transfer marine debris to the western continental shelf and the elevated area of water can be tracked using satellite radar altimeter data. Additionally, using sea surface height, geostrophic velocity, and particle path data, foretracking and backtracking simulations were created. These simulation runs demonstrated that marine debris on Padre Island National Seashore may arise from a variety of sources, such as commercial fishing/shrimping, the oil and gas industry, recreational boaters, and from rivers that empty into the Gulf of Mexico.

Quantitative Feedback Technique (QFT): Bridging the Gap

DTIC Science & Technology

2003-05-01

with Eq. (2) illustrates: (a) the effect of changes of the uncertainty set P(s) upon the output of the closed -loop control system is reduced by the...Bridging the Gap root-locus technique the dominant closed -loop poles are determined for a ζ= 0.45. Table 3 presents the required value of Kx and...degree of decoupling will have been enhanced. Method 1 is then more readily applicable, with the additional benefit of reduced closed -loop BW. E.R.2

Anisotropic magnetic switching along hard [1 1 0]-type axes in Er-doped DyFe2/YFe2 thin films

NASA Astrophysics Data System (ADS)

Stenning, G. B. G.; Bowden, G. J.; van der Laan, G.; Figueroa, A. I.; Bencok, P.; Steadman, P.; Hesjedal, T.

2017-10-01

Epitaxial-grown DyFe2/YFe2 multilayer thin films form an ideal model system for the study of magnetic exchange springs. Here the DyFe2 (YFe2) layers are magnetically hard (soft). In the presence of a magnetic field, exchange springs form in the YFe2 layers. Recently, it has been demonstrated that placing small amounts of Er into the centre of the YFe2 springs generates substantial changes in magnetic behavior. In particular, (i) the number of exchange-spring states is increased dramatically, (ii) the resulting domain-wall states cannot simply be described as either Néel or Bloch walls, (iii) the Er and Dy magnetic loops are strikingly different, and (iv) it is possible to engineer Er-induced magnetic exchange-spring collapse. Here, results are presented for Er-doped (1 1 0)-oriented DyFe2 (60 Å/YFe2(240 Å)15 multilayer films, at 100 K in fields of up to 12 T. In particular, we contrast magnetic loops for fields applied along seemingly equivalent hard-magnetic [1 1 0]-type axes. MBE-grown cubic Laves thin films offer the unique feature of allowing to apply the magnetic field along (i) a hard out-of-plane [1 1 0]-axis (the growth axis) and (ii) a similar hard in-plane [ 1 bar 10 ] -axis. Differences are found and attributed to the competition between the crystal-field interaction at the Er site and the long-range dipole-dipole interaction. In particular, the out-of-plane [1 1 0] Er results show the existence of a new magnetic exchange spring state, which would be very difficult to identify without the aid of element-specific technique of X-ray magnetic circular dichroism (XMCD).

Architectural Specialization for Inter-Iteration Loop Dependence Patterns

DTIC Science & Technology

2015-10-01

Architectural Specialization for Inter-Iteration Loop Dependence Patterns Christopher Batten Computer Systems Laboratory School of Electrical and...Trends in Computer Architecture Transistors (Thousands) Frequency (MHz) Typical Power (W) MIPS R2K Intel P4 DEC Alpha 21264 Data collected by M...T as ks p er Jo ule ) Simple Processor Design Power Constraint High-Performance Architectures Embedded Architectures Design Performance

Systematic mutational analysis of the intracellular regions of yeast Gap1 permease.

PubMed

Merhi, Ahmad; Gérard, Nicolas; Lauwers, Elsa; Prévost, Martine; André, Bruno

2011-04-19

The yeast general amino acid permease Gap1 is a convenient model for studying the intracellular trafficking of membrane proteins. Present at the plasma membrane when the nitrogen source is poor, it undergoes ubiquitin-dependent endocytosis and degradation upon addition of a good nitrogen source, e.g., ammonium. It comprises 12 transmembrane domains (TM) flanked by cytosol-facing N- and C-terminal tails (NT, CT). The NT of Gap1 contains the acceptor lysines for ubiquitylation and its CT includes a sequence essential to exit from the endoplasmic reticulum (ER). We used alanine-scanning mutagenesis to isolate 64 mutant Gap1 proteins altered in the NT, the CT, or one of the five TM-connecting intracellular loops (L2, -4, -6, -8 and -10). We found 17 mutations (in L2, L8, L10 and CT) impairing Gap1 exit from the ER. Of the 47 mutant proteins reaching the plasma membrane normally, two are unstable and rapidly down-regulated even when the nitrogen source is poor. Six others are totally inactive and another four, altered in a 16-amino-acid sequence in the NT, are resistant to ammonium-induced down-regulation. Finally, a mutation in L6 causes missorting of Gap1 from the secretory pathway to the vacuole. Interestingly, this direct vacuolar sorting seems to be independent of Gap1 ubiquitylation. This study illustrates the importance of multiple intracellular regions of Gap1 in its secretion, transport activity, and down-regulation.

The effects of estradiol and selective estrogen receptor modulators on gene expression and messenger RNA stability in immortalized sheep endometrial stromal cells and human endometrial adenocarcinoma cells.

PubMed

Farnell, Yuhua Z; Ing, Nancy H

2003-03-01

The purpose of this study was to identify an endometrial cell line that maintained the E2 up-regulation of estrogen receptor (ER) mRNA by enhanced message stability and to assess its dependence on ER protein. Estradiol (E2) effects on gene expression were measured in three cell lines: one immortalized from sheep endometrial stroma (ST) and two from human endometrial adenocarcinomas (Ishikawa and ECC-1). E2 up-regulated ER mRNA levels in ST and Ishikawa cells, but down-regulated ER mRNA levels in ECC-1 cells. E2 up-regulated progesterone receptor (PR), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and transforming growth factor-alpha (TGF-alpha) in both Ishikawa and ECC-1 cells. The selective estrogen receptor modulator ICI 182,780 antagonized the E2-induced up-regulation of ER and/or PR mRNA levels in all three cells, while another, GW 5638, antagonized the up-regulation of PR mRNA in Ishikawa and ECC-1 cells. In mechanistic studies, E2 had no effect on ER mRNA stability in ST cells and it destabilized ER mRNA in ECC-1 cells. Thus, Ishikawa cells appear to be the most physiologically relevant cell line in which to study the up-regulation of ER mRNA levels by enhanced mRNA stability. Its antagonism by ICI 182,780 reveals that ER protein is involved in this E2 response.

Emotion regulation deficits in eating disorders: a marker of eating pathology or general psychopathology?

PubMed

Svaldi, Jennifer; Griepenstroh, Julia; Tuschen-Caffier, Brunna; Ehring, Thomas

2012-05-15

Preliminary evidence indicates that individuals with eating disorders (ED) show emotion regulation (ER) difficulties. However, it is yet unclear whether different types of ED differ in their ER profile and whether certain ER difficulties are specific for ED or rather a transdiagnostic factor. Twenty women with anorexia nervosa (AN), 18 with bulimia nervosa (BN), 25 with binge eating disorder (BED), 15 with borderline personality disorder (BPD), 16 with major depressive disorder (MDD) and 42 female healthy controls (HC) were administered the Emotion Regulation Questionnaire, the Inventory of Cognitive Affect Regulation Strategies, the Difficulties in Emotion Regulation Scale and the Affect Intensity Measure. The ED groups reported significantly higher levels of emotion intensity, lower acceptance of emotions, less emotional awareness and clarity, more self-reported ER problems as well as decreased use of functional and increased use of dysfunctional emotion regulation strategies when compared to HC. No significant differences between the ED groups emerged for most ER variables. However, there were indications that the BED group may show a slightly more adaptive pattern of ER than the two other ED groups. As a whole, all clinical groups performed very similar on most ER variables and reported more difficulties regulating their emotions than HC. The findings suggest that ER difficulties are not linked to a particular diagnostic category. Instead, ER difficulties appear to be a transdiagnostic risk and/or maintenance factor rather than being disorder-specific. Copyright © 2012 Elsevier Ltd. All rights reserved.

Self- and Co-regulation of Anger and Fear in Preschoolers with Autism Spectrum Disorders: The Role of Maternal Parenting Style and Temperament.

PubMed

Hirschler-Guttenberg, Yael; Feldman, Ruth; Ostfeld-Etzion, Sharon; Laor, Nathaniel; Golan, Ofer

2015-09-01

Emotion regulation (ER) difficulties are a major concern in children with autism spectrum disorder (ASD). Maternal temperament and parenting style have significant effects on children's ER. However, these effects have not been studied in children with ASD. Forty preschoolers with ASD and their mothers and forty matched controls engaged in fear and anger ER paradigms, micro-coded for child self- and co-regulatory behaviors and parent's regulation-facilitation. Mothers' parenting style and temperament were self-reported. In the ASD group only, maternal authoritarian style predicted higher self-regulation and lower co-regulation of anger and maternal authoritative style predicted higher self-regulation of fear. Maternal temperament did not predict child's ER. Findings emphasize the importance of maternal flexible parenting style in facilitating ER among children with ASD.

Regulation of plant vascular stem cells by endodermis-derived EPFL-family peptide hormones and phloem-expressed ERECTA-family receptor kinases.

PubMed

Uchida, Naoyuki; Tasaka, Masao

2013-12-01

Plant vasculatures are complex tissues consisting of (pro)cambium, phloem, and xylem. The (pro)cambium serves as vascular stem cells that produce all vascular cells. The Arabidopsis ERECTA (ER) receptor kinase is known to regulate the architecture of inflorescence stems. It was recently reported that the er mutation enhances a vascular phenotype induced by a mutation of TDR/PXY, which plays a significant role in procambial proliferation, suggesting that ER participates in vascular development. However, detailed molecular mechanisms of the ER-dependent vascular regulation are largely unknown. Here, this work found that ER and its paralogue, ER-LIKE1, were redundantly involved in procambial development of inflorescence stems. Interestingly, their activity in the phloem was sufficient for vascular regulation. Furthermore, two endodermis-derived peptide hormones, EPFL4 and EPFL6, were redundantly involved in such regulation. It has been previously reported that EPFL4 and EPFL6 act as ligands of phloem-expressed ER for stem elongation. Therefore, these findings indicate that cell-cell communication between the endodermis and the phloem plays an important role in procambial development as well as stem elongation. Interestingly, similar EPFL-ER modules control two distinct developmental events by slightly changing their components: the EPFL4/6-ER module for stem elongation and the EPFL4/6-ER/ERL1 module for vascular development.

Can functional emotion regulation protect children's mental health from war trauma? A Palestinian study.

PubMed

Diab, Marwan; Peltonen, Kirsi; Qouta, Samir R; Palosaari, Esa; Punamäki, Raija-Leena

2017-04-19

Effective emotion regulation (ER) is expected to protect mental health in traumatic stress. We first analysed the protective (moderator) function of different ER strategies and the associations between ER and mental health. Second, we tested gender differences in the protective function of ER and the associations between ER strategies and mental health. Participants were 482 Palestinian children (girls 49.4%; 10-13 years, M = 11.29, SD = .68) whose ER was assessed by the Emotion Regulation Questionnaire and mental health by post-traumatic stress (Children's Impact Event Scale), depressive, and psychological distress (Strengths and Difficulties Questionnaire) symptoms, and by psychosocial well-being (Mental Health Continuum-Short Form). War trauma involved 42 events. Results showed, first, that none of the ER strategies could protect a child's mental health from negative impact of war trauma, but self-focused ER was associated with low depressive symptoms, and other-facilitated ER with high psychological well-being. However, controlling of emotions formed a comprehensive risk for children's mental health. Second, gender differences were found in the protective role of ER, as self-focused and distractive ER formed a vulnerability among boys. The results are discussed in the context of emotional and regulative demands of war and life-threat. © 2017 International Union of Psychological Science.

Distributed Simulation Testing for Weapons System Performance of the F/A-18 and AIM-120 AMRAAM

DTIC Science & Technology

1998-01-01

Support Facility (WSSF) at China Lake, CA and the AIM-120 Hardware in the Loop (HWIL) laboratory at Point Mugu, CA. The link was established in response to...ROCKET MOTOR TARGET DETECTION (FUZE) SEEKERIASSEMBLYWAH D . ANTENN ’ A TRA-kN.SiV, ITfrER’I" ACTUATOR ELECTRONICS DATA LIX -K PARAMETERS ADIMI20AI AIMI...test series. 3.2 Hardware in the Loop : The AMRAAM Hardware-In-the- Loop (HWIL) lab located at the Naval Air Warfare Center in Point Mugu, CA provides

The Cognitive Consequences of Emotion Regulation: An ERP Investigation

PubMed Central

Deveney, C.M.; Pizzagalli, D.A.

2008-01-01

Increasing evidence suggests that emotion regulation (ER) strategies modulate encoding of information presented during regulation; however, no studies have assessed the impact of cognitive reappraisal ER strategies on the processing of stimuli presented after the ER period. Participants in the present study regulated emotions to unpleasant pictures and then judged whether a word was negative or neutral. Electromyographic measures (corrugator supercilli) confirmed that individuals increased and decreased negative affect according to ER condition. Event-related potential analyses revealed smallest N400 amplitudes to negative and neutral words presented after decreasing unpleasant emotions and smallest P300 amplitudes to words presented after increasing unpleasant emotions whereas reaction time data failed to show ER modulations. Results are discussed in the context of the developing ER literature, as well as theories of emotional incongruity (N400) and resource allocation (P300). PMID:18221443

Mechanism of auxiliary β-subunit-mediated membrane targeting of L-type (CaV1.2) channels

PubMed Central

Fang, Kun; Colecraft, Henry M

2011-01-01

Abstract Ca2+ influx via CaV1/CaV2 channels drives processes ranging from neurotransmission to muscle contraction. Association of a pore-forming α1 and cytosolic β is necessary for trafficking CaV1/CaV2 channels to the cell surface through poorly understood mechanisms. A prevalent idea suggests β binds the α1 intracellular I–II loop, masking an endoplasmic reticulum (ER) retention signal as the dominant mechanism for CaV1/CaV2 channel membrane trafficking. There are hints that other α1 subunit cytoplasmic domains may play a significant role, but the nature of their potential contribution is unclear. We assessed the roles of all intracellular domains of CaV1.2-α1C by generating chimeras featuring substitutions of all possible permutations of intracellular loops/termini of α1C into the β-independent CaV3.1-α1G channel. Surprisingly, functional analyses demonstrated α1C I–II loop strongly increases channel surface density while other cytoplasmic domains had a competing opposing effect. Alanine-scanning mutagenesis identified an acidic-residue putative ER export motif responsible for the I–II loop-mediated increase in channel surface density. β-dependent increase in current arose as an emergent property requiring four α1C intracellular domains, with the I–II loop and C-terminus being essential. The results suggest β binding to the α1C I–II loop causes a C-terminus-dependent rearrangement of intracellular domains, shifting a balance of power between export signals on the I–II loop and retention signals elsewhere. PMID:21746784

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction.

PubMed

Fu, Hai Ying; Sanada, Shoji; Matsuzaki, Takashi; Liao, Yulin; Okuda, Keiji; Yamato, Masaki; Tsuchida, Shota; Araki, Ryo; Asano, Yoshihiro; Asanuma, Hiroshi; Asakura, Masanori; French, Brent A; Sakata, Yasushi; Kitakaze, Masafumi; Minamino, Tetsuo

2016-03-04

Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment. © 2016 American Heart Association, Inc.

Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes

PubMed Central

Wen, Gaiping; Eder, Klaus

2017-01-01

Endoplasmic reticulum (ER) stress is characterized by the accumulation of misfolded proteins due to an impairment of ER quality control pathways leading to the activation of a defense system, called unfolded protein response (UPR). While thyrocytes are supposed to be highly susceptible to environmental conditions that cause ER stress due to the synthesis of large amounts of secretory proteins required for thyroid hormone synthesis, systematic investigations on the effect of ER stress on expression of key genes of thyroid hormone synthesis and their transcriptional regulators are lacking. Since the aim of the ER stress-induced UPR is to restore ER homeostasis and to facilitate cell survival through transient shutdown of ribosomal protein translation, we hypothesized that the expression of genes involved in thyroid hormone synthesis and their transcriptional regulators, all of which are not essential for cell survival, are down-regulated in thyrocytes during ER stress, while sterol regulatory element-binding proteins (SREBPs) are activated during ER stress in thyrocytes. Treatment of FRTL-5 thyrocytes with the ER stress inducer tunicamycin (TM) dose-dependently increased the mRNA and/or protein levels of known UPR target genes, stimulated phosphorylation of the ER stress sensor protein kinase RNA-like ER kinase (PERK) and of the PERK target protein eukaryotic initiation factor 2α (eIF2α) and caused splicing of the ER stress-sensitive transcription factor X-box binding protein (XBP-1) (P < 0.05). The mRNA levels and/or protein levels of genes involved in thyroid hormone synthesis, sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), their transcriptional regulators and thyrotropin (TSH) receptor and the uptake of Na125I were reduced at the highest concentration of TM tested (0.1 μg/mL; P < 0.05). Proteolytic activation of the SREBP-1c pathway was not observed in FRTL-5 cells treated with TM, whereas TM reduced proteolytic activation of the SREBP-2 pathway at 0.1 μg TM/mL (P < 0.05). In conclusion, the expression of key genes involved in thyroid hormone synthesis and their critical regulators and of the TSH receptor as well as the uptake of iodide is attenuated in thyrocytes during mild ER stress. Down-regulation of NIS, TPO and TG during ER stress is likely the consequence of impaired TSH/TSHR signaling in concert with reduced expression of critical transcriptional regulators of these genes. PMID:29095946

Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes.

PubMed

Wen, Gaiping; Ringseis, Robert; Eder, Klaus

2017-01-01

Endoplasmic reticulum (ER) stress is characterized by the accumulation of misfolded proteins due to an impairment of ER quality control pathways leading to the activation of a defense system, called unfolded protein response (UPR). While thyrocytes are supposed to be highly susceptible to environmental conditions that cause ER stress due to the synthesis of large amounts of secretory proteins required for thyroid hormone synthesis, systematic investigations on the effect of ER stress on expression of key genes of thyroid hormone synthesis and their transcriptional regulators are lacking. Since the aim of the ER stress-induced UPR is to restore ER homeostasis and to facilitate cell survival through transient shutdown of ribosomal protein translation, we hypothesized that the expression of genes involved in thyroid hormone synthesis and their transcriptional regulators, all of which are not essential for cell survival, are down-regulated in thyrocytes during ER stress, while sterol regulatory element-binding proteins (SREBPs) are activated during ER stress in thyrocytes. Treatment of FRTL-5 thyrocytes with the ER stress inducer tunicamycin (TM) dose-dependently increased the mRNA and/or protein levels of known UPR target genes, stimulated phosphorylation of the ER stress sensor protein kinase RNA-like ER kinase (PERK) and of the PERK target protein eukaryotic initiation factor 2α (eIF2α) and caused splicing of the ER stress-sensitive transcription factor X-box binding protein (XBP-1) (P < 0.05). The mRNA levels and/or protein levels of genes involved in thyroid hormone synthesis, sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), their transcriptional regulators and thyrotropin (TSH) receptor and the uptake of Na125I were reduced at the highest concentration of TM tested (0.1 μg/mL; P < 0.05). Proteolytic activation of the SREBP-1c pathway was not observed in FRTL-5 cells treated with TM, whereas TM reduced proteolytic activation of the SREBP-2 pathway at 0.1 μg TM/mL (P < 0.05). In conclusion, the expression of key genes involved in thyroid hormone synthesis and their critical regulators and of the TSH receptor as well as the uptake of iodide is attenuated in thyrocytes during mild ER stress. Down-regulation of NIS, TPO and TG during ER stress is likely the consequence of impaired TSH/TSHR signaling in concert with reduced expression of critical transcriptional regulators of these genes.

Children's Emotion Regulation: Self-Report and Physiological Response to Peer Provocation

ERIC Educational Resources Information Center

Hessler, Danielle M.; Katz, Lynn Fainsilber

2007-01-01

The authors examined the notion that children's emotion regulation (ER) is a uniform skill by (a) investigating the concordance between self-report of ER and physiological measures and by (b) examining ER in a specific context (e.g., peer provocation) and context-free manner (e.g., during a semistructured interview of ER abilities). Seventy-two…

48 CFR 53.301-1435 - Settlement Proposal (Inventory Basis).

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Settlement Proposal (Inventory Basis). 53.301-1435 Section 53.301-1435 Federal Acquisition Regulations System FEDERAL ACQUISITION... (Inventory Basis). ER09DE97.004 ER09DE97.005 ER09DE97.006 ER09DE97.007 [62 FR 64943, Dec. 9, 1997] ...

Bisphenol A at a low concentration boosts mouse spermatogonial cell proliferation by inducing the G protein-coupled receptor 30 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheng, Zhi-Guo; Huang, Wei; Liu, Yu-Xiang

Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials, therefore, human exposure to BPA is ubiquitous. We found that low concentrations of BPA stimulate the spermatogonial GC-1 cells proliferation by G protein-coupled receptor 30 (GPR30)-mediated epidermal growth factor receptor (EGFR)-extracellular regulated kinase (ERK)-c-Fos pathway. However, through the same pathway GPR30 expression has been shown to be induced by EGF, an EGFR ligand. Thus, we want to know if low concentrations of BPA are able to induce the GPR30 expression and the possible mechanism(s) in GC-1 cells. By transient transfection with expression plasmids, 10{sup −9} M BPAmore » significantly transactivates the Gpr30-5′-flanking region through activating the GPR30, cGMP-dependent protein kinase (PKG), estrogen receptor-α (ER-α), and EFGR-ERK pathways. Furthermore, an activator protein-1 (AP-1) site located within this region is found to be responsible for the transactivation of BPA. Expectedly, through the same pathways, BPA significantly induces the gene and protein expression of GPR30. c-Fos is further observed to be strongly recruited to the AP-1 site in a chromatin immunoprecipitation assay and its dysfunction on the AP-1 site markedly suppresses the expression of GPR30, p-ERK1/2, p-Ser118-ER-α and cell proliferation by BPA. Our results demonstrate that a low-concentration BPA induces GPR30 expression through the GPR30-EFGR-ERK-c-Fos, ER-α, and PKG pathways, presumably boosting the cells proliferation via a regulatory loop. The present study provides a novel insight into the potential role of GPR30 in the initiation and progression of male germ cell cancer induced by environmentally relevant BPA. - Highlights: ► Low concentrations of BPA activate the PKG and GPR30-EFGR-ERK-ER-α pathways. ► Low concentrations of BPA activate the AP-1 site of Gpr30-5′-flanking region. ► Low concentrations of BPA induce the expression of GPR30 gene and protein. ► Low concentrations of BPA boost GC-1 cells proliferation via a regulatory loop.« less

ER sheet persistence is coupled to myosin 1c–regulated dynamic actin filament arrays

PubMed Central

Joensuu, Merja; Belevich, Ilya; Rämö, Olli; Nevzorov, Ilya; Vihinen, Helena; Puhka, Maija; Witkos, Tomasz M.; Lowe, Martin; Vartiainen, Maria K.; Jokitalo, Eija

2014-01-01

The endoplasmic reticulum (ER) comprises a dynamic three-dimensional (3D) network with diverse structural and functional domains. Proper ER operation requires an intricate balance within and between dynamics, morphology, and functions, but how these processes are coupled in cells has been unclear. Using live-cell imaging and 3D electron microscopy, we identify a specific subset of actin filaments localizing to polygons defined by ER sheets and tubules and describe a role for these actin arrays in ER sheet persistence and, thereby, in maintenance of the characteristic network architecture by showing that actin depolymerization leads to increased sheet fluctuation and transformations and results in small and less abundant sheet remnants and a defective ER network distribution. Furthermore, we identify myosin 1c localizing to the ER-associated actin filament arrays and reveal a novel role for myosin 1c in regulating these actin structures, as myosin 1c manipulations lead to loss of the actin filaments and to similar ER phenotype as observed after actin depolymerization. We propose that ER-associated actin filaments have a role in ER sheet persistence regulation and thus support the maintenance of sheets as a stationary subdomain of the dynamic ER network. PMID:24523293

Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

PubMed

Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

2015-03-01

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes. © 2015 The Authors.

ER sheet persistence is coupled to myosin 1c-regulated dynamic actin filament arrays.

PubMed

Joensuu, Merja; Belevich, Ilya; Rämö, Olli; Nevzorov, Ilya; Vihinen, Helena; Puhka, Maija; Witkos, Tomasz M; Lowe, Martin; Vartiainen, Maria K; Jokitalo, Eija

2014-04-01

The endoplasmic reticulum (ER) comprises a dynamic three-dimensional (3D) network with diverse structural and functional domains. Proper ER operation requires an intricate balance within and between dynamics, morphology, and functions, but how these processes are coupled in cells has been unclear. Using live-cell imaging and 3D electron microscopy, we identify a specific subset of actin filaments localizing to polygons defined by ER sheets and tubules and describe a role for these actin arrays in ER sheet persistence and, thereby, in maintenance of the characteristic network architecture by showing that actin depolymerization leads to increased sheet fluctuation and transformations and results in small and less abundant sheet remnants and a defective ER network distribution. Furthermore, we identify myosin 1c localizing to the ER-associated actin filament arrays and reveal a novel role for myosin 1c in regulating these actin structures, as myosin 1c manipulations lead to loss of the actin filaments and to similar ER phenotype as observed after actin depolymerization. We propose that ER-associated actin filaments have a role in ER sheet persistence regulation and thus support the maintenance of sheets as a stationary subdomain of the dynamic ER network.

COPI-mediated retrograde trafficking from the Golgi to the ER regulates EGFR nuclear transport

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Ying-Nai; Wang, Hongmei; Yamaguchi, Hirohito

2010-09-03

Research highlights: {yields} ARF1 activation is involved in the EGFR transport to the ER and the nucleus. {yields} Assembly of {gamma}-COP coatomer mediates EGFR transport to the ER and the nucleus. {yields} Golgi-to-ER retrograde trafficking regulates nuclear transport of EGFR. -- Abstract: Emerging evidence indicates that cell surface receptors, such as the entire epidermal growth factor receptor (EGFR) family, have been shown to localize in the nucleus. A retrograde route from the Golgi to the endoplasmic reticulum (ER) is postulated to be involved in the EGFR trafficking to the nucleus; however, the molecular mechanism in this proposed model remains unexplored.more » Here, we demonstrate that membrane-embedded vesicular trafficking is involved in the nuclear transport of EGFR. Confocal immunofluorescence reveals that in response to EGF, a portion of EGFR redistributes to the Golgi and the ER, where its NH{sub 2}-terminus resides within the lumen of Golgi/ER and COOH-terminus is exposed to the cytoplasm. Blockage of the Golgi-to-ER retrograde trafficking by brefeldin A or dominant mutants of the small GTPase ADP-ribosylation factor, which both resulted in the disassembly of the coat protein complex I (COPI) coat to the Golgi, inhibit EGFR transport to the ER and the nucleus. We further find that EGF-dependent nuclear transport of EGFR is regulated by retrograde trafficking from the Golgi to the ER involving an association of EGFR with {gamma}-COP, one of the subunits of the COPI coatomer. Our findings experimentally provide a comprehensive pathway that nuclear transport of EGFR is regulated by COPI-mediated vesicular trafficking from the Golgi to the ER, and may serve as a general mechanism in regulating the nuclear transport of other cell surface receptors.« less

Endoplasmic Reticulum Ca2+ Handling in Excitable Cells in Health and Disease

PubMed Central

Mattson, Mark P.

2011-01-01

The endoplasmic reticulum (ER) is a morphologically and functionally diverse organelle capable of integrating multiple extracellular and internal signals and generating adaptive cellular responses. It plays fundamental roles in protein synthesis and folding and in cellular responses to metabolic and proteotoxic stress. In addition, the ER stores and releases Ca2+ in sophisticated scenarios that regulate a range of processes in excitable cells throughout the body, including muscle contraction and relaxation, endocrine regulation of metabolism, learning and memory, and cell death. One or more Ca2+ ATPases and two types of ER membrane Ca2+ channels (inositol trisphosphate and ryanodine receptors) are the major proteins involved in ER Ca2+ uptake and release, respectively. There are also direct and indirect interactions of ER Ca2+ stores with plasma membrane and mitochondrial Ca2+-regulating systems. Pharmacological agents that selectively modify ER Ca2+ release or uptake have enabled studies that revealed many different physiological roles for ER Ca2+ signaling. Several inherited diseases are caused by mutations in ER Ca2+-regulating proteins, and perturbed ER Ca2+ homeostasis is implicated in a range of acquired disorders. Preclinical investigations suggest a therapeutic potential for use of agents that target ER Ca2+ handling systems of excitable cells in disorders ranging from cardiac arrhythmias and skeletal muscle myopathies to Alzheimer disease. PMID:21737534

Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate.

PubMed

Choi, Sung Won; Ryu, Ok Hee; Choi, Sun Jin; Song, In Sun; Bleyer, Anthony J; Hart, Thomas C

2005-10-01

As a consequence of uromodulin gene mutations, individuals develop precocious hyperuricemia, gout, and progressive renal failure. In vitro studies suggest that pathologic accumulation of uromodulin/Tamm-Horsfall glycoprotein (THP) occurs in the endoplasmic reticulum (ER), but the pathophysiology of renal damage is unclear. It was hypothesized that programmed cell death triggered by accumulation of misfolded THP in the ER causes progressive renal disease. Stably transfected human embryonic kidney 293 cells and immortalized thick ascending limb of Henle's loop cells with wild-type and mutated uromodulin cDNA were evaluated to test this hypothesis. Immunocytochemistry, ELISA, and deglycosylation studies indicated that accumulation of mutant THP occurred in the ER. FACS analyses showed a significant increase in early apoptosis signal in human embryonic kidney 293 and thick ascending limb of Henle's loop cells that were transfected with mutant uromodulin constructs. Colchicine and sodium 4-phenylbutyrate treatment increased secretion of THP from the ER to the cell membrane and into the culture media and significantly improved cell viability. These findings indicate that intracellular accumulation of THP facilitates apoptosis and that this may provide the pathologic mechanism responsible for the progressive renal damage associated with uromodulin gene mutations. Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases.

ER stress upregulated PGE2/IFNγ-induced IL-6 expression and down-regulated iNOS expression in glial cells

NASA Astrophysics Data System (ADS)

Hosoi, Toru; Honda, Miya; Oba, Tatsuya; Ozawa, Koichiro

2013-12-01

The disruption of endoplasmic reticulum (ER) function can lead to neurodegenerative disorders, in which inflammation has also been implicated. We investigated the possible correlation between ER stress and immune function using glial cells. We demonstrated that ER stress synergistically enhanced prostaglandin (PG) E2 + interferon (IFN) γ-induced interleukin (IL)-6 production. This effect was mediated through cAMP. Immune-activated glial cells produced inducible nitric oxide synthase (iNOS). Interestingly, ER stress inhibited PGE2 + IFNγ-induced iNOS expression. Similar results were obtained when cells were treated with dbcAMP + IFNγ. Thus, cAMP has a dual effect on immune reactions; cAMP up-regulated IL-6 expression, but down-regulated iNOS expression under ER stress. Therefore, our results suggest a link between ER stress and immune reactions in neurodegenerative diseases.

Drosophila melanogaster Activating Transcription Factor 4 Regulates Glycolysis During Endoplasmic Reticulum Stress

PubMed Central

Lee, Ji Eun; Oney, McKenna; Frizzell, Kimberly; Phadnis, Nitin; Hollien, Julie

2015-01-01

Endoplasmic reticulum (ER) stress results from an imbalance between the load of proteins entering the secretory pathway and the ability of the ER to fold and process them. The response to ER stress is mediated by a collection of signaling pathways termed the unfolded protein response, which plays important roles in development and disease. Here we show that in Drosophila melanogaster S2 cells, ER stress induces a coordinated change in the expression of genes involved in carbon metabolism. Genes encoding enzymes that carry out glycolysis were up-regulated, whereas genes encoding proteins in the tricarboxylic acid cycle and respiratory chain complexes were down-regulated. The unfolded protein response transcription factor Atf4 was necessary for the up-regulation of glycolytic enzymes and Lactate dehydrogenase (Ldh). Furthermore, Atf4 binding motifs in promoters for these genes could partially account for their regulation during ER stress. Finally, flies up-regulated Ldh and produced more lactate when subjected to ER stress. Together, these results suggest that Atf4 mediates a shift from a metabolism based on oxidative phosphorylation to one more heavily reliant on glycolysis, reminiscent of aerobic glycolysis or the Warburg effect observed in cancer and other proliferative cells. PMID:25681259

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.

PubMed

Sepulveda, Denisse; Rojas-Rivera, Diego; Rodríguez, Diego A; Groenendyk, Jody; Köhler, Andres; Lebeaupin, Cynthia; Ito, Shinya; Urra, Hery; Carreras-Sureda, Amado; Hazari, Younis; Vasseur-Cognet, Mireille; Ali, Maruf M U; Chevet, Eric; Campos, Gisela; Godoy, Patricio; Vaisar, Tomas; Bailly-Maitre, Béatrice; Nagata, Kazuhiro; Michalak, Marek; Sierralta, Jimena; Hetz, Claudio

2018-01-18

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR. Copyright © 2018 Elsevier Inc. All rights reserved.

Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties.

PubMed

Bui, Michael; Gilady, Susanna Y; Fitzsimmons, Ross E B; Benson, Matthew D; Lynes, Emily M; Gesson, Kevin; Alto, Neal M; Strack, Stefan; Scott, John D; Simmen, Thomas

2010-10-08

The mitochondria-associated membrane (MAM) has emerged as an endoplasmic reticulum (ER) signaling hub that accommodates ER chaperones, including the lectin calnexin. At the MAM, these chaperones control ER homeostasis but also play a role in the onset of ER stress-mediated apoptosis, likely through the modulation of ER calcium signaling. These opposing roles of MAM-localized chaperones suggest the existence of mechanisms that regulate the composition and the properties of ER membrane domains. Our results now show that the GTPase Rab32 localizes to the ER and mitochondria, and we identify this protein as a regulator of MAM properties. Consistent with such a role, Rab32 modulates ER calcium handling and disrupts the specific enrichment of calnexin on the MAM, while not affecting the ER distribution of protein-disulfide isomerase and mitofusin-2. Furthermore, Rab32 determines the targeting of PKA to mitochondrial and ER membranes and through its overexpression or inactivation increases the phosphorylation of Bad and of Drp1. Through a combination of its functions as a PKA-anchoring protein and a regulator of MAM properties, the activity and expression level of Rab32 determine the speed of apoptosis onset.

SELF-CANCELLATION OF EPHEMERAL REGIONS IN THE QUIET SUN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Shuhong; Zhang, Jun; Li, Ting

2012-06-20

With the observations from the Helioseismic and Magnetic Imager aboard the Solar Dynamics Observatory, we statistically investigate the ephemeral regions (ERs) in the quiet Sun. We find that there are two types of ERs: normal ERs (NERs) and self-canceled ERs (SERs). Each NER emerges and grows with separation of its opposite polarity patches which will cancel or coalesce with other surrounding magnetic flux. Each SER also emerges and grows and its dipolar patches separate at first, but a part of the magnetic flux of the SER will move together and cancel gradually, which is described with the term 'self-cancellation' bymore » us. We identify 2988 ERs, among which there are 190 SERs, about 6.4% of the ERs. The mean value of self-cancellation fraction of SERs is 62.5%, and the total self-canceled flux of SERs is 9.8% of the total ER flux. Our results also reveal that the higher the ER magnetic flux is, (1) the easier the performance of ER self-cancellation is, (2) the smaller the self-cancellation fraction is, and (3) the more the self-canceled flux is. We think that the self-cancellation of SERs is caused by the submergence of magnetic loops connecting the dipolar patches, without magnetic energy release.« less

Self-focused cognitive emotion regulation style as associated with widespread diminished EEG fractal dimension.

PubMed

Bornas, Xavier; Tortella-Feliu, Miquel; Balle, Maria; Llabrés, Jordi

2013-01-01

The cognitive regulation of emotions is important for human adaptation. Self-focused emotion regulation (ER) strategies have been linked to the development and persistence of anxiety and depression. A vast array of research has provided valuable knowledge about the neural correlates of the use of specific self-focused ER strategies; however, the resting neural correlates of cognitive ER styles, which reflect an individual's disposition to engage in different forms of ER in order to manage distress, are largely unknown. In this study, associations between theoretically negative ER style (self-focused or not) and the complexity (fractal dimension, FD) of the resting EEG at frontal, central, parietal, and occipital regions were investigated in 58 healthy volunteers. The Cognitive Emotion Regulation Questionnaire was used as the self-report measure of ER style. Results showed that a diminished FD over the scalp significantly correlated with self-focused ER style scores, even after controlling for negative affect, which has been also considered to influence the use of ER strategies. The lower the EEG FD, the higher were the self-focused ER style scores. Correlational analyses of specific self-focused ER strategies showed that self-blaming and rumination were negatively associated with diminished FD of the EEG, but catastrophizing and blaming others were not. No significant correlations were found for ER strategies more focused on situation or others. Results are discussed within the self-organized criticality theory of brain dynamics: The diminished FD of the EEG may reflect a disposition to engage in self-focused ER strategies as people prone to ruminate and self-blame show a less complex resting EEG activity, which may make it more difficult for them to exit their negative emotional state.

Drosophila melanogaster activating transcription factor 4 regulates glycolysis during endoplasmic reticulum stress.

PubMed

Lee, Ji Eun; Oney, McKenna; Frizzell, Kimberly; Phadnis, Nitin; Hollien, Julie

2015-02-13

Endoplasmic reticulum (ER) stress results from an imbalance between the load of proteins entering the secretory pathway and the ability of the ER to fold and process them. The response to ER stress is mediated by a collection of signaling pathways termed the unfolded protein response, which plays important roles in development and disease. Here we show that in Drosophila melanogaster S2 cells, ER stress induces a coordinated change in the expression of genes involved in carbon metabolism. Genes encoding enzymes that carry out glycolysis were up-regulated, whereas genes encoding proteins in the tricarboxylic acid cycle and respiratory chain complexes were down-regulated. The unfolded protein response transcription factor Atf4 was necessary for the up-regulation of glycolytic enzymes and Lactate dehydrogenase (Ldh). Furthermore, Atf4 binding motifs in promoters for these genes could partially account for their regulation during ER stress. Finally, flies up-regulated Ldh and produced more lactate when subjected to ER stress. Together, these results suggest that Atf4 mediates a shift from a metabolism based on oxidative phosphorylation to one more heavily reliant on glycolysis, reminiscent of aerobic glycolysis or the Warburg effect observed in cancer and other proliferative cells. Copyright © 2015 Lee et al.

Deficits in general emotion regulation skills-Evidence of a transdiagnostic factor.

PubMed

Lukas, Christian Aljoscha; Ebert, David Daniel; Fuentes, Hugo Trevisi; Caspar, Franz; Berking, Matthias

2017-12-15

Deficits in emotion regulation (ER) skills are discussed as a transdiagnostic factor contributing to the development and maintenance of various mental disorders. However, systematic comparisons of a broad range of ER skills across diagnostic groups that are based on comparable definitions and measures of ER are still rare. Therefore, we conducted two studies assessing a broad range of ER skills with the Emotion Regulation Skills Questionnaire in individuals meeting criteria for mental disorders (N 1  = 1448; N 2  = 137) and in a general population sample (N = 214). Consistent across the two studies, participants in the clinical samples reported lower general and lower specific ER skills than participants in the general population sample. Also consistent across the two studies, diagnostic subgroups of the clinical samples differed significantly with regard to general and specific ER skills. The studies provide evidence that deficits in ER are associated with various forms of psychopathology. However, mental disorders seem to differ with regard to how strongly they are linked to ER skills. © 2017 Wiley Periodicals, Inc.

Relationships between Perron-Frobenius eigenvalue and measurements of loops in networks

NASA Astrophysics Data System (ADS)

Chen, Lei; Kou, Yingxin; Li, Zhanwu; Xu, An; Chang, Yizhe

2018-07-01

The Perron-Frobenius eigenvalue (PFE) is widely used as measurement of the number of loops in networks, but what exactly the relationship between the PFE and the number of loops in networks is has not been researched yet, is it strictly monotonically increasing? And what are the relationships between the PFE and other measurements of loops in networks? Such as the average loop degree of nodes, and the distribution of loop ranks. We make researches on these questions based on samples of ER random network, NW small-world network and BA scale-free network, and the results confirm that, both the number of loops in network and the average loop degree of nodes of all samples do increase with the increase of the PFE in general trend, but neither of them are strictly monotonically increasing, so the PFE is capable to be used as a rough estimative measurement of the number of loops in networks and the average loop degree of nodes. Furthermore, we find that a majority of the loop ranks of all samples obey Weibull distribution, of which the scale parameter A and the shape parameter B have approximate power-law relationships with the PFE of the samples.

Emotion regulation and mania risk: Differential responses to implicit and explicit cues to regulate.

PubMed

Ajaya, Yatrika; Peckham, Andrew D; Johnson, Sheri L

2016-03-01

People prone to mania use emotion regulation (ER) strategies well when explicitly coached to do so in laboratory settings, but they find these strategies ineffective in daily life. We hypothesized that, compared with control participants, mania-prone people would show ER deficits when they received implicit, but not explicit, cues to use ER. Undergraduates (N = 66) completed the Hypomanic Personality Scale (HPS) and were randomly assigned to one of three experimental conditions: automatic ER (scrambled sentence primes), deliberate ER (verbal instructions), or control (no priming or instructions to use ER). Then, participants played a videogame designed to evoke anger. Emotion responses were measured with a multi-modal assessment of self-reported affect, psychophysiology, and facial expressions. Respiratory sinus arrhythmia (RSA) was used to index ER. The videogame effectively elicited subjective anger, angry facial expressions, and heart rate increases when keys malfunctioned. As hypothesized, persons who were more mania prone showed greater RSA increases in the deliberate ER condition than in the automatic or control conditions. One potential limitation is the use of an analog sample. Findings suggest that those at risk for mania require more explicit instruction to engage ER effectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

SIRT1 attenuates palmitate-induced endoplasmic reticulum stress and insulin resistance in HepG2 cells via induction of oxygen-regulated protein 150

USGS Publications Warehouse

Jung, T.W.; Lee, K.T.; Lee, M.W.; Ka, K.H.

2012-01-01

Endoplasmic reticulum (ER) stress has been implicated in the pathology of type 2 diabetes mellitus (T2DM). Although SIRT1 has a therapeutic effect on T2DM, the mechanisms by which SIRT1 ameliorates insulin resistance (IR) remain unclear. In this study, we investigated the impact of SIRT1 on palmitate-induced ER stress in HepG2 cells and its underlying signal pathway. Treatment with resveratrol, a SIRT1 activator significantly inhibited palmitate-induced ER stress, leading to the protection against palmitate-induced ER stress and insulin resistance. Resveratrol and SIRT1 overexpression induced the expression of oxygen-regulated protein (ORP) 150 in HepG2 cells. Forkhead box O1 (FOXO1) was involved in the regulation of ORP150 expression because suppression of FOXO1 inhibited the induction of ORP150 by SIRT1. Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.

Tamoxifen resistance and metastasis of human breast cancer cells were mediated by the membrane-associated estrogen receptor ER-α36 signaling in vitro.

PubMed

Gu, Wenwen; Dong, Nian; Wang, Peng; Shi, Changgen; Yang, Jun; Wang, Jian

2017-04-01

The drug resistance and tumor metastasis have been the main obstacles for the longer-term therapeutic effects of tamoxifen (TAM) on estrogen receptor-positive (ER + ) breast cancer, but the mechanisms underlying the TAM resistance are still unclear. Here, we demonstrated that the membrane-associated estrogen receptor ER-α36 signaling, but not the G protein-coupled estrogen receptor 1 (GPER1) signaling, might be involved in the TAM resistance and metastasis of breast cancer cells. In this study, a model of ER + breast cancer cell MCF-7 that involves the up-regulated expression of ER-α36 and unchanged expression of ER-α66 and GPER1 was established via the removal of insulin from the cell culture medium. The mechanism of TAM resistance in the ER + breast cancer cell line MCF-7 was investigated, and the results showed that the stimulating effect of insulin on susceptibility of MCF-7 to TAM was mediated by ER-α36 and that the expression level of ER-α36 in TAM-resistant MCF-7 cells was also significantly increased. Both TAM and estradiol (E2) could promote the migration of triple negative (ER-α66 - /PR - /HER2 - ) and ER-α36 + /GPER1 + breast cancer cells MDA-MB-231. The migration of MDA-MB-231 cells was inhibited by the down-regulated intracellular expression of ER-α36 by transient transfection of specific small interfering RNA, whereas no effect of GPER1 down-regulation was observed. Meanwhile, the effect of TAM on the migration of ER-α36-down-regulated MDA-MB-231 cells was also reduced. Furthermore, it was found that TAM enhanced the distribution of integrin β1 on the cell surface but did not affect the expression of integrin β1 in MDA-MB-231 cells. Collectively, these data suggested that ER-α36 signaling might play critical roles in acquired and de novo TAM resistance and metastasis of breast cancer, and ER-α36 might present a potential biomarker of TAM resistance in the clinical diagnosis and treatment of ER + breast cancer.

HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase.

PubMed

Nonboe, Annika W; Krigslund, Oliver; Soendergaard, Christoffer; Skovbjerg, Signe; Friis, Stine; Andersen, Martin N; Ellis, Vincent; Kawaguchi, Makiko; Kataoka, Hiroaki; Bugge, Thomas H; Vogel, Lotte K

2017-06-01

It has recently been shown that hepatocyte growth factor activator inhibitor-2 (HAI-2) is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In this study, we describe 3 mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the endoplasmic reticulum (ER). We suggest that, like other known SEA domains, the matriptase SEA domain auto-cleaves and reflects that correct oligomerization, maturation, and/or folding has been obtained. Our results suggest that the HAI-2 Kunitz domain 1 mutants influence the flux of matriptase to the plasma membrane by affecting the oligomerization, maturation and/or folding of matriptase, and as a result the SEA domain cleavage of matriptase. Two of the HAI-2 Kunitz domain 1 mutants investigated (C47F, R48L and C47F/R48L) also displayed a reduced ability to proteolytically silence matriptase. Hence, HAI-2 separately stabilizes matriptase, regulates the secretory transport, possibly via maturation/oligomerization and inhibits the proteolytic activity of matriptase in the ER, and possible throughout the secretory pathway. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Emotion Regulation Questionnaire for Children and Adolescents (ERQ-CA): A Psychometric Evaluation

ERIC Educational Resources Information Center

Gullone, Eleonora; Taffe, John

2012-01-01

Despite the recognized importance of emotion regulation (ER) for healthy psychological development, ER research has focused predominantly on the developmental periods of infancy, early childhood, and adulthood, while the middle childhood to adolescence years have been relatively neglected. An obstacle to ER research during these periods is the…

Associations between Attachment and Emotion-Specific Emotion Regulation with and without Relationship Insecurity Priming

ERIC Educational Resources Information Center

Clear, Sarah J.; Zimmer-Gembeck, Melanie J.

2017-01-01

Attachment theory and previous research on emotion regulation (ER) suggest that ER will be associated with adult attachment orientation, with the expectation of different associations of attachment avoidance, anxiety, and security with specific ER patterns. In addition, research has shown that the emotion under consideration and the context may…

Emotion Regulation and Academic Perceptions in Adolescence

ERIC Educational Resources Information Center

Oram, Rylee; Ryan, Julia; Rogers, Maria; Heath, Nancy

2017-01-01

Although studied extensively in the field of adolescent mental health, the role of emotion regulation (ER) in the academic functioning of adolescents is not well understood. This study examined the role of ER in adolescents' perceptions of themselves and their learning environments. We compared adolescents with high and low levels of ER on…

48 CFR 1352.301 - Solicitation provisions and contract clauses (Matrix).

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Solicitation provisions and contract clauses (Matrix). 1352.301 Section 1352.301 Federal Acquisition Regulations System... Matrix 1352.301 Solicitation provisions and contract clauses (Matrix). ER08MR10.000 ER08MR10.001 ER08MR10...

Regulation of G-protein coupled receptor traffic by an evolutionary conserved hydrophobic signal.

PubMed

Angelotti, Tim; Daunt, David; Shcherbakova, Olga G; Kobilka, Brian; Hurt, Carl M

2010-04-01

Plasma membrane (PM) expression of G-protein coupled receptors (GPCRs) is required for activation by extracellular ligands; however, mechanisms that regulate PM expression of GPCRs are poorly understood. For some GPCRs, such as alpha2c-adrenergic receptors (alpha(2c)-ARs), heterologous expression in non-native cells results in limited PM expression and extensive endoplasmic reticulum (ER) retention. Recently, ER export/retentions signals have been proposed to regulate cellular trafficking of several GPCRs. By utilizing a chimeric alpha(2a)/alpha(2c)-AR strategy, we identified an evolutionary conserved hydrophobic sequence (ALAAALAAAAA) in the extracellular amino terminal region that is responsible in part for alpha(2c)-AR subtype-specific trafficking. To our knowledge, this is the first luminal ER retention signal reported for a GPCR. Removal or disruption of the ER retention signal dramatically increased PM expression and decreased ER retention. Conversely, transplantation of this hydrophobic sequence into alpha(2a)-ARs reduced their PM expression and increased ER retention. This evolutionary conserved hydrophobic trafficking signal within alpha(2c)-ARs serves as a regulator of GPCR trafficking.

An early ethylene up-regulated gene encoding a calmodulin-binding protein involved in plant senescence and death

NASA Technical Reports Server (NTRS)

Yang, T.; Poovaiah, B. W.

2000-01-01

35S-Labeled calmodulin (CaM) was used to screen a tobacco anther cDNA library. A positive clone (NtER1) with high homology to an early ethylene-up-regulated gene (ER66) in tomato, and an Arabidopsis homolog was isolated and characterized. Based on the helical wheel projection, a 25-mer peptide corresponding to the predicted CaM-binding region of NtER1 (amino acids 796-820) was synthesized. The gel-mobility shift assay showed that the peptide formed a stable complex with CaM only in the presence of Ca(2+). CaM binds to NtER1 with high affinity (K(d) approximately 12 nm) in a calcium-dependent manner. Tobacco flowers at different stages of development were treated with ethylene or with 1-methylcyclopropene for 2 h before treating with ethylene. Northern analysis showed that the NtER1 was rapidly induced after 15 min of exposure to ethylene. However, the 2-h 1-methylcyclopropene treatment totally blocked NtER1 expression in flowers at all stages of development, suggesting that NtER1 is an early ethylene-up-regulated gene. The senescing leaves and petals had significantly increased NtER1 induction as compared with young leaves and petals, implying that NtER1 is developmentally regulated and acts as a trigger for senescence and death. This is the first documented evidence for the involvement of Ca(2+)/CaM-mediated signaling in ethylene action.

Human MI-ER1 Alpha and Beta Function as Transcriptional Repressors by Recruitment of Histone Deacetylase 1 to Their Conserved ELM2 Domain

PubMed Central

Ding, Zhihu; Gillespie, Laura L.; Paterno, Gary D.

2003-01-01

mi-er1 (previously called er1) was first isolated from Xenopus laevis embryonic cells as a novel fibroblast growth factor-regulated immediate-early gene. Xmi-er1 was shown to encode a nuclear protein with an N-terminal acidic transcription activation domain. The human orthologue of mi-er1 (hmi-er1) displays 91% similarity to the Xenopus sequence at the amino acid level and was shown to be upregulated in breast carcinoma cell lines and tumors. Alternative splicing at the 3′ end of hmi-er1 produces two major isoforms, hMI-ER1α and hMI-ER1β, which contain distinct C-terminal domains. In this study, we investigated the role of hMI-ER1α and hMI-ER1β in the regulation of transcription. Using fusion proteins of hMI-ER1α or hMI-ER1β tethered to the GAL4 DNA binding domain, we show that both isoforms, when recruited to the G5tkCAT minimal promoter, function to repress transcription. We demonstrate that this repressor activity is due to interaction and recruitment of a trichostatin A-sensitive histone deacetylase 1 (HDAC1). Furthermore, deletion analysis revealed that recruitment of HDAC1 to hMI-ER1α and hMI-ER1β occurs through their common ELM2 domain. The ELM2 domain was first described in the Caenorhabditis elegans Egl-27 protein and is present in a number of SANT domain-containing transcription factors. This is the first report of a function for the ELM2 domain, highlighting its role in the regulation of transcription. PMID:12482978

Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain.

PubMed

Ding, Zhihu; Gillespie, Laura L; Paterno, Gary D

2003-01-01

mi-er1 (previously called er1) was first isolated from Xenopus laevis embryonic cells as a novel fibroblast growth factor-regulated immediate-early gene. Xmi-er1 was shown to encode a nuclear protein with an N-terminal acidic transcription activation domain. The human orthologue of mi-er1 (hmi-er1) displays 91% similarity to the Xenopus sequence at the amino acid level and was shown to be upregulated in breast carcinoma cell lines and tumors. Alternative splicing at the 3' end of hmi-er1 produces two major isoforms, hMI-ER1alpha and hMI-ER1beta, which contain distinct C-terminal domains. In this study, we investigated the role of hMI-ER1alpha and hMI-ER1beta in the regulation of transcription. Using fusion proteins of hMI-ER1alpha or hMI-ER1beta tethered to the GAL4 DNA binding domain, we show that both isoforms, when recruited to the G5tkCAT minimal promoter, function to repress transcription. We demonstrate that this repressor activity is due to interaction and recruitment of a trichostatin A-sensitive histone deacetylase 1 (HDAC1). Furthermore, deletion analysis revealed that recruitment of HDAC1 to hMI-ER1alpha and hMI-ER1beta occurs through their common ELM2 domain. The ELM2 domain was first described in the Caenorhabditis elegans Egl-27 protein and is present in a number of SANT domain-containing transcription factors. This is the first report of a function for the ELM2 domain, highlighting its role in the regulation of transcription.

Integrated self-organization of transitional ER and early Golgi compartments.

PubMed

Glick, Benjamin S

2014-02-01

COPII coated vesicles bud from an ER domain termed the transitional ER (tER), but the mechanism that clusters COPII vesicles at tER sites is unknown. tER sites are closely associated with early Golgi or pre-Golgi structures, suggesting that the clustering of nascent COPII vesicles could be achieved by tethering to adjacent membranes. This model challenges the prevailing view that COPII vesicles are clustered by a scaffolding protein at the ER surface. Although Sec16 was proposed to serve as such a scaffolding protein, recent data suggest that rather than organizing COPII into higher-order structures, Sec16 acts at the level of individual COPII vesicles to regulate COPII turnover. A plausible synthesis is that tER sites are created by tethering to Golgi membranes and are regulated by Sec16. Meanwhile, the COPII vesicles that bud from tER sites are thought to nucleate new Golgi cisternae. Thus, an integrated self-organization process may generate tER-Golgi units. © 2014 WILEY Periodicals, Inc.

Identification of differentially expressed genes in human breast cancer cells induced by 4-hydroxyltamoxifen and elucidation of their pathophysiological relevance and mechanisms

PubMed Central

Fang, Qi; Yao, Shuang; Luo, Guanghua; Zhang, Xiaoying

2018-01-01

While tamoxifen (TAM) is used for treating estrogen receptor (ER)a-positive breast cancer patients, its anti-breast cancer mechanisms are not completely elucidated. This study aimed to examine effects of 4-hydroxyltamoxifen (4-OH-TAM) on ER-positive (ER+) breast cancer MCF-7 cell growth and gene expression profiles. MCF-7 cell growth was inhibited by 4-OH-TAM dose-dependently with IC50 of 29 μM. 332 genes were up-regulated while 320 genes were down-regulated. The mRNA levels of up-regulated genes including STAT1, STAT2, EIF2AK2, TGM2, DDX58, PARP9, SASH1, RBL2 and USP18 as well as down-regulated genes including CCDN1, S100A9, S100A8, ANXA1 and PGR were confirmed by quantitative real-time PCR (qRT-PCR). In human breast tumor tissues, mRNA levels of EIF2Ak2, USP18, DDX58, RBL2, STAT2, PGR, S1000A9, and CCND1 were significantly higher in ER+- than in ER--breast cancer tissues. The mRNA levels of EIF2AK2, TGM2, USP18, DDX58, PARP9, STAT2, STAT1, PGR and CCND1 were all significantly higher in ER+-tumor tissues than in their corresponding tumor-adjacent tissues. These genes, except PGR and CCND1 which were down-regulated, were also up-regulated in ER+ MCF-7 cells by 4-OH-TAM. Total 14 genes mentioned above are involved in regulation of cell proliferation, apoptosis, cell cycles, and estrogen and interferon signal pathways. Bioinformatics analysis also revealed other novel and important regulatory factors that are associated with these genes and involved in the mentioned functional processes. This study has paved a foundation for elucidating TAM anti-breast cancer mechanisms in E2/ER-dependent and independent pathways. PMID:29416786

Identification of differentially expressed genes in human breast cancer cells induced by 4-hydroxyltamoxifen and elucidation of their pathophysiological relevance and mechanisms.

PubMed

Fang, Qi; Yao, Shuang; Luo, Guanghua; Zhang, Xiaoying

2018-01-05

While tamoxifen (TAM) is used for treating estrogen receptor (ER)a-positive breast cancer patients, its anti-breast cancer mechanisms are not completely elucidated. This study aimed to examine effects of 4-hydroxyltamoxifen (4-OH-TAM) on ER-positive (ER + ) breast cancer MCF-7 cell growth and gene expression profiles. MCF-7 cell growth was inhibited by 4-OH-TAM dose-dependently with IC 50 of 29 μM. 332 genes were up-regulated while 320 genes were down-regulated. The mRNA levels of up-regulated genes including STAT1, STAT2, EIF2AK2, TGM2, DDX58, PARP9, SASH1, RBL2 and USP18 as well as down-regulated genes including CCDN1, S100A9, S100A8, ANXA1 and PGR were confirmed by quantitative real-time PCR (qRT-PCR). In human breast tumor tissues, mRNA levels of EIF2Ak2, USP18, DDX58, RBL2, STAT2, PGR, S1000A9, and CCND1 were significantly higher in ER + - than in ER - -breast cancer tissues. The mRNA levels of EIF2AK2, TGM2, USP18, DDX58, PARP9, STAT2, STAT1, PGR and CCND1 were all significantly higher in ER + -tumor tissues than in their corresponding tumor-adjacent tissues. These genes, except PGR and CCND1 which were down-regulated, were also up-regulated in ER + MCF-7 cells by 4-OH-TAM. Total 14 genes mentioned above are involved in regulation of cell proliferation, apoptosis, cell cycles, and estrogen and interferon signal pathways. Bioinformatics analysis also revealed other novel and important regulatory factors that are associated with these genes and involved in the mentioned functional processes. This study has paved a foundation for elucidating TAM anti-breast cancer mechanisms in E2/ER-dependent and independent pathways.

Expression pattern and signalling pathways in neutrophil like HL-60 cells after treatment with estrogen receptor selective ligands.

PubMed

Blesson, Chellakkan Selvanesan; Sahlin, Lena

2012-09-25

Estrogens play a role in the regulation of genes associated with inflammation and immunity in neutrophils. Estrogen signalling is mediated by estrogen receptor (ER)α, ERβ, and G-protein-coupled estrogen receptor-1 (GPER). The mechanisms by which estrogen regulate genes in neutrophils are poorly understood. Our aim was to identify the presence of ERs and to characterize estrogen responsive genes in terminally differentiated neutrophil like HL-60 (nHL-60) cells using estradiol and selective ER agonists. ERs were identified by Western blotting and immunocytochemistry. Microarray technique was used to screen for differentially expressed genes and the selected genes were verified by quantitative PCR. We show the presence of functional ERα, ERβ and GPER. Microarray analysis showed the presence of genes that are uniquely regulated by a single ligand and also genes that are regulated by multiple ligands. We conclude that ERs are functionally active in nHL-60 cells regulating genes involved in key physiological functions. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

INTER-REGULATION OF THE UNFOLDED PROTEIN RESPONSE AND AUXIN SIGNALING

PubMed Central

Chen, Yani; Aung, Kyaw; Rolčík, Jakub; Walicki, Kathryn; Friml, Jiří; Brandizzi, Federica

2013-01-01

SUMMARY The unfolded protein response (UPR) is a signaling network triggered by overload of protein-folding demand in the endoplasmic reticulum (ER), a condition termed ER stress. The UPR is critical for growth and development; nonetheless, connections between the UPR and other cellular regulatory processes remain largely unknown. Here, we identify a link between the UPR and the phytohormone auxin, a master regulator of plant physiology. We show that ER stress triggers down-regulation of auxin sensors and transporters in Arabidopsis thaliana. We also demonstrate that an Arabidopsis mutant of a conserved ER stress sensor IRE1 exhibits defects in the auxin response and levels. These data not only support that the plant IRE1 is required for auxin homeostasis, they also reveal a species-specific feature of IRE1 in multicellular eukaryotes. Furthermore, by establishing that UPR activation is reduced in mutants of ER-localized auxin transporters, including PIN5, we define a long-neglected biological significance of ER-based auxin regulation. We further examine the functional relationship of IRE1 and PIN5 by showing that an ire1 pin5 triple mutant enhances defects of UPR activation and auxin homeostasis in ire1 or pin5. Our results imply that the plant UPR has evolved a hormone-dependent strategy for coordinating ER function with physiological processes. PMID:24180465

Endoplasmic reticulum stress in the pathogenesis of hypertension.

PubMed

Young, Colin N

2017-08-01

What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an integrative view of ER stress in cardiovascular control systems, including systems within the brain, kidney and peripheral vasculature, as related to development of hypertension. The endoplasmic reticulum (ER) is a cellular organelle specialized in the synthesis, folding, assembly and modification of proteins. In situations of increased protein demand, complex signalling pathways, termed the unfolded protein response, influence a series of cellular feedback loops to control ER function strictly. Although this is initially a compensatory attempt to maintain cellular homeostasis, chronic activation of the unfolded protein response, known as ER stress, leads to sustained changes in cellular function. A growing body of literature points to ER stress in diverse cardioregulatory systems, including the brain, kidney and vasculature, as central to the development of hypertension. Here, these recent findings from essential and obesity-related forms of hypertension are highlighted in an integrative manner, with discussion of the potential upstream causes and downstream consequences of ER stress. Given that hypertension is a leading medical and socio-economic global challenge, emerging findings suggest that targeting ER stress might represent a viable strategy for the treatment of hypertensive disease. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Circuit Regulates Speed Of dc Motor

NASA Technical Reports Server (NTRS)

Weaver, Charles; Padden, Robin; Brown, Floyd A., Jr.

1990-01-01

Driving circuit regulates speed of small dc permanent-magnet motor in tape recorder. Two nested feedback loops maintain speed within 1 percent of constant value. Inner loop provides coarse regulation, while outer loop removes most of variation in speed that remains in the presence of regulation by the inner loop. Compares speed of motor with commanded speed and adjusts current supplied to motor accordingly.

Rab7a modulates ER stress and ER morphology.

PubMed

Mateus, Duarte; Marini, Elettra Sara; Progida, Cinzia; Bakke, Oddmund

2018-05-01

The Endoplasmic Reticulum (ER) is a membranous organelle with diverse structural and functional domains. Peripheral ER includes interconnected tubules, and dense tubular arrays called "ER matrices" together with bona fide flat cisternae. Transitions between these states are regulated by membrane-associated proteins and cytosolic factors. Recently, the small GTPases Rab10 and Rab18 were reported to control ER shape by regulating ER dynamics and fusion. Here, we present evidence that another Rab protein, Rab7a, modulates the ER morphology by controlling the ER homeostasis and ER stress. Indeed, inhibition of Rab7a expression by siRNA or expression of the dominant negative mutant Rab7aT22 N, leads to enlargement of sheet-like ER structures and spreading towards the cell periphery. Notably, such alterations are ascribable neither to a direct modulation of the ER shaping proteins Reticulon-4b and CLIMP63, nor to interactions with Protrudin, a Rab7a-binding protein known to affect the ER organization. Conversely, depletion of Rab7a leads to basal ER stress, in turn causing ER membrane expansion. Both ER enlargement and basal ER stress are reverted in rescue experiments by Rab7a re-expression, as well as by the ER chemical chaperone tauroursodeoxycholic acid (TUDCA). Collectively, these findings reveal a new role of Rab7a in ER homeostasis, and indicate that genetic and pharmacological ER stress manipulation may restore ER morphology in Rab7a silenced cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Emotion regulation in preschoolers: the roles of behavioral inhibition, maternal affective behavior, and maternal depression.

PubMed

Feng, Xin; Shaw, Daniel S; Kovacs, Maria; Lane, Tonya; O'Rourke, Flannery E; Alarcon, Joseph H

2008-02-01

This study examined preschoolers' emotion regulation (ER) strategies and the association with temperament, maternal interactive style, and maternal history of childhood-onset depression (COD). Participants were 62 children and their mothers, 37 of whom had mothers with COD. Children's ER was assessed using a disappointment paradigm; temperament assessment also was laboratory-based. Maternal COD was inversely related to offspring's active ER and positive mood. Among children of COD mothers, behavioral inhibition was associated with passive regulation and sadness, and maternal positivity toward these children was associated with child active ER and positive mood. Behavioral inhibition may place children of COD mothers at risk for developing maladaptive ways of regulating negative emotion, whereas mothers' positivity may serve as a protective factor for them.

Synergism between a half-site and an imperfect estrogen-responsive element, and cooperation with COUP-TFI are required for estrogen receptor (ER) to achieve a maximal estrogen-stimulation of rainbow trout ER gene.

PubMed

Petit, F G; Métivier, R; Valotaire, Y; Pakdel, F

1999-01-01

In all oviparous, liver represents one of the main E2-target tissues where estrogen receptor (ER) constitutes the key mediator of estrogen action. The rainbow trout estrogen receptor (rtER) gene expression is markedly up-regulated by estrogens and the sequences responsible for this autoregulation have been located in a 0.2 kb upstream transcription start site within - 40/- 248 enhancer region. Absence of interference with steroid hormone receptors and tissue-specific factors and a conserved basal transcriptional machinery between yeast and higher eukaryotes, make yeast a simple assay system that will enable determination of important cis-acting regulatory sequences within rtER gene promoter and identification of transcription factors implicated in the regulation of this gene. Deletion analysis allowed to show a synergistic effect between an imperfect estrogen-responsive element (ERE) and a consensus half-ERE to achieve a high hormone-dependent transcriptional activation of the rtER gene promoter in the presence of stably expressed rtER. As in mammalian cells, here we observed a positive regulation of the rtER gene promoter by the chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) through enhancing autoregulation. Using a point mutation COUP-TFI mutant unable to bind DNA demonstrates that enhancement of rtER gene autoregulation requires the interaction of COUP-TFI to the DNA. Moreover, this enhancement of transcriptional activation by COUP-TFI requires specifically the AF-1 transactivation function of ER and can be observed in the presence of E2 or 4-hydroxytamoxifen but not ICI 164384. Thus, this paper describes the reconstitution of a hormone-responsive transcription unit in yeast in which the regulation of rtER gene promoter could be enhanced by the participation of cis-elements and/or trans-acting factors, such as ER itself or COUP-TF.

Emotions and Emotion Regulation in Breast Cancer Survivorship

PubMed Central

Conley, Claire C.; Bishop, Brenden T.; Andersen, Barbara L.

2016-01-01

Emotional distress in cancer patients is an important outcome; however, emotional experience does not begin and end with emotion generation. Attempts to regulate emotions may lessen their potentially negative effects on physical and psychological well-being. Researchers have called for the study of emotion regulation (ER) in health psychology and psycho-oncology. Thus, this review has three aims. First, we discuss current understandings of emotion and ER across the cancer trajectory, including the principles of ER and methods for its assessment. Second, we present a model for examining the mediating effects of ER on psychosocial outcomes. Third, we “round out” the discussion with an example: new data on the role of ER in recurrent breast cancer. Taken together, these aims illustrate the impact of affective regulatory processes on cancer patients’ long-term outcomes. As survival rates increase, long-term follow-up studies are needed to characterize the dynamic, reciprocal effects of emotion and ER for cancer survivors. Further research on ER may help women with breast cancer better manage the challenges associated with diagnosis and treatment. PMID:27517969

4‑Phenylbutyrate protects rat skin flaps against ischemia‑reperfusion injury and apoptosis by inhibiting endoplasmic reticulum stress.

PubMed

Yue, Zhen-Shuang; Zeng, Lin-Ru; Quan, Ren-Fu; Tang, Yang-Hua; Zheng, Wen-Jie; Qu, Gang; Xu, Can-Da; Zhu, Fang-Bing; Huang, Zhong-Ming

2016-02-01

4‑phenylbutyrate (4‑PBA) is a low molecular weight fatty acid, which has been demonstrated to regulate endoplasmic reticulum (ER) stress. ER stress‑induced cell apoptosis has an important role in skin flap ischemia; however, a pharmacological approach for treating ischemia‑induced ER dysfunction has yet to be reported. In the present study, the effects of 4‑PBA‑induced ER stress inhibition on ischemia‑reperfusion injury were investigated in the skin flap of rats, and transcriptional regulation was examined. 4‑PBA attenuated ischemia‑reperfusion injury and inhibited cell apoptosis in the skin flap. Furthermore, 4‑PBA reversed the increased expression levels of two ER stress markers: CCAAT/enhancer-binding protein‑homologous protein and glucose‑regulated protein 78. These results suggested that 4‑PBA was able to protect rat skin flaps against ischemia‑reperfusion injury and apoptosis by inhibiting ER stress marker expression and ER stress‑mediated apoptosis. The beneficial effects of 4‑PBA may prove useful in the treatment of skin flap ischemia‑reperfusion injury.

4-Phenylbutyrate protects rat skin flaps against ischemia-reperfusion injury and apoptosis by inhibiting endoplasmic reticulum stress

PubMed Central

YUE, ZHEN-SHUANG; ZENG, LIN-RU; QUAN, REN-FU; TANG, YANG-HUA; ZHENG, WEN-JIE; QU, GANG; XU, CAN-DA; ZHU, FANG-BING; HUANG, ZHONG-MING

2016-01-01

4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid, which has been demonstrated to regulate endoplasmic reticulum (ER) stress. ER stress-induced cell apoptosis has an important role in skin flap ischemia; however, a pharmacological approach for treating ischemia-induced ER dysfunction has yet to be reported. In the present study, the effects of 4-PBA-induced ER stress inhibition on ischemia-reperfusion injury were investigated in the skin flap of rats, and transcriptional regulation was examined. 4-PBA attenuated ischemia-reperfusion injury and inhibited cell apoptosis in the skin flap. Furthermore, 4-PBA reversed the increased expression levels of two ER stress markers: CCAAT/enhancer-binding protein-homologous protein and glucose-regulated protein 78. These results suggested that 4-PBA was able to protect rat skin flaps against ischemia-reperfusion injury and apoptosis by inhibiting ER stress marker expression and ER stress-mediated apoptosis. The beneficial effects of 4-PBA may prove useful in the treatment of skin flap ischemia-reperfusion injury. PMID:26648447

Longitudinal association between child emotion regulation and aggression, and the role of parenting: a comparison of three cultures

PubMed Central

Bozicevic, Laura; De Pascalis, Leonardo; Schuitmaker, Nicole; Tomlinson, Mark; Cooper, Peter J.; Murray, Lynne

2017-01-01

Background The ability to regulate emotions is a key developmental achievement, acquired during social interactions and associated with better behavioral and social outcomes. We examined the influence of culture on child emotion regulation (ER) and aggression, and on early parenting practices, and the role of parenting in child ER. Methods We assessed 48 mother-infant dyads from three cultures (one UK, two South African (SA)), at three months infant age for maternal sensitivity during face-to-face interaction, and responses to infant distress during daily life, and at two years for child ER strategies and maternally-reported aggression. Results There were cultural differences in child ER, and these were associated with differences in levels of aggression. Maternal strategies in response to early infant distress also differed by culture and predicted later child ER. Maternal sensitivity during face-to-face interactions was not associated with culture and showed no clear relationship with child ER. Conclusion Cultural differences in maternal responses to infant distress mediated differences in child ER that are, in turn, related to differences in child aggression. PMID:27486811

ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43

NASA Astrophysics Data System (ADS)

Stoica, Radu; de Vos, Kurt J.; Paillusson, Sébastien; Mueller, Sarah; Sancho, Rosa M.; Lau, Kwok-Fai; Vizcay-Barrena, Gema; Lin, Wen-Lang; Xu, Ya-Fei; Lewis, Jada; Dickson, Dennis W.; Petrucelli, Leonard; Mitchell, Jacqueline C.; Shaw, Christopher E.; Miller, Christopher C. J.

2014-06-01

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

Longitudinal Association between Child Emotion Regulation and Aggression, and the Role of Parenting: A Comparison of Three Cultures.

PubMed

Bozicevic, Laura; De Pascalis, Leonardo; Schuitmaker, Nicole; Tomlinson, Mark; Cooper, Peter J; Murray, Lynne

The ability to regulate emotions is a key developmental achievement acquired during social interactions and associated with better behavioral and social outcomes. We examined the influence of culture on child emotion regulation (ER) and aggression and on early parenting practices, and the role of parenting in child ER. We assessed 48 mother-infant dyads from three cultures (1 UK, 2 South African) at infant age of 3 months for maternal sensitivity during face-to-face interactions and responses to infant distress during daily life, and at 2 years for child ER strategies and maternally reported aggression. There were cultural differences in child ER, and these were associated with differences in levels of aggression. Maternal strategies in response to early infant distress also differed by culture and predicted later child ER. Maternal sensitivity during face-to-face interactions was not associated with culture and showed no clear relationship with child ER. Cultural differences in maternal responses to infant distress mediated differences in child ER that are, in turn, related to differences in child aggression. © 2016 S. Karger AG, Basel.

Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.

PubMed

Hayashi, Teruo; Su, Tsung-Ping

2007-11-02

Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.

Lace plant ethylene receptors, AmERS1a and AmERS1c, regulate ethylene-induced programmed cell death during leaf morphogenesis.

PubMed

Rantong, Gaolathe; Evans, Rodger; Gunawardena, Arunika H L A N

2015-10-01

The lace plant, Aponogeton madagascariensis, is an aquatic monocot that forms perforations in its leaves as part of normal leaf development. Perforation formation occurs through developmentally regulated programmed cell death (PCD). The molecular basis of PCD regulation in the lace plant is unknown, however ethylene has been shown to play a significant role. In this study, we examined the role of ethylene receptors during perforation formation. We isolated three lace plant ethylene receptors AmERS1a, AmERS1b and AmERS1c. Using quantitative PCR, we examined their transcript levels at seven stages of leaf development. Through laser-capture microscopy, transcript levels were also determined in cells undergoing PCD and cells not undergoing PCD (NPCD cells). AmERS1a transcript levels were significantly lower in window stage leaves (in which perforation formation and PCD are occurring) as compared to all other leaf developmental stages. AmERS1a and AmERS1c (the most abundant among the three receptors) had the highest transcript levels in mature stage leaves, where PCD is not occurring. Their transcript levels decreased significantly during senescence-associated PCD. AmERS1c had significantly higher transcript levels in NPCD compared to PCD cells. Despite being significantly low in window stage leaves, AmERS1a transcripts were not differentially expressed between PCD and NPCD cells. The results suggested that ethylene receptors negatively regulate ethylene-controlled PCD in the lace plant. A combination of ethylene and receptor levels determines cell fate during perforation formation and leaf senescence. A new model for ethylene emission and receptor expression during lace plant perforation formation and senescence is proposed.

Regulative Loops, Step Loops and Task Loops

ERIC Educational Resources Information Center

VanLehn, Kurt

2016-01-01

This commentary suggests a generalization of the conception of the behavior of tutoring systems, which the target article characterized as having an outer loop that was executed once per task and an inner loop that was executed once per step of the task. A more general conception sees these two loops as instances of regulative loops, which…

Emotion Regulation and Parent Co-Regulation in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Ting, Victoria; Weiss, Jonathan A.

2017-01-01

Children with autism spectrum disorder (ASD) often exhibit emotional problems, which can be associated with emotion regulation (ER) difficulties. Parent co-regulation is often associated with child ER and emotional problems, though little work has been done with reference to youth with ASD. This study investigated the association among parent…

Emotion regulation and mental well-being before and six months after bariatric surgery.

PubMed

Efferdinger, Christiane; König, Dorothea; Klaus, Alexander; Jagsch, Reinhold

2017-06-01

According to the current state of research, mental health improves due to bariatric surgery. However, improvements in weight and psychosocial aspects often show a gradual decline with time. As emotion regulation (ER) appears to be a key variable in the successful outcome of weight loss treatments, the present study aimed at investigating ER-strategies applied by bariatric surgery candidates pre- and post-surgery and examining interactions between ER, depressive symptoms, health-related quality of life (HrQoL), and post-surgical weight loss. Prior to and 6 months after bariatric surgery, 45 patients (76% women) completed self-report questionnaires assessing depressive symptoms (Beck Depression Inventory-II), HrQoL (Short Form-36 Health Survey), and ER-strategies (Emotion Regulation Inventory for Negative Emotions). Six months post-surgery, the patients reported significant improvements in depressive symptomatology, HrQoL, and satisfaction with ER compared to pre-surgery. Groups differing in their course of ER-satisfaction also differed in psychosocial dimensions pre- to post-surgery, increased satisfaction being related to less impairment and enhanced communication of negative emotions as a form of an adaptive regulation. Patients with higher weight loss applied the strategy of controlled expression more frequently post-surgery than pre-surgery and compared to patients with lower weight loss. Postoperative weight loss leads to improvements in ER-satisfaction and mental well-being. As satisfaction with ER seems to be associated with less impaired mental well-being among bariatric surgery candidates, presumably even more positive psychosocial outcomes could be obtained post-surgery by implementing trainings explicitly encouraging the use of adaptive ER-strategies.

Endoplasmic reticulum turnover: ER-phagy and other flavors in selective and non-selective ER clearance.

PubMed

Fregno, Ilaria; Molinari, Maurizio

2018-01-01

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells. It is deputed to lipid and protein biosynthesis, calcium storage, and the detoxification of various exogenous and endogenous harmful compounds. ER activity and size must be adapted rapidly to environmental and developmental conditions or biosynthetic demand. This is achieved on induction of thoroughly studied transcriptional/translational programs defined as "unfolded protein responses" that increase the ER volume and the expression of ER-resident proteins regulating the numerous ER functions. Less understood are the lysosomal catabolic processes that maintain ER size at steady state, that prevent excessive ER expansion during ER stresses, or that ensure return to physiologic ER size during recovery from ER stresses. These catabolic processes may also be activated to remove ER subdomains where proteasome-resistant misfolded proteins or damaged lipids have been segregated. Insights into these catabolic mechanisms have only recently emerged with the identification of so-called ER-phagy receptors, which label specific ER subdomains for selective lysosomal delivery for clearance. Here, in eight chapters and one addendum, we comment on recent advances in ER turnover pathways induced by ER stress, nutrient deprivation, misfolded proteins, and live bacteria. We highlight the role of yeast (Atg39 and Atg40) and mammalian (FAM134B, SEC62, RTN3, and CCPG1) ER-phagy receptors and of autophagy genes in selective and non-selective catabolic processes that regulate cellular proteostasis by controlling ER size, turnover, and function.

Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress.

PubMed

Lee, Samuel; Min Kim, Soo; Dotimas, James; Li, Letitia; Feener, Edward P; Baldus, Stephan; Myers, Ronald B; Chutkow, William A; Patwari, Parth; Yoshioka, Jun; Lee, Richard T

2014-06-01

The endoplasmic reticulum (ER) is responsible for protein folding, modification, and trafficking. Accumulation of unfolded or misfolded proteins represents the condition of ER stress and triggers the unfolded protein response (UPR), a key mechanism linking supply of excess nutrients to insulin resistance and type 2 diabetes in obesity. The ER harbors proteins that participate in protein folding including protein disulfide isomerases (PDIs). Changes in PDI activity are associated with protein misfolding and ER stress. Here, we show that thioredoxin-interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling. We found that Txnip binds to PDIs and increases their enzymatic activity. Genetic deletion of Txnip in cells and mice led to increased protein ubiquitination and splicing of the UPR regulated transcription factor X-box-binding protein 1 (Xbp1s) at baseline as well as under ER stress. Our results reveal Txnip as a novel direct regulator of PDI activity and a feedback mechanism of UPR signaling to decrease ER stress. © 2014 Brigham and Women's Hospital. Published under the terms of the CC BY 4.0 license.

Estradiol-induced gene expression in largemouth bass (Micropterus salmoides)

USGS Publications Warehouse

Bowman, C.J.; Kroll, K.J.; Gross, T.G.; Denslow, N.D.

2002-01-01

Vitellogenin (Vtg) and estrogen receptor (ER) gene expression levels were measured in largemouth bass to evaluate the activation of the ER-mediated pathway by estradiol (E2). Single injections of E2 ranging from 0.0005 to 5 mg/kg up-regulated plasma Vtg in a dose-dependent manner. Vtg and ER mRNAs were measured using partial cDNA sequences corresponding to the C-terminal domain for Vtg and the ligand-binding domain of ER?? sequences. After acute E2-exposures (2 mg/kg), Vtg and ER mRNAs and plasma Vtg levels peaked after 2 days. The rate of ER mRNA accumulation peaked 36-42 h earlier than Vtg mRNA. The expression window for ER defines the primary response to E2 in largemouth bass and that for Vtg a delayed primary response. The specific effect of E2 on other estrogen-regulated genes was tested during these same time windows using differential display RT-PCR. Specific up-regulated genes that are expressed in the same time window as Vtg were ERp72 (a membrane-bound disulfide isomerase) and a gene with homology to an expressed gene identified in zebrafish. Genes that were expressed in a pattern that mimics the ER include the gene for zona radiata protein ZP2, and a gene with homology to an expressed gene found in winter flounder. One gene for fibrinogen ?? was down-regulated and an unidentified gene was transiently up-regulated after 12 h of exposure and returned to basal levels by 48 h. Taken together these studies indicate that the acute molecular response to E2 involves a complex network of responses over time. ?? 2002 Elsevier Science Ireland Ltd. All rights reserved.

The Neural Correlates of Emotion Regulation by Implementation Intentions

PubMed Central

Hallam, Glyn P.; Webb, Thomas L.; Sheeran, Paschal; Miles, Eleanor; Wilkinson, Iain D.; Hunter, Michael D.; Barker, Anthony T.; Woodruff, Peter W. R.; Totterdell, Peter; Lindquist, Kristen A.; Farrow, Tom F. D.

2015-01-01

Several studies have investigated the neural basis of effortful emotion regulation (ER) but the neural basis of automatic ER has been less comprehensively explored. The present study investigated the neural basis of automatic ER supported by ‘implementation intentions’. 40 healthy participants underwent fMRI while viewing emotion-eliciting images and used either a previously-taught effortful ER strategy, in the form of a goal intention (e.g., try to take a detached perspective), or a more automatic ER strategy, in the form of an implementation intention (e.g., “If I see something disgusting, then I will think these are just pixels on the screen!”), to regulate their emotional response. Whereas goal intention ER strategies were associated with activation of brain areas previously reported to be involved in effortful ER (including dorsolateral prefrontal cortex), ER strategies based on an implementation intention strategy were associated with activation of right inferior frontal gyrus and ventro-parietal cortex, which may reflect the attentional control processes automatically captured by the cue for action contained within the implementation intention. Goal intentions were also associated with less effective modulation of left amygdala, supporting the increased efficacy of ER under implementation intention instructions, which showed coupling of orbitofrontal cortex and amygdala. The findings support previous behavioural studies in suggesting that forming an implementation intention enables people to enact goal-directed responses with less effort and more efficiency. PMID:25798822

BARC: A Novel Apoptosis Regulator

DTIC Science & Technology

2005-06-01

of other well-character- pathway for apoptosis. ized cell death-regulatory genes, including caspase 12, Because ischemia - reperfusion injury is known...in- creased sensitivity of cultured neurons to ischemia - cluding induction of ER chaperones associated with un- reperfusion injury , we compared bi-1...induced apoptosis. BI-1 and anti-apoptotic Bcl - 2 -family protein, regulate ER calcium. Our work revealed structural elements in Bcl - 2 and other ER

TMEM203 Is a Novel Regulator of Intracellular Calcium Homeostasis and Is Required for Spermatogenesis

PubMed Central

Shambharkar, Prashant B.; Bittinger, Mark; Latario, Brian; Xiong, ZhaoHui; Bandyopadhyay, Somnath; Davis, Vanessa; Lin, Victor; Yang, Yi; Valdez, Reginald; Labow, Mark A.

2015-01-01

Intracellular calcium signaling is critical for initiating and sustaining diverse cellular functions including transcription, synaptic signaling, muscle contraction, apoptosis and fertilization. Trans-membrane 203 (TMEM203) was identified here in cDNA overexpression screens for proteins capable of modulating intracellular calcium levels using activation of a calcium/calcineurin regulated transcription factor as an indicator. Overexpression of TMEM203 resulted in a reduction of Endoplasmic Reticulum (ER) calcium stores and elevation in basal cytoplasmic calcium levels. TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux. Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis. Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation. Expression profiling studies showed significant alternations in expression of calcium channels and pumps in testes and concurrently Tmem203 deficient spermatocytes demonstrated significantly altered calcium handling. Thus Tmem203 is an evolutionarily conserved regulator of cellular calcium homeostasis, is required for spermatogenesis and provides a causal link between intracellular calcium regulation and spermiogenesis. PMID:25996873

Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Mu-Yun; Shen, Yuh-Chiang; National Research Institute of Chinese Medicine, Taipei, Taiwan

Prodigiosin is a bacterial tripyrrole pigment with potent cytotoxicity against diverse human cancer cell lines. Endoplasmic reticulum (ER) stress is initiated by accumulation of unfolded or misfolded proteins in the ER lumen and may induce cell death when irremediable. In this study, the role of ER stress in prodigiosin-induced cytotoxicity was elucidated for the first time. Comparable to the ER stress inducer thapsigargin, prodigiosin up-regulated signature ER stress markers GRP78 and CHOP in addition to activating the IRE1, PERK and ATF6 branches of the unfolded protein response (UPR) in multiple human breast carcinoma cell lines, confirming prodigiosin as an ERmore » stress inducer. Prodigiosin transcriptionally up-regulated CHOP, as evidenced by its promoting effect on the CHOP promoter activity. Of note, knockdown of CHOP effectively lowered prodigiosin's capacity to evoke PARP cleavage, reduce cell viability and suppress colony formation, highlighting an essential role of CHOP in prodigiosin-induced cytotoxic ER stress response. In addition, prodigiosin down-regulated BCL2 in a CHOP-dependent manner. Importantly, restoration of BCL2 expression blocked prodigiosin-induced PARP cleavage and greatly enhanced the survival of prodigiosin-treated cells, suggesting that CHOP-dependent BCL2 suppression mediates prodigiosin-elicited cell death. Moreover, pharmacological inhibition of JNK by SP600125 or dominant-negative blockade of PERK-mediated eIF2α phosphorylation impaired prodigiosin-induced CHOP up-regulation and PARP cleavage. Collectively, these results identified ER stress-mediated cell death as a mode-of-action of prodigiosin's tumoricidal effect. Mechanistically, prodigiosin engages the IRE1–JNK and PERK–eIF2α branches of the UPR signaling to up-regulate CHOP, which in turn mediates BCL2 suppression to induce cell death. Highlights: ► Prodigiosin is a bacterial tripyrrole pigment with potent anticancer effect. ► Prodigiosin is herein identified as an endoplasmic reticulum (ER) stress inducer. ► Prodigiosin-induced cytotoxicity involves ER stress-mediated cell death. ► Prodigiosin transcriptionally induces CHOP to suppress BCL2 for evoking cell death. ► Prodigiosin engages the IRE1–JNK and PERK–eIF2α pathways to up-regulate CHOP.« less

AAV delivery of GRP78/BiP promotes adaptation of human RPE cell to ER stress.

PubMed

Ghaderi, Shima; Ahmadian, Shahin; Soheili, Zahra-Soheila; Ahmadieh, Hamid; Samiei, Shahram; Kheitan, Samira; Pirmardan, Ehsan R

2018-02-01

Adeno associated virus (AAV)-mediated gene delivery of GRP78 (78 kDa glucose-regulated protein) attenuates the condition of endoplasmic reticulum (ER) stress and prevents apoptotic loss of photoreceptors in Retinitis pigmentosa (RP) rats. In the current study we overexpressed Grp78 with the help of AAV-2 in primary human retinal pigmented epithelium (hRPE) cell cultures and examined its effect on cell response to ER stress. The purpose of this work was studying potential stimulating effect of GRP78 on adaptation/pro-survival of hRPE cells under ER stress, as an in vitro model for RPE degeneration. To investigate the effect of Grp78 overexpression on unfolded protein response (UPR) markers under ER stress, hRPE primary cultures were transduced by recombinant virus rAAV/Grp78, and treated with ER stressor drug, tunicamycin. Expression changes of four UPR markers including GRP78, PERK, ATF6α, and GADD153/CHOP, were assessed by real-time PCR and western blotting. We found that GRP78 has a great contribution in modulation of UPR markers to favor adaptive response in ER-stressed hRPE cells. In fact, GRP78 overexpression affected adaptation and apoptotic phases of early UPR, through enhancement of two master regulators/ER stress sensors (PERK and ATF6α) and down-regulation of a key pro-apoptotic cascade activator (GADD153/CHOP). Together these findings demonstrate the promoting effect of GRP78 on adaptation/pro-survival of hRPE cells under ER stress. This protein with anti-apoptotic actions in the early UPR and important role in cell fate regulation, can be recruited as a useful candidate for future investigations of RPE degenerative diseases. © 2017 Wiley Periodicals, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cervia, Davide, E-mail: d.cervia@unitus.it; Department of Biomedical and Clinical Sciences, “Luigi Sacco” University Hospital, University of Milan, Milano; Catalani, Elisabetta

Water-soluble protein signals (pheromones) of the ciliate Euplotes have been supposed to be functional precursors of growth factors and cytokines that regulate cell–cell interaction in multi-cellular eukaryotes. This work provides evidence that native preparations of the Euplotes raikovi pheromone Er-1 (a helical protein of 40 amino acids) specifically increases viability, DNA synthesis, proliferation, and the production of interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-2, and IL-13 in human Jurkat T-cells. Also, Er-1 significantly decreases the mRNA levels of the β and γ subunits of IL-2 receptor (IL-2R), while the mRNA levels of the α subunit appeared to be not affected.more » Jurkat T-cell treatments with Er-1 induced the down-regulation of the IL-2Rα subunit by a reversible and time-dependent endocytosis, and increased the levels of phosphorylation of the extracellular signal-regulated kinases (ERK). The cell-type specificity of these effects was supported by the finding that Er-1, although unable to directly influence the growth of human glioma U-373 cells, induced Jurkat cells to synthesize and release factors that, in turn, inhibited the U-373 cell proliferation. Overall, these findings imply that Er-1 coupling to IL-2R and ERK immuno-enhances T-cell activity, and that this effect likely translates to an inhibition of glioma cell growth. -- Highlights: ► Euplotes pheromone Er-1 increases the growth of human Jurkat T-cells. ► Er-1 increases the T-cell production of specific cytokines. ► Er-1 activates interleukin-2 receptor and extracellular signal-regulated kinases. ► The immuno-enhancing effect of Er-1 on Jurkat cells translates to an inhibition of human glioma cell growth.« less

The Role of the Family Context in the Development of Emotion Regulation

PubMed Central

Morris, Amanda Sheffield; Silk, Jennifer S.; Steinberg, Laurence; Myers, Sonya S.; Robinson, Lara Rachel

2008-01-01

This article reviews current literature examining associations between components of the family context and children and adolescents’ emotion regulation (ER). The review is organized around a tripartite model of familial influence. Firstly, it is posited that children learn about ER through observational learning, modeling and social referencing. Secondly, parenting practices specifically related to emotion and emotion management affect ER. Thirdly, ER is affected by the emotional climate of the family via parenting style, the attachment relationship, family expressiveness and the marital relationship. The review ends with discussions regarding the ways in which child characteristics such as negative emotionality and gender affect ER, how socialization practices change as children develop into adolescents, and how parent characteristics such as mental health affect the socialization of ER. PMID:19756175

Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription

PubMed Central

Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

2015-01-01

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPRER) to restore ER homeostasis. The AAA+ ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPRER genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA+ ATPase, as a novel repressor of a subset of UPRER genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPRER genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes. PMID:25652260

A role for post-transcriptional control of endoplasmic reticulum dynamics and function in C. elegans germline stem cell maintenance.

PubMed

Maheshwari, Richa; Pushpa, Kumari; Subramaniam, Kuppuswamy

2016-09-01

Membrane-bound receptors, which are crucial for mediating several key developmental signals, are synthesized on endoplasmic reticulum (ER). The functional integrity of ER must therefore be important for the regulation of at least some developmental programs. However, the developmental control of ER function is not well understood. Here, we identify the C. elegans protein FARL-11, an ortholog of the mammalian STRIPAK complex component STRIP1/2 (FAM40A/B), as an ER protein. In the C. elegans embryo, we find that FARL-11 is essential for the cell cycle-dependent morphological changes of ER and for embryonic viability. In the germline, FARL-11 is required for normal ER morphology and for membrane localization of the GLP-1/Notch receptor involved in germline stem cell (GSC) maintenance. Furthermore, we provide evidence that PUF-8, a key translational regulator in the germline, promotes the translation of farl-11 mRNA. These findings reveal that ER form and function in the C. elegans germline are post-transcriptionally regulated and essential for the niche-GSC signaling mediated by GLP-1. © 2016. Published by The Company of Biologists Ltd.

Foliage Penetration Radar: History and Developed Technology

DTIC Science & Technology

1974-05-01

26 M-FOPEN Antenna Mast with Delta- Loop Antennas 44 27 AB-577/GRC Antenna Mast Used to Extend the Range of the Man-Portable Radar 45 28 Base Station...Ground Control Unit 47 29 Base Station Tov.er with Delta- Loop Antennas 48 30 Test Configuration for the AN/fPS-5 Comparison Test and Tactical Exercise...00 UNDERGROW 1H TRANSMTTTING ANTENN . HEIG IT: 2 m 5(6- 13 m ) \\\\7 \\ Seo \\................ $A1 U, -< o\\ 31 I~ ~ A ,M\\;’ I10 31 ’•...GJ, FIGURE 3

Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

PubMed Central

Lindström, Riitta; Lindholm, Päivi; Kallijärvi, Jukka; Palgi, Mari; Saarma, Mart; Heino, Tapio I.

2016-01-01

Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. ER stress activates unfolded protein response (UPR), a cellular mechanism the purpose of which is to restore ER homeostasis. Previous studies show that Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an important novel component in the regulation of UPR. In vertebrates, MANF is upregulated by ER stress and protects cells against ER stress-induced cell death. Biochemical studies have revealed an interaction between mammalian MANF and GRP78, the major ER chaperone promoting protein folding. In this study we discovered that the upregulation of MANF expression in response to drug-induced ER stress is conserved between Drosophila and mammals. Additionally, by using a genetic in vivo approach we found genetic interactions between Drosophila Manf and genes encoding for Drosophila homologues of GRP78, PERK and XBP1, the key components of UPR. Our data suggest a role for Manf in the regulation of Drosophila UPR. PMID:26975047

Specific emotion regulation impairments in major depression and anorexia nervosa.

PubMed

Brockmeyer, Timo; Bents, Hinrich; Holtforth, Martin Grosse; Pfeiffer, Nils; Herzog, Wolfgang; Friederich, Hans-Christoph

2012-12-30

Emotion regulation (ER) difficulties have been considered to play an important role in the development and maintenance of various mental disorders such as depression and anorexia nervosa. However, previous research has failed to provide detailed insight into the disorder-specificity of ER difficulties. Therefore, the present study investigated specific ER difficulties in female samples of patients with major depression, patients with anorexia nervosa, and healthy controls (total sample: N=140). As compared to healthy controls, both clinical groups reported greater ER difficulties concerning both the experience and the differentiation as well as the attenuation and the modulation of emotions. Patients in both clinical groups reported comparably elevated ER difficulties regarding the experience and differentiation of emotions. However, depressed patients reported stronger ER difficulties regarding the attenuation and modulation of emotions as compared to patients with anorexia nervosa. These findings support the notion of ER difficulties as transdiagnostic phenomena, and suggest that depression may be characterized by broader and greater ER difficulties than anorexia nervosa. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Mothering, fathering, and the regulation of negative and positive emotions in high-functioning preschoolers with autism spectrum disorder.

PubMed

Hirschler-Guttenberg, Yael; Golan, Ofer; Ostfeld-Etzion, Sharon; Feldman, Ruth

2015-05-01

Children with autism spectrum disorder (ASD) exhibit difficulties in regulating emotions and authors have called to study the specific processes underpinning emotion regulation (ER) in ASD. Yet, little observational research examined the strategies preschoolers with ASD use to regulate negative and positive emotions in the presence of their mothers and fathers. Forty preschoolers with ASD and 40 matched typically developing children and their mothers and fathers participated. Families were visited twice for identical battery of paradigms with mother or father. Parent-child interactions were coded for parent and child behaviors and children engaged in ER paradigms eliciting negative (fear) and positive (joy) emotions with each parent. ER paradigms were microcoded for negative and positive emotionality, ER strategies, and parent regulation facilitation. During free play, mothers' and fathers' sensitivity and warm discipline were comparable across groups; however, children with ASD displayed lower positive engagement and higher withdrawal. During ER paradigms, children with ASD expressed less positive emotionality overall and more negative emotionality during fear with father. Children with ASD used more simple self-regulatory strategies, particularly during fear, but expressed comparable levels of assistance seeking behavior toward mother and father in negative and positive contexts. Parents of children with ASD used less complex regulation facilitation strategies, including cognitive reappraisal and emotional reframing, and employed simple tactics, such as physical comforting to manage fear and social gaze to maintain joy. Findings describe general and parent- and emotion-specific processes of child ER and parent regulation facilitation in preschoolers with ASD. Results underscore the ability of such children to seek parental assistance during moments of high arousal and the parents' sensitive adaptation to their children's needs. Reduced positive emotionality, rather than increased negative reactivity and self-regulatory efforts, emerges as the consistent element associated with ER processes in this group. © 2014 Association for Child and Adolescent Mental Health.

Cut! that’s a wrap: regulating negative emotion by ending emotion-eliciting situations

PubMed Central

Vujovic, Lara; Opitz, Philipp C.; Birk, Jeffrey L.; Urry, Heather L.

2014-01-01

Little is known about the potentially powerful set of emotion regulation (ER) processes that target emotion-eliciting situations. We thus studied the decision to end emotion-eliciting situations in the laboratory. We hypothesized that people would try to end negative situations more frequently than neutral situations to regulate distress. In addition, motivated by the selection, optimization, and compensation with ER framework, we hypothesized that failed attempts to end the situation would prompt either (a) greater negative emotion or (b) compensatory use of a different ER process, attentional deployment (AD). Fifty-eight participants (18–26 years old, 67% women) viewed negative and neutral pictures and pressed a key whenever they wished to stop viewing them. After key press, the picture disappeared (“success”) or stayed (“failure”) on screen. To index emotion, we measured corrugator and electrodermal activity, heart rate, and self-reported arousal. To index overt AD, we measured eye gaze. As their reason for ending the situation, participants more frequently reported being upset by high- than low-arousal negative pictures; they more frequently reported being bored by low- than high-arousal neutral pictures. Nevertheless, participants’ negative emotional responding did not increase in the context of ER failure nor did they use overt AD as a compensatory ER strategy. We conclude that situation-targeted ER processes are used to regulate emotional responses to high-arousal negative and low-arousal neutral situations; ER processes other than overt AD may be used to compensate for ER failure in this context. PMID:24592251

Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction.

PubMed

Hu, Zhenyu; Li, Guang; Wang, Jiong-Wei; Chong, Suet Yen; Yu, Dejie; Wang, Xiaoyuan; Soon, Jia Lin; Liang, Mui Cheng; Wong, Yuk Peng; Huang, Na; Colecraft, Henry M; Liao, Ping; Soong, Tuck Wah

2018-04-12

Background -L-type Ca V 1.2 channels play crucial roles in regulation of blood pressure. Galectin-1 (Gal-1), has been reported to bind to the I-II loop of Ca V 1.2 channels to reduce their current density. However, the mechanistic understanding for the down-regulation of Ca V 1.2 channels by Gal-1, and whether Gal-1 plays a direct role in blood pressure regulation remain unclear. Methods - In vitro experiments involving co-IP, western blot, patch-clamp recordings, immunohistochemistry and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 down-regulates Ca V 1.2 channel in transfected HEK 293 cells, smooth muscle cells, arteries from Lgasl1 -/- mice, rat and human patients. In vivo experiments involving delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting Ca V 1.2-Gal-1 interaction on blood pressure monitored by tail cuff or telemetry methods. Results -Our study reveals that Gal-1 is a key regulator for proteasomal degradation of Ca V 1.2 channels. Gal-1 competed allosterically with Ca V β subunit for binding to the I-II loop of Ca V 1.2 channel. This competitive disruption of Ca V β binding led to Ca V 1.2 degradation by exposing the channels to poly-ubiquitination. Notably, we demonstrated that the inverse relationship of reduced Gal-1 and increased Ca V 1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice due to up-regulated Ca V 1.2 protein level in arteries. To directly regulate blood pressure by targeting the Ca V 1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1, by a mini-osmotic pump and this specific disruption of Ca V 1.2-Gal-1 coupling increased smooth muscle Ca V 1.2 currents, induced larger arterial contraction and caused hypertension in rats. In contrasting experiments, over-expression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats. Conclusions -We have defined molecularly that Gal-1 promotes Ca V 1.2 degradation by replacing Ca V β and thereby exposing specific lysines for poly-ubiquitination, and by masking I-II loop ER export signals. This mechanistic understanding provided the basis for targeting Ca V 1.2-Gal-1 interaction to demonstrate clearly the modulatory role Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.

Combining autophagy-inducing peptides and brefeldin A delivered by perinuclear-localized mesoporous silica nanoparticles: a manipulation strategy for ER-phagy.

PubMed

Wang, Yimin; Zhao, Zhao; Wei, Fujing; Luo, Zewei; Duan, Yixiang

2018-05-10

Autophagic degradation of the endoplasmic reticulum (ER-phagy) has been found to play a critical role in human sensory neuropathy. So far, however, specific and efficient intervention means for ER-phagy remain unexplored. Herein, brefeldin A (BFA), a blocking agent on protein transport between the ER and Golgi, was screened from ER stress inducers. BFA was then delivered to the perinuclear area co-localized with the ER by a mesoporous silica nanoparticle-based drug-carrier functionalized with autophagy-inducing peptides of TAT-beclin 1 (MSNs-BFA), to evoke a perturbation of ER-phagy. The molecular mechanism of ER-phagy regulated by BFA was explored by biochemical evaluation including time-lapse live-cell fluorescence imaging. We found that MSNs-BFA treatment caused a lower mRNA/protein expression level of FAM134b even under a compensation of autophagic flux in U2OS cells, and resulted in ER-expansion. The fragmentation of the ER was blocked as a response to ER stress mediated by inactivation of the AKT/TSC/mTOR pathway. Our work developed an efficient external manipulation strategy to regulate ER-phagy and may contribute to the therapeutic application of autophagy-related major human diseases.

Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival.

PubMed

Mori, Tomohisa; Hayashi, Teruo; Hayashi, Eri; Su, Tsung-Ping

2013-01-01

The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.

Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival

PubMed Central

Mori, Tomohisa; Hayashi, Teruo; Hayashi, Eri; Su, Tsung-Ping

2013-01-01

The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus. PMID:24204710

A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division.

PubMed

Manor, Uri; Bartholomew, Sadie; Golani, Gonen; Christenson, Eric; Kozlov, Michael; Higgs, Henry; Spudich, James; Lippincott-Schwartz, Jennifer

2015-08-25

Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction and division. We propose Spire1C cooperates with INF2 to regulate actin assembly at ER-mitochondrial contacts. Simulations support this model's feasibility and demonstrate polymerizing actin filaments can induce mitochondrial constriction. Thus, Spire1C is optimally positioned to serve as a molecular hub that links mitochondria to actin and the ER for regulation of mitochondrial division.

48 CFR 53.301-25 - Performance Bond.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 2 2014-10-01 2014-10-01 false Performance Bond. 53.301-25 Section 53.301-25 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-25 Performance Bond. ER29AP14.003 ER29AP14.004 [79...

48 CFR 53.301-25 - Performance Bond.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 2 2012-10-01 2012-10-01 false Performance Bond. 53.301-25 Section 53.301-25 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-25 Performance Bond. ER18DE98.007 ER18DE98.008 [63...

48 CFR 53.301-25 - Performance Bond.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Performance Bond. 53.301-25 Section 53.301-25 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-25 Performance Bond. ER18DE98.007 ER18DE98.008 [63...

48 CFR 53.301-25 - Performance Bond.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 2 2013-10-01 2013-10-01 false Performance Bond. 53.301-25 Section 53.301-25 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-25 Performance Bond. ER18DE98.007 ER18DE98.008 [63...

48 CFR 53.301-25 - Performance Bond.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 false Performance Bond. 53.301-25 Section 53.301-25 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION (CONTINUED) CLAUSES AND FORMS FORMS Illustrations of Forms 53.301-25 Performance Bond. ER18DE98.007 ER18DE98.008 [63...

Detection of Orexin A Neuropeptide in Biological Fluids Using a Zinc Oxide Field Effect Transistor

DTIC Science & Technology

2012-06-01

can rapidly cross the blood-brain barrier10. In contrast, orexin B has low lipophilicity and is rapidly metabolized in blood which makes it difficult...Tris (Sigma) pH 9.1. The eluate was added to 20 mL E. coli ER2738 culture and incubated at 37 ºC with vigorous shaking for 4.5 h. The culture was...plates using a sterile inoculation loops, and were amplified individually for 4.5-5 hours at 37 ºC in 1.5 mL of E. coli ER2738 culture grown in LB broth

Stability analysis and compensation of a boost regulator with two-loop control

NASA Technical Reports Server (NTRS)

Wester, G. W.

1974-01-01

A useful stability measure has been demonstrated by Wester (1973) for switching regulators with a single feedback loop by applying the Nyquist criterion to the approximate loop gain determined by a time-averaging technique. This approach is extended and applied to the characterization, stability analysis, and compensation design of a switching regulator with two-loop control. The role and relative significance of each control loop is clarified on the basis of a description of circuit operation, and the major and minor loops are identified. In view of the inapplicability of linear feedback theory, describing functions of the feedback loops and power stage are derived, using small-signal analysis. Several phenomena revealed from an analysis of the major loop gain are discussed.

49 CFR Appendix A to Part 595 - Information Brochure

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 7 2012-10-01 2012-10-01 false Information Brochure A Appendix A to Part 595 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY... to Part 595—Information Brochure ER21NO97.000 ER21NO97.001 ER21NO97.002 ER21NO97.003 ER21NO97.004...

49 CFR Appendix B to Part 230 - Diagrams and Drawings

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Diagrams and Drawings B Appendix B to Part 230 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... to Part 230—Diagrams and Drawings ER17No99.015 ER17No99.016 ER17No99.017 ER17No99.018 ER17No99.019...

49 CFR Appendix A to Part 595 - Information Brochure

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Information Brochure A Appendix A to Part 595 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY TRAFFIC SAFETY... to Part 595—Information Brochure ER21NO97.001 ER21NO97.002 ER21NO97.003 ER21NO97.004 ER21NO97.005...

Testing predictions of the emotion regulation model of binge-eating disorder.

PubMed

Kenny, Therese E; Singleton, Christopher; Carter, Jacqueline C

2017-11-01

The emotion regulation (ER) model of binge eating posits that individuals with binge-eating disorder (BED) experience more intense emotions and greater difficulties in ER than individuals without BED, leading them to binge eat as a means of regulating emotions. According to this model, individuals with BED should report greater difficulties in ER than their non-BED counterparts, the severity of these difficulties should be positively associated with BED symptoms, and this association should be stronger when individuals experience persistent negative emotions (i.e., depression). Studies examining these hypotheses, however, have been limited. Data were collected from adults meeting the DSM 5 criteria for BED (n = 71; 93% female) and no history of an eating disorder (NED; n =  79; 83.5% female). Participants completed self-report measures of difficulties in ER, eating disorder (ED) psychopathology, and depression. Individuals with BED reported greater difficulties in ER compared to those with NED. Moreover, difficulties in ER predicted unique variance in binge frequency and ED psychopathology in BED. Depression moderated the association between ER difficulties and binge frequency such that emotion dysregulation and binge frequency were positively associated in those reporting high, but not low, depression levels. The association between difficulties in ER and ED pathology in BED suggests that treatments focusing on improving ER skills may be effective in treating this ED; however, the moderating effect of depression underscores the need for research on individual differences and treatment moderators. These findings suggest the importance of ER in understanding and treating BED. © 2017 Wiley Periodicals, Inc.

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

PubMed Central

Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

2017-01-01

Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition. PMID:28146117

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin.

PubMed

Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

2017-01-31

Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.

Children with social anxiety and other anxiety disorders show similar deficits in habitual emotional regulation: evidence for a transdiagnostic phenomenon.

PubMed

Keil, Verena; Asbrand, Julia; Tuschen-Caffier, Brunna; Schmitz, Julian

2017-07-01

Deficits in emotion regulation (ER) are an important factor in maintaining social anxiety disorder (SAD) in adults. As SAD and ER problems typically develop during childhood and adolescence, and are maintained dynamically within the parent-child dyad, research on families can help to reveal the role ER plays in the early development of SAD. The current study assessed self-reported habitual ER in dyads of children with SAD (n = 31), children with mixed anxiety disorders (MAD; n = 41) and healthy control children (HC; n = 36), and their parents. Results indicate a transdiagnostic quality of ER in that, children with SAD and children with MAD similarly reported less adaptive and more maladaptive ER strategies than HC children, whereas no group differences in parental ER strategies emerged. Furthermore, children's ER strategies aggressive action, withdrawal and self-devaluation and the parental ER strategy reappraisal were associated with social anxiety symptoms. These results suggest that there may be deficits in ER which generalize across childhood anxiety disorders. Our results are discussed in relation to current theories and their implications for treatment of childhood SAD.

ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mera, Kentaro; Kawahara, Ko-ichi; Tada, Ko-ichi

Proteins are folded properly in the endoplasmic reticulum (ER). Various stress such as hypoxia, ischemia and starvation interfere with the ER function, causing ER stress, which is defined by the accumulation of unfolded protein (UP) in the ER. ER stress is prevented by the UP response (UPR) and ER-associated degradation (ERAD). These signaling pathways are activated by three major ER molecules, ATF6, IRE-1 and PERK. Using HaCaT cells, we investigated ER signaling in human keratinocytes irradiated by environmental doses of ultraviolet B (UVB). The expression of Ero1-L{alpha}, an upstream signaling molecule of ER stress, decreased at 1-4 h after 10more » mJ/cm{sup 2} irradiation, indicating that the environmental dose of UVB-induced ER stress in HaCaT cells, without growth retardation. Furthermore, expression of intact ATF6 was decreased and it was translocated to the nuclei. The expression of XBP-1, a downstream molecule of IRE-1, which is an ER chaperone whose expression is regulated by XBP-1, and UP ubiquitination were induced by 10 mJ/cm{sup 2} UVB at 4 h. PERK, which regulates apoptosis, was not phosphorylated. Our results demonstrate that UVB irradiation generates UP in HaCaT cells and that the UPR and ERAD systems are activated to protect cells from UVB-induced ER stress. This is the first report to show ER signaling in UVB-irradiated keratinocytes.« less

The Role of Emotion Regulation in Autism Spectrum Disorder RH: Emotion Regulation in ASD

PubMed Central

Mazefsky, Carla A.; Herrington, John; Siegel, Matthew; Scarpa, Angela; Maddox, Brenna B.; Scahill, Lawrence; White, Susan W.

2013-01-01

Objective Autism spectrum disorder (ASD) is associated with amplified emotional responses and poor emotional control, but little is known about the underlying mechanisms. This paper provides a conceptual and methodological framework for understanding compromised emotion regulation (ER) in ASD. Method After defining ER and related constructs, methods to study ER were reviewed with special consideration on how to apply these approaches to ASD. Against the backdrop of cognitive characteristics in ASD and existing ER theories, available research was examined to identify likely contributors to emotional dysregulation in ASD. Results Little is currently known about ER in youth with ASD. Some mechanisms that contribute to poor ER in ASD may be shared with other clinical populations (e.g., physiological arousal, degree of negative and positive affect, alterations in the amygdala and prefrontal cortex), whereas other mechanisms may be more unique to ASD (e.g., differences in information processing/perception, cognitive factors (e.g., rigidity), less goal-directed behavior and more disorganized emotion in ASD). Conclusions Although assignment of concomitant psychiatric diagnoses is warranted in some cases, poor ER may be inherent in ASD and may provide a more parsimonious conceptualization for the many associated socio-emotional and behavioral problems in this population. Further study of ER in youth with ASD may identify meaningful subgroups of patients and lead to more effective individualized treatments. PMID:23800481

Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells.

PubMed

Choi, Min Jung; Park, Eun Jung; Min, Kyoung Jin; Park, Jong-Wook; Kwon, Taeg Kyu

2011-04-01

The accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER) results in cellular stress that initiates a specialized response designated as the unfolded protein response. ER stress has been implicated in a variety of common diseases, such as diabetes, ischemia and neurodegenerative disorders. Withaferin A, a major chemical constituent of Withania somnifera, has been reported to inhibit tumor cell growth. We show that withaferin A induced a dose-dependent apoptotic cell death in several types of human cancer cells, as measured by FACS analysis and PARP cleavage. Treatment of Caki cells with withaferin A induced a number of signature ER stress markers, including phosphorylation of eukaryotic initiation factor-2α (eIF-2 α), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78. In addition, withaferin A caused up-regulation of CAAT/enhancer-binding protein-homologous protein (CHOP), suggesting the induction of ER stress. Pretreatment with N-acetyl cysteine (NAC) significantly inhibited withaferin A-mediated ER stress proteins and cell death, suggesting that reactive oxygen species (ROS) mediate withaferin A-induced ER stress. Furthermore, CHOP siRNA or inhibition of caspase-4 activity attenuated withaferin A-induced apoptosis. Taken together, the present study provides strong evidence supporting an important role of the ER stress response in mediating withaferin A-induced apoptosis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Conceptualizing gambling disorder with the process model of emotion regulation.

PubMed

Rogier, Guyonne; Velotti, Patrizia

2018-06-25

Introduction Nowadays, gambling disorder (GD) is a worldwide health issue and there is a growing need to both improve our understanding of this disorder and to tailor specific interventions for its treatment. Moreover, theoretical models and preliminary empirical results suggest that difficulty in regulating emotional states might be involved in GD. However, literature describing clinical and theoretical aspects of emotional dysregulation among pathological gamblers (PGs) shows a lack of systematic description. Objectives We aimed to provide, within an exhaustive theoretical framework of emotion regulation (ER) processing, empirical evidence supporting a conceptual model of GD as an ER affliction. Methods We commented on empirical evidence on the relationship between ER and GD in the light of two main conceptual models of emotion (dys)regulation. Results The results suggest there are actual deficits of ER processing among PGs, manifesting themselves through different ways and in different steps of the ER timeline. In addition, dysregulation of positive emotions may play a central role in GD. From a clinical point of view, we pointed out that deficits in ER might be multiple in nature and an assessment for GD should be accurate to identify the specific components accounting for the development and maintenance of the disorder. It should also orientate the clinician in selecting therapeutic objectives. Conclusions The nature of emotional states that are difficult to regulate might account for the GD severity and indicate the subtype of PGs the patient belongs to. Treatment programs should be tailored on the specificity of PGs.

How do postgraduate GP trainees regulate their learning and what helps and hinders them? A qualitative study.

PubMed

Sagasser, Margaretha H; Kramer, Anneke W M; van der Vleuten, Cees P M

2012-08-06

Self-regulation is essential for professional development. It involves monitoring of performance, identifying domains for improvement, undertaking learning activities, applying newly learned knowledge and skills and self-assessing performance. Since self-assessment alone is ineffective in identifying weaknesses, learners should seek external feedback too. Externally regulated educational interventions, like reflection, learning portfolios, assessments and progress meetings, are increasingly used to scaffold self-regulation.The aim of this study is to explore how postgraduate trainees regulate their learning in the workplace, how external regulation promotes self-regulation and which elements facilitate or impede self-regulation and learning. In a qualitative study with a phenomenologic approach we interviewed first- and third-year GP trainees from two universities in the Netherlands. Twenty-one verbatim transcripts were coded. Through iterative discussion the researchers agreed on the interpretation of the data and saturation was reached. Trainees used a short and a long self-regulation loop. The short loop took one week at most and was focused on problems that were easy to resolve and needed minor learning activities. The long loop was focused on complex or recurring problems needing multiple and planned longitudinal learning activities. External assessments and formal training affected the long but not the short loop. The supervisor had a facilitating role in both loops. Self-confidence was used to gauge competence.Elements influencing self-regulation were classified into three dimensions: personal (strong motivation to become a good doctor), interpersonal (stimulation from others) and contextual (organizational and educational features). Trainees did purposefully self-regulate their learning. Learning in the short loop may not be visible to others. Trainees should be encouraged to actively seek and use external feedback in both loops. An important question for further research is which educational interventions might be used to scaffold learning in the short loop. Investing in supervisor quality remains important, since they are close to trainee learning in both loops.

How do postgraduate GP trainees regulate their learning and what helps and hinders them? A qualitative study

PubMed Central

2012-01-01

Background Self-regulation is essential for professional development. It involves monitoring of performance, identifying domains for improvement, undertaking learning activities, applying newly learned knowledge and skills and self-assessing performance. Since self-assessment alone is ineffective in identifying weaknesses, learners should seek external feedback too. Externally regulated educational interventions, like reflection, learning portfolios, assessments and progress meetings, are increasingly used to scaffold self-regulation. The aim of this study is to explore how postgraduate trainees regulate their learning in the workplace, how external regulation promotes self-regulation and which elements facilitate or impede self-regulation and learning. Methods In a qualitative study with a phenomenologic approach we interviewed first- and third-year GP trainees from two universities in the Netherlands. Twenty-one verbatim transcripts were coded. Through iterative discussion the researchers agreed on the interpretation of the data and saturation was reached. Results Trainees used a short and a long self-regulation loop. The short loop took one week at most and was focused on problems that were easy to resolve and needed minor learning activities. The long loop was focused on complex or recurring problems needing multiple and planned longitudinal learning activities. External assessments and formal training affected the long but not the short loop. The supervisor had a facilitating role in both loops. Self-confidence was used to gauge competence.Elements influencing self-regulation were classified into three dimensions: personal (strong motivation to become a good doctor), interpersonal (stimulation from others) and contextual (organizational and educational features). Conclusions Trainees did purposefully self-regulate their learning. Learning in the short loop may not be visible to others. Trainees should be encouraged to actively seek and use external feedback in both loops. An important question for further research is which educational interventions might be used to scaffold learning in the short loop. Investing in supervisor quality remains important, since they are close to trainee learning in both loops. PMID:22866981

Social Contextual Links to Emotion Regulation in an Adolescent Psychiatric Inpatient Population: Do Gender and Symptomatology Matter?

ERIC Educational Resources Information Center

Adrian, Molly; Zeman, Janice; Erdley, Cynthia; Lisa, Ludmila; Homan, Kendra; Sim, Leslie

2009-01-01

Background: The regulation of emotion is essential for adaptive functioning. However, delineating the pathways of emotion regulation (ER) processes that lead to psychological adaptation remains under-studied, with mixed evidence for the specificity vs. generality of ER deficits in relation to specific forms of psychopathology. To examine this…

Cross-lagged relations among parenting, children's emotion regulation, and psychosocial adjustment in early adolescence.

PubMed

Otterpohl, Nantje; Wild, Elke

2015-01-01

Numerous studies have reported substantive correlations between indicators of parenting, children's emotion regulation (ER), and children's psychosocial adjustment. However, studies on underlying mechanisms are scarce. Particularly in early adolescence, it is still unclear whether relations between parenting and ER are caused by adolescent behavior, by parent behavior, or by reciprocal processes. Moreover, it is unclear whether ER can be seen as an antecedent or a consequence of psychosocial adjustment. The aim of this study was to examine predictive relations among parenting and adolescents' ER, and adolescents' ER and psychosocial adjustment, respectively. We collected longitudinal, multiple informant data at two measurement occasions (Grade 6, Grade 7). All told, 1,100 adolescents (10-14 years) and their parents filled out questionnaires assessing responsiveness and psychological control, adolescents' anger regulation, and adolescents' problem and prosocial behavior. Cross-lagged analyses revealed reciprocal effects between parenting, ER, and adjustment for the parent and boys', but not for the girls', report. Moreover, relations were different for adolescents with versus without clinically elevated symptoms of psychopathology. Our findings support the assumption that reciprocal relations between parenting, ER, and psychosocial adjustment are likely to persist until early adolescence. Nevertheless, the moderating role of gender and psychopathology should be taken into account. Possible reasons for the different findings, and practical implications, are discussed.

Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes.

PubMed

Alam, Shafiul; Abdullah, Chowdhury S; Aishwarya, Richa; Orr, A Wayne; Traylor, James; Miriyala, Sumitra; Panchatcharam, Manikandan; Pattillo, Christopher B; Bhuiyan, Md Shenuarin

2017-08-31

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes. © 2017 The Author(s).

Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes

PubMed Central

Alam, Shafiul; Abdullah, Chowdhury S.; Aishwarya, Richa; Orr, A. Wayne; Traylor, James; Miriyala, Sumitra; Panchatcharam, Manikandan; Pattillo, Christopher B.

2017-01-01

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes. PMID:28667101

Long non-coding RNA MIAT is estrogen-responsive and promotes estrogen-induced proliferation in ER-positive breast cancer cells.

PubMed

Li, Yuehua; Jiang, Baohong; Wu, Xiaoping; Huang, Qin; Chen, Wenqi; Zhu, Hongbo; Qu, Xiaofei; Xie, Liming; Ma, Xin; Huang, Guo

2018-05-21

Estrogen drives the development and progression of estrogen receptor (ER)-positive breast cancer. However, the detailed mechanism underlying ER-driven carcinogenesis remains unclear despite extensive studies. Previously reports indicated higher expression of long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) in ER-positive breast cancer tissues than in ER-negative tissues. However, the functional relevance of MIAT in ER-positive breast cancer tumorigenesis was poorly understood. Here, we investigated the role of lncRNA MIAT in ER-positive breast cancer cells. MIAT was over-expressed in ER-positive breast cancer tissues and ER-positive breast cancer cell line MCF-7. Activating estrogen signaling by diethylstilbestrol (DES) led to a dose- and time-dependent up-regulation of MIAT in MCF-7 cells that was dependent on ERα, as evidenced by ERα silencing and pharmacological inhibition using ER antagonist ICI 182780. Silencing MIAT decreased DES-induced MCF-7 cell proliferation while overexpressing MIAT increased MCF-7 cell proliferation. Further mechanistic study identified that MIAT was critical for G1 to S phase cell cycle transition. Taken together, these results suggest that lncRNA MIAT is an estrogen-inducible lncRNA and a key regulator in ER-positive breast cancer cell growth. MIAT could serve as a potential biomarker and promising therapeutic target for ER-positive breast cancer. Copyright © 2018. Published by Elsevier Inc.

Gene expression profiles of estrogen receptors α and β in the fetal bovine hypothalamus and immunohistochemical characterization during development.

PubMed

Panin, M; Corain, L; Montelli, S; Cozzi, B; Peruffo, A

2015-02-01

Steroid hormones intervene in the structural and functional regulation of neuronal processes during development and thus determine brain differentiation. The effects of estrogens are mediated by two transcription factors, namely estrogen receptor α (ER-α) and estrogen receptor β (ER-β), that regulate the expression of target genes through their binding to specific DNA target sequences. We describe the mRNA expression of ER-α and ER-β in the hypothalamus of developing male and female bovines as revealed by quantitative real-time polymerase chain reaction, and the distribution of the two ERs in hypothalamic sections of all fetal stages as shown by immunohistochemistry. The expression profiles of the mRNAs of both ERs are mutually correlated throughout the gestation period, and their levels increase significantly in the last stages of gestation. No sexual differences in the mRNA expression of either ER-α or ER-β have been found in our fetal specimens. The use of specific antisera against ER-α and ER-β has allowed us to characterize and confirm the distribution of these receptors in the hypothalami of all fetal stages considered. Our results offer detailed information concerning the distribution of ER-α and ER-β in the developing bovine hypothalamus and provide additional insights into the processes involved in the hypothalamic development of a mammal with a long gestation and a highly gyrencephalic brain.

20 CFR 228.50 - Tier II annuity component widow(er), child, or parent.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., or parent. 228.50 Section 228.50 Employees' Benefits RAILROAD RETIREMENT BOARD REGULATIONS UNDER THE... annuity component widow(er), child, or parent. (a) General. The tier II annuity component is an additional amount payable to a widow(er), disabled widow(er), child, or parent, but not to a surviving divorced...

BiP: Master Regulator of the Unfolded Protein Response and Crucial Factor in Flavivirus Biology


PubMed Central

Lewy, Tyler G.; Grabowski, Jeffrey M.; Bloom, Marshall E.

2017-01-01

Flaviviruses have an intimate relationship with their host cells, utilizing host proteins during replication. Much of viral genome replication and virion assembly occurs on and within the endoplasmic reticulum (ER). As a cellular protein folding hub, the ER provides an ideal environment for flaviviruses to replicate. Flaviviruses can interact with several ER processes, including the unfolded protein response (UPR), a cellular stress mechanism responsible for managing unfolded protein accumulation and ER stress. The UPR can alter the ER environment in several ways, including increasing ER volume and quantity of available chaperones, both of which can favor viral replication. BiP, a chaperone and master regulator of the UPR, has been demonstrated to play a key role in several flavivirus infections. Here we describe what is known in regard to BiP, its implicated role with flavivirus infection, and what remains to be discovered. PMID:28656015

BiP: Master Regulator of the Unfolded Protein Response and Crucial Factor in Flavivirus Biology
.

PubMed

Lewy, Tyler G; Grabowski, Jeffrey M; Bloom, Marshall E

2017-06-01

Flaviviruses have an intimate relationship with their host cells, utilizing host proteins during replication. Much of viral genome replication and virion assembly occurs on and within the endoplasmic reticulum (ER). As a cellular protein folding hub, the ER provides an ideal environment for flaviviruses to replicate. Flaviviruses can interact with several ER processes, including the unfolded protein response (UPR), a cellular stress mechanism responsible for managing unfolded protein accumulation and ER stress. The UPR can alter the ER environment in several ways, including increasing ER volume and quantity of available chaperones, both of which can favor viral replication. BiP, a chaperone and master regulator of the UPR, has been demonstrated to play a key role in several flavivirus infections. Here we describe what is known in regard to BiP, its implicated role with flavivirus infection, and what remains to be discovered.

Inhibition of endoplasmic reticulum stress by intermedin1-53 attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE KO Mice.

PubMed

Ni, Xian-Qiang; Lu, Wei-Wei; Zhang, Jin-Sheng; Zhu, Qing; Ren, Jin-Ling; Yu, Yan-Rong; Liu, Xiu-Ying; Wang, Xiu-Jie; Han, Mei; Jing, Qing; Du, Jie; Tang, Chao-Shu; Qi, Yong-Fen

2018-06-26

Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1-53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII. Increased ERS levels were accompanied by severe VSMC apoptosis in human AAA aorta. In vivo administration of IMD1-53 greatly reduced AngII-induced AAA and abrogated the activation of ERS. To determine whether IMD inhibited AAA by ameliorating ERS, we used 2 non-selective ERS inhibitors phenyl butyrate (4-PBA) and taurine (TAU). Similar to IMD, PBA, and TAU significantly reduced the incidence of AAA and AAA-related pathological disorders. In vitro, AngII infusion up-regulated CHOP, caspase12 expression and led to VSMC apoptosis. IMD siRNA aggravated the CHOP, caspase12-mediated VSMC apoptosis, which was abolished by ATF4 silencing. IMD infusion promoted the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in aortas in ApoE KO mice, and the AMPK inhibitor compound C abolished the protective effect of IMD on VSMC ERS and apoptosis induced by AngII. In conclusion, IMD may protect against AAA formation by inhibiting ERS via activating AMPK phosphorylation.

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress.

PubMed

Deegan, Shane; Saveljeva, Svetlana; Gorman, Adrienne M; Samali, Afshin

2013-07-01

Macroautophagy (autophagy) is a cellular catabolic process which can be described as a self-cannibalism. It serves as an essential protective response during conditions of endoplasmic reticulum (ER) stress through the bulk removal and degradation of unfolded proteins and damaged organelles; in particular, mitochondria (mitophagy) and ER (reticulophagy). Autophagy is genetically regulated and the autophagic machinery facilitates removal of damaged cell components and proteins; however, if the cell stress is acute or irreversible, cell death ensues. Despite these advances in the field, very little is known about how autophagy is initiated and how the autophagy machinery is transcriptionally regulated in response to ER stress. Some three dozen autophagy genes have been shown to be required for the correct assembly and function of the autophagic machinery; however; very little is known about how these genes are regulated by cellular stress. Here, we will review current knowledge regarding how ER stress and the unfolded protein response (UPR) induce autophagy, including description of the different autophagy-related genes which are regulated by the UPR.

A novel feedforward compensation canceling input filter-regulator interaction

NASA Technical Reports Server (NTRS)

Kelkar, S. S.; Lee, F. C.

1983-01-01

The interaction between the input and the control loop of switching regulators often results in deterimental effects, such as loop instability, degradation of transient response, and audiosusceptibility, etc. The concept of pole-zero cancelation is employed to mitigate some of these detrimental effects and is implemented using a novel feedforward loop, in addition to existing feedback loops of a buck regulator. Experimental results are presented which show excellent correlation with theory.

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells

PubMed Central

Caballano-Infantes, Estefania; Terron-Bautista, José; Beltrán-Povea, Amparo; Cahuana, Gladys M; Soria, Bernat; Nabil, Hajji; Bedoya, Francisco J; Tejedo, Juan R

2017-01-01

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies. PMID:28289506

Effects of Self-Image on Anxiety, Judgement Bias and Emotion Regulation in Social Anxiety Disorder.

PubMed

Lee, Hannah; Ahn, Jung-Kwang; Kwon, Jung-Hye

2018-04-25

Research to date has focused on the detrimental effects of negative self-images for individuals with social anxiety disorder (SAD), but the benefits of positive self-images have been neglected. The present study examined the effect of holding a positive versus negative self-image in mind on anxiety, judgement bias and emotion regulation (ER) in individuals with SAD. Forty-two individuals who met the diagnostic criteria for SAD were randomly assigned to either a positive or a negative self-image group. Participants were assessed twice with a week's interval in between using the Reactivity and Regulation Situation Task, which measures social anxiety, discomfort, judgement bias and ER, prior to and after the inducement of a positive or negative self-image. Individuals in the positive self-image group reported less social anxiety, discomfort and distress from social cost when compared with their pre-induction state. They also used more adaptive ER strategies and experienced less anxiety and discomfort after using ER. In contrast, individuals in the negative self-image group showed no significant differences in anxiety, judgement bias or ER strategies before and after the induction. This study highlights the beneficial effects of positive self-images on social anxiety and ER.

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells.

PubMed

Caballano-Infantes, Estefania; Terron-Bautista, José; Beltrán-Povea, Amparo; Cahuana, Gladys M; Soria, Bernat; Nabil, Hajji; Bedoya, Francisco J; Tejedo, Juan R

2017-02-26

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca 2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.

A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division

PubMed Central

Manor, Uri; Bartholomew, Sadie; Golani, Gonen; Christenson, Eric; Kozlov, Michael; Higgs, Henry; Spudich, James; Lippincott-Schwartz, Jennifer

2015-01-01

Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction and division. We propose Spire1C cooperates with INF2 to regulate actin assembly at ER-mitochondrial contacts. Simulations support this model's feasibility and demonstrate polymerizing actin filaments can induce mitochondrial constriction. Thus, Spire1C is optimally positioned to serve as a molecular hub that links mitochondria to actin and the ER for regulation of mitochondrial division. DOI: http://dx.doi.org/10.7554/eLife.08828.001 PMID:26305500

A minimal mathematical model combining several regulatory cycles from the budding yeast cell cycle.

PubMed

Sriram, K; Bernot, G; Képès, F

2007-11-01

A novel topology of regulatory networks abstracted from the budding yeast cell cycle is studied by constructing a simple nonlinear model. A ternary positive feedback loop with only positive regulations is constructed with elements that activates the subsequent element in a clockwise fashion. A ternary negative feedback loop with only negative regulations is constructed with the elements that inhibit the subsequent element in an anticlockwise fashion. Positive feedback loop exhibits bistability, whereas the negative feedback loop exhibits limit cycle oscillations. The novelty of the topology is that the corresponding elements in these two homogeneous feedback loops are linked by the binary positive feedback loops with only positive regulations. This results in the emergence of mixed feedback loops in the network that displays complex behaviour like the coexistence of multiple steady states, relaxation oscillations and chaos. Importantly, the arrangement of the feedback loops brings in the notion of checkpoint in the model. The model also exhibits domino-like behaviour, where the limit cycle oscillations take place in a stepwise fashion. As the aforementioned topology is abstracted from the budding yeast cell cycle, the events that govern the cell cycle are considered for the present study. In budding yeast, the sequential activation of the transcription factors, cyclins and their inhibitors form mixed feedback loops. The transcription factors that involve in the positive regulation in a clockwise orientation generates ternary positive feedback loop, while the cyclins and their inhibitors that involve in the negative regulation in an anticlockwise orientation generates ternary negative feedback loop. The mutual regulation between the corresponding elements in the transcription factors and the cyclins and their inhibitors generates binary positive feedback loops. The bifurcation diagram constructed for the whole system can be related to the different events of the cell cycle in terms of dynamical system theory. The checkpoint mechanism that plays an important role in different phases of the cell cycle are accounted for by silencing appropriate feedback loops in the model.

New insights on the functional role of URG7 in the cellular response to ER stress.

PubMed

Armentano, Maria Francesca; Caterino, Marianna; Miglionico, Rocchina; Ostuni, Angela; Pace, Maria Carmela; Cozzolino, Flora; Monti, Maria; Milella, Luigi; Carmosino, Monica; Pucci, Piero; Bisaccia, Faustino

2018-04-28

Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is up-regulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus-infected hepatocytes, URG7 shows an anti-apoptotic activity due to the PI3K/AKT signalling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown. To shed light on URG7 activity, we first analysed its interactome in HepG2 transfected cells: this analysis suggests that URG7 could have a role in affecting protein synthesis, folding and promoting proteins degradation. Moreover, keeping into account its subcellular localisation in the ER and that several viral infections give rise to ER stress, a panel of experiments was performed to evaluate a putative role of URG7 in ER stress. Our main results demonstrate that in ER-stressed cells URG7 is able to modulate the expression of Unfolded Protein Response (UPR) markers towards survival outcomes, up-regulating GRP78 protein and down-regulating the pro-apoptotic protein CHOP. Furthermore, URG7 reduces the ER stress by decreasing the amount of unfolded proteins, by increasing both the total protein ubiquitination and the AKT activation and reducing Caspase 3 activation. All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress-induced apoptosis. This is the first characterisation of URG7 activity under ER stress conditions. The results presented here will help to hypothesise new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection. © 2018 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

Ero1alpha requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM).

PubMed

Gilady, Susanna Y; Bui, Michael; Lynes, Emily M; Benson, Matthew D; Watts, Russell; Vance, Jean E; Simmen, Thomas

2010-09-01

Protein secretion from the endoplasmic reticulum (ER) requires the enzymatic activity of chaperones and oxidoreductases that fold polypeptides and form disulfide bonds within newly synthesized proteins. The best-characterized ER redox relay depends on the transfer of oxidizing equivalents from molecular oxygen through ER oxidoreductin 1 (Ero1) and protein disulfide isomerase to nascent polypeptides. The formation of disulfide bonds is, however, not the sole function of ER oxidoreductases, which are also important regulators of ER calcium homeostasis. Given the role of human Ero1alpha in the regulation of the calcium release by inositol 1,4,5-trisphosphate receptors during the onset of apoptosis, we hypothesized that Ero1alpha may have a redox-sensitive localization to specific domains of the ER. Our results show that within the ER, Ero1alpha is almost exclusively found on the mitochondria-associated membrane (MAM). The localization of Ero1alpha on the MAM is dependent on oxidizing conditions within the ER. Chemical reduction of the ER environment, but not ER stress in general leads to release of Ero1alpha from the MAM. In addition, the correct localization of Ero1alpha to the MAM also requires normoxic conditions, but not ongoing oxidative phosphorylation.

Autonomic regulation in response to stress: The influence of anticipatory emotion regulation strategies and trait rumination.

PubMed

Nasso, Selene; Vanderhasselt, Marie-Anne; Demeyer, Ineke; De Raedt, Rudi

2018-05-21

According to the neurocognitive framework for regulation expectation, adaptively regulating emotions in anticipation of a stressful event should help individuals deal with the stressor itself. The goal of this study was twofold: first, the authors compared the influence of adaptive versus maladaptive anticipatory emotion regulation (ER) on the autonomic system during anticipation of, confrontation with, and recovery from a stressor; second, they explored whether trait rumination moderated this relationship. The authors collected data from 56 healthy female undergraduates during a public speaking task. The task involved 4 phases: baseline, anticipatory ER, stressor, and recovery. Participants were assigned to 1 of 2 anticipatory ER instructions (reappraisal or catastrophizing). Heart rate variability (HRV) indexed autonomic regulation. Results confirmed that HRV was higher in the reappraisal than in the catastrophizing group (over all time points, except for baseline). Trait rumination levels moderated the effect of anticipatory ER strategy on HRV during the stressor phase. Specifically, whereas for low ruminators reappraisal (versus catastrophizing) in the anticipation phase led to higher HRV when confronted to the stressor, high ruminators demonstrated lower HRV in that same condition. To conclude, over all participants, using reappraisal during the anticipation phase allowed participants to better cope with stress. However, only low, but not high ruminators could profit from the beneficial effect of anticipatory reappraisal on autonomic regulation. Even though further research is needed, this study suggests that, in female undergraduates, the tendency to ruminate is associated with abnormal anticipatory ER that might hinder an adaptive response to a stressor. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oh, Yohan; Chung, Kwang Chul, E-mail: kchung@yonsei.ac.kr

Highlights: Black-Right-Pointing-Pointer ZNF131 directly interacts with ER{alpha}. Black-Right-Pointing-Pointer The binding affinity of ZNF131 to ER{alpha} increases upon E2 stimulation. Black-Right-Pointing-Pointer ZNF131 inhibits ER{alpha}-mediated trans-activation by suppressing its homo-dimerization. Black-Right-Pointing-Pointer ZNF131 inhibits ER{alpha}-dimerization and E2-induced breast cancer cell proliferation. Black-Right-Pointing-Pointer ZNF131 inhibits estrogen signaling by acting as an ER{alpha}-co-repressor. -- Abstract: Steroid hormone estrogen elicits various physiological functions, many of which are mediated through two structurally and functionally distinct estrogen receptors, ER{alpha} and ER{beta}. The functional role of zinc finger protein 131 (ZNF131) is poorly understood, but it is assumed to possess transcriptional regulation activity due to the presence of amore » DNA binding motif. A few recent reports, including ours, revealed that ZNF131 acts as a negative regulator of ER{alpha} and that SUMO modification potentiates the negative effect of ZNF131 on estrogen signaling. However, its molecular mechanism for ER{alpha} inhibition has not been elucidated in detail. Here, we demonstrate that ZNF131 directly interacts with ER{alpha}, which consequently inhibits ER{alpha}-mediated trans-activation by suppressing its homo-dimerization. Moreover, we show that the C-terminal region of ZNF131 containing the SUMOylation site is necessary for its inhibition of estrogen signaling. Taken together, these data suggest that ZNF131 inhibits estrogen signaling by acting as an ER{alpha}-co-repressor.« less

Emotion Regulation and Depressive Symptoms: Close Relationships as Social Context and Influence

PubMed Central

Marroquín, Brett; Nolen-Hoeksema, Susan

2015-01-01

Depression is associated with social dysfunction and maladaptive social environments, but mechanisms through which social relationships affect depressive psychopathology are unclear. We hypothesized that emotion regulation (ER) is such a mechanism, with outcomes of individuals’ ER efforts sensitive to the social context, and individuals’ ER strategy repertoire and use sensitive to social influence. In Study 1, a longitudinal study of community adults (N = 1,319), associations of individuals’ ER strategies with depressive symptoms depended on social connectedness and romantic relationship status (social context hypothesis). Moreover, associations of social connectedness and relationship status with symptoms were accounted for by maladaptive ER concurrently and, for social connectedness, prospectively over 1 year (social influence hypothesis). Study 2a, using a national sample (N = 772), replicated and extended these findings with a broader array of ER strategies, and ruled out alternative explanations regarding social skills and psychological wellbeing. Among participants in romantic relationships (Study 2b; N = 558), intimacy and trust buffered associations of maladaptive ER strategies with symptoms (context), and maladaptive and adaptive ER mediated links between relationship variables and symptoms (influence). Findings suggest that close relationships—and variation in underlying relational processes within relationships— influence the ER strategies people use, and also affect whether individuals’ own ER repertoires contribute to depression when deployed. Results elucidate core social mechanisms of ER in terms of both basic processes and depressive psychopathology, suggest ER is a channel through which social factors affect internal functioning and mental health, and inform relationship pathways for clinical intervention. PMID:26479366

Emotion Regulation as a Transdiagnostic Feature Among Eating Disorders: Cross-sectional and Longitudinal Approach.

PubMed

Mallorquí-Bagué, Núria; Vintró-Alcaraz, Cristina; Sánchez, Isabel; Riesco, Nadine; Agüera, Zaida; Granero, Roser; Jiménez-Múrcia, Susana; Menchón, José M; Treasure, Janet; Fernández-Aranda, Fernando

2018-01-01

Emotion regulation (ER) difficulties are observed in eating disorders (EDs). However, few studies have explored ER before and after treatment. The aims are as follows: to explore ER difficulties across ED types and a healthy control (HC) group (Study 1) and to assess pretreatment and post-treatment changes among ED types (Study 2). In Study 1, adult women with EDs (n = 438) and HC (n = 126) completed an assessment including Eating Disorders Inventory-2, Difficulties in Emotion Regulation Scale and Symptom Checklist-90-Revised. Patients in Study 2 (n = 69) were also reassessed after treatment. All ED types reported worse ER compared with HC (p < .001); also, ER differences were found between ED types. Prospective analyses show ER improvements after treatment (p < .001; |d| = 0.51), especially in patients with bulimia nervosa (p < .001; |d| = 1.03; Reliable Change Index = 9.79) with greater improvement in those with a better treatment outcome (p = .034). In conclusion, emotion dysregulation is a part of all forms of EDs. Furthermore, emotional dysregulation can be modified. ED treatments for anorexia nervosa and binge eating disorder might be enhanced by targeting ER skills. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Lipocalin-2 Promotes Endoplasmic Reticulum Stress and Proliferation by Augmenting Intracellular Iron in Human Pulmonary Arterial Smooth Muscle Cells

PubMed Central

Wang, Guoliang; Liu, Shenghua; Wang, Li; Meng, Liukun; Cui, Chuanjue; Zhang, Hao; Hu, Shengshou; Ma, Ning; Wei, Yingjie

2017-01-01

Endoplasmic reticulum (ER) stress, a feature of many conditions associated with pulmonary hypertension (PH), is increasingly recognized as a common response to promote proliferation in the walls of pulmonary arteries. Increased expression of Lipocalin-2 in PH led us to test the hypothesis that Lipocalin-2, a protein known to sequester iron and regulate it intracellularly, might facilitate the ER stress and proliferation in pulmonary arterial smooth muscle cells (PASMCs). In this study, we observed greatly increased Lcn2 expression accompanied with increased ATF6 cleavage in a standard rat model of pulmonary hypertension induced by monocrotaline. In cultured human PASMCs, Lcn2 significantly promoted ER stress (determined by augmented cleavage and nuclear localization of ATF6, up-regulated transcription of GRP78 and NOGO, increased expression of SOD2, and mild augmented mitochondrial membrane potential) and proliferation (assessed by Ki67 staining and BrdU incorporation). Lcn2 promoted ER stress accompanied with augmented intracellular iron levels in human PASMCs. Treatment human PASMCs with FeSO4 induced the similar ER stress and proliferation response and iron chelator (deferoxamine) abrogated the ER stress and proliferation induced by Lcn2 in cultured human PASMCs. In conclusion, Lcn2 significantly promoted human PASMC ER stress and proliferation by augmenting intracellular iron. The up-regulation of Lcn2 probably involved in the pathogenesis and progression of PH. PMID:28255266

Palmitate induces cisternal ER expansion via the activation of XBP-1/CCTα-mediated phospholipid accumulation in RAW 264.7 cells.

PubMed

Kim, Seong Keun; Oh, Eunhye; Yun, Mihee; Lee, Seong-Beom; Chae, Gue Tae

2015-07-16

Endoplasmic reticulum (ER) stress induces ER expansion. The expansion of the intracisternal space of the ER was found in macrophages associated with human atherosclerotic lesions. We also previously reported that palmitate induces cisternal ER expansion and necrosis in RAW 264.7 cells. In this study, we report on an investigation of the likely mechanism responsible for this palmitate-induced cisternal ER expansion in a mouse macrophage cell line, RAW 264.7 cells. RAW 264.7 cells were pre-treated with the designated inhibitor or siRNA, followed by treatment with palmitate. Changes in the ER structure were examined by transmission electron microscopy. The induction of ER stress was confirmed by an increase in the extent of phosphorylation of PERK, the expression of BiP and CHOP, and the splicing of XBP-1 mRNA. Phospholipid staining was performed with the LipidTOX Red phospholipidosis detection reagent. Related gene expressions were detected by quantitative real time-RT-PCR or RT-PCR. Palmitate was found to induce ER stress and cisternal ER expansion. In addition, palmitate-induced cisternal ER expansion was attenuated by ER stress inhibitors, such as 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA). The findings also show that palmitate induced-mRNA expression of CCTα, which increases phospholipid synthesis, was attenuated by the down-regulation of XBP-1, a part of ER stress. Furthermore, palmitate-induced phospholipid accumulation and cisternal ER expansion were attenuated by the down-regulation of XBP-1 or CCTα. The findings reported herein indicate that palmitate-induced cisternal ER expansion is dependent on the activation of XBP-1/CCTα-mediated phospholipid accumulation in RAW 264.7 cells.

Integrating emotion regulation and emotional intelligence traditions: a meta-analysis

PubMed Central

Peña-Sarrionandia, Ainize; Mikolajczak, Moïra; Gross, James J.

2015-01-01

Two relatively independent research traditions have developed that address emotion management. The first is the emotion regulation (ER) tradition, which focuses on the processes which permit individuals to influence which emotions they have, when they have them, and how they experience and express these emotions. The second is the emotional intelligence (EI) tradition, which focuses—among other things—on individual differences in ER. To integrate these two traditions, we employed the process model of ER (Gross, 1998b) to review the literature on EI. Two key findings emerged. First, high EI individuals shape their emotions from the earliest possible point in the emotion trajectory and have many strategies at their disposal. Second, high EI individuals regulate their emotions successfully when necessary but they do so flexibly, thereby leaving room for emotions to emerge. We argue that ER and EI traditions stand to benefit substantially from greater integration. PMID:25759676

Endoplasmic Reticulum - Plasma Membrane Crosstalk Mediated by the Extended Synaptotagmins.

PubMed

Saheki, Yasunori

2017-01-01

The endoplasmic reticulum (ER) possesses multiplicity of functions including protein synthesis, membrane lipid biogenesis, and Ca 2+ storage and has broad localization throughout the cell. While the ER and most other membranous organelles are highly interconnected via vesicular traffic that relies on membrane budding and fusion reactions, the ER forms direct contacts with virtually all other membranous organelles, including the plasma membrane (PM), without membrane fusion. Growing evidence suggests that these contacts play major roles in cellular physiology, including the regulation of Ca 2+ homeostasis and signaling and control of cellular lipid homeostasis. Extended synaptotagmins (E-Syts) are evolutionarily conserved family of ER-anchored proteins that tether the ER to the PM in PM PI(4,5)P 2 -dependent and cytosolic Ca 2+ -regulated manner. In addition, E-Syts possess a cytosolically exposed lipid-harboring module that confers the ability to transfer/exchange glycerolipids between the ER and the PM at E-Syts-mediated ER-PM contacts. In this chapter, the functions of ER-PM contacts and their role in non-vesicular lipid transport with special emphasis on the crosstalk between the two bilayers mediated by E-Syts will be discussed.

Frequency dependent polarisation switching in h-ErMnO3

NASA Astrophysics Data System (ADS)

Ruff, Alexander; Li, Ziyu; Loidl, Alois; Schaab, Jakob; Fiebig, Manfred; Cano, Andres; Yan, Zewu; Bourret, Edith; Glaum, Julia; Meier, Dennis; Krohns, Stephan

2018-04-01

We report an electric-field poling study of the geometrically-driven improper ferroelectric h-ErMnO3. From a detailed dielectric analysis, we deduce the temperature and the frequency dependent range for which single-crystalline h-ErMnO3 exhibits purely intrinsic dielectric behaviour, i.e., free from the extrinsic so-called Maxwell-Wagner polarisations that arise, for example, from surface barrier layers. In this regime, ferroelectric hysteresis loops as a function of frequency, temperature, and applied electric fields are measured, revealing the theoretically predicted saturation polarisation on the order of 5-6 μC/cm2. Special emphasis is put on frequency dependent polarisation switching, which is explained in terms of domain-wall movement similar to proper ferroelectrics. Controlling the domain walls via electric fields brings us an important step closer to their utilization in domain-wall-based electronics.

Slow Magnetic Relaxation and Single-Molecule Toroidal Behaviour in a Family of Heptanuclear {CrIII LnIII6 } (Ln=Tb, Ho, Er) Complexes.

PubMed

Vignesh, Kuduva R; Langley, Stuart K; Swain, Abinash; Moubaraki, Boujemaa; Damjanović, Marko; Wernsdorfer, Wolfgang; Rajaraman, Gopalan; Murray, Keith S

2018-01-15

The synthesis, magnetic properties, and theoretical studies of three heterometallic {Cr III Ln III 6 } (Ln=Tb, Ho, Er) complexes, each containing a metal topology consisting of two Ln 3 triangles connected via a Cr III linker, are reported. The {CrTb 6 } and {CrEr 6 } analogues display slow relaxation of magnetization in a 3000 Oe static magnetic field. Single-crystal measurements reveal opening up of the hysteresis loop for {CrTb 6 } and {CrHo 6 } molecules at low temperatures. Ab initio calculations predict toroidal magnetic moments in the two Ln 3 triangles, which are found to couple, stabilizing a con-rotating ferrotoroidal ground state in Tb and Ho examples and extend the possibility of observing toroidal behaviour in non Dy III complexes for the first time. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Longitudinal Associations of Parental Emotion Socialization and Children's Emotion Regulation: The Moderating Role of ADHD Symptomatology.

PubMed

Breaux, Rosanna P; McQuade, Julia D; Harvey, Elizabeth A; Zakarian, Rebecca J

2018-05-01

Theory and research suggest that parents' reactions to children's emotions play a critical role in teaching children effective emotion regulation (ER) skills, but no studies have directly examined the role that parent emotion socialization plays in the development of ER in children with ADHD. Gaining insight into the causes of impaired ER, particularly in youth with ADHD who are known to have poor ER, has important theoretical and translational significance. The present study is the first to longitudinally examine whether emotion socialization predicts later physiological and adult-reported measures of ER in children with and without ADHD. It also sought to determine if these relations are moderated by ADHD symptoms. Participants were 61 children (31 girls, 30 boys; M = 10.67 years, SD = 1.28) with and without clinically significant ADHD symptoms. At Time 1, parent reports of emotion socialization and parent- and teacher-report of child ADHD symptoms were collected. At Time 2, child ER measures were collected based on parent- and teacher-report and physiological reactivity during an impossible puzzle and a social rejection task. Physiological measures included respiratory sinus arrhythmia and skin conductance level (SCL). Supportive parenting practices were associated with better parent-rated emotion regulation skills for all children and greater SCL reactivity for children with high ADHD symptoms. Non-supportive parenting reactions were associated with greater adult-rated emotional lability for children with high ADHD symptoms. Results highlight the importance of considering multiple aspects of ER, including physiological manifestations. Findings suggest that parents' use of adaptive emotion socialization practices may serve as a protective factor for children's ER development and may be particularly critical for youth with ADHD. Our findings support the use of interventions addressing parent emotion socialization to help foster better ER in children.

Inhibition of Nogo-B promotes cardiac hypertrophy via endoplasmic reticulum stress.

PubMed

Li, Junli; Wu, Wenchao; Xin, Yanguo; Zhao, Mingyue; Liu, Xiaojing

2018-05-14

Nogo-B is a key endoplasmic reticulum (ER) protein that regulates ER stress signaling. However, its role in cardiac hypertrophy remains poorly understood. ER stress is interrelated with autophagy in the process of cardiac hypertrophy. Therefore, we aimed to test the hypothesis that both ER stress and autophagy signaling mediate the function of Nogo-B in cardiac hypertrophy. Rat models of transverse aortic constriction (TAC), neonatal rat cardiomyocytes (NRCMs) stimulated with norepinephrine (Ne) and primary cardiac fibroblasts treated with transforming growth factor β1 (TGF-β1) were used in this study. The expression of Nogo-B and markers of ER stress were determined by quantitative RT-PCR, western blotting and immunofluorescence. Autophagy was measured by monitoring autophagic flux. Specific small interfering RNA (siRNA) of Nogo-B was transfected to investigate the role of Nogo-B in regulating cardiac hypertrophy. In TAC-induced hypertrophic heart tissues, Ne-treated hypertrophic cardiomyocytes and TGF-β1-stimulated cardiac fibroblasts, the expression of Nogo-B, and markers of ER stress were significantly elevated. Impairment of autophagic flux was observed in the activated cardiac fibroblasts. Down-regulation of Nogo-B by siRNA further exacerbated Ne-induced cardiomyocyte hypertrophy and TGF-β1-induced cardiac fibroblast activation. Gene silencing of Nogo-B promoted the activation of the ER stress pathway and the impairment of autophagic flux. Moreover, inhibition of Nogo-B activated the protein kinase RNA-like ER kinase (PERK)/activating transcriptional factor 4 (ATF4) and activating transcriptional factor 6 (ATF6) branches of ER stress pathways. These findings suggest that inhibition of Nogo-B promotes cardiomyocyte hypertrophy and cardiac fibroblast activation by activating the PERK/ATF4 signaling pathway and defects of autophagic flux. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Taurine ameliorated homocysteine-induced H9C2 cardiomyocyte apoptosis by modulating endoplasmic reticulum stress.

PubMed

Zhang, Zhimin; Zhao, Lianyou; Zhou, Yanfen; Lu, Xuanhao; Wang, Zhengqiang; Wang, Jipeng; Li, Wei

2017-05-01

Homocysteine (Hcy)-triggered endoplasmic reticulum (ER) stress-mediated endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury. However, whether ER stress is the molecular mechanism linking Hcy and cardiomyocytes death is unclear. Taurine has been reported to exert cardioprotective effects via various mechanisms. However, whether taurine protects against Hcy-induced cardiomyocyte death by attenuating ER stress is unknown. This study aimed to evaluate the opposite effects of taurine on Hcy-induced cardiomyocyte apoptosis and their underlying mechanisms. Our results demonstrated that low-dose or short-term Hcy treatment increased the expression of glucose-regulated protein 78 (GRP78) and activated protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), which in turn prevented apoptotic cell death. High-dose Hcy or prolonged Hcy treatment duration significantly up-regulated levels of C/EBP homologous protein (CHOP), cleaved caspase-12, p-c-Jun N-terminal kinase (JNK), and then triggered apoptotic events. High-dose Hcy also resulted in a decrease in mitochondrial membrane potential (Δψm) and an increase in cytoplasmic cytochrome C and the expression of cleaved caspase-9. Pretreatment of cardiomyocytes with sodium 4-phenylbutyric acid (an ER stress inhibitor) significantly inhibited Hcy-induced apoptosis. Furthermore, blocking the PERK pathway partly alleviated Hcy-induced ER stress-modulated cardiomyocyte apoptosis, and down-regulated the levels of Bax and cleaved caspase-3. Experimental taurine pretreatment inhibited the expression of ER stress-related proteins, and protected against apoptotic events triggered by Hcy-induced ER stress. Taken together, our results suggest that Hcy triggered ER stress in cardiomyocytes, which was the crucial molecular mechanism mediating Hcy-induced cardiomyocyte apoptosis, and the adverse effect of Hcy could be prevented by taurine.

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

PubMed

Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S; Bowden, Michaela; Rao, Prakash; Long, Henry W; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

2017-05-30

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

PubMed Central

Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S.; Bowden, Michaela; Rao, Prakash; Long, Henry W.; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

2017-01-01

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2–ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists. PMID:28507152

Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases.

PubMed

Martin-Jiménez, Cynthia A; García-Vega, Ángela; Cabezas, Ricardo; Aliev, Gjumrakch; Echeverria, Valentina; González, Janneth; Barreto, George E

2017-11-01

Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis. However, the exact contributions to the effects of ER stress in astrocytes in the various neurodegenerative diseases and its relation with obesity are not well known. Here, we discuss recent advances in the understanding of molecular mechanisms that regulate ER stress-related disorders in astrocytes such as obesity and neurodegeneration. Moreover, we outline the correlation between the activated proteins of the unfolded protein response (UPR) in these pathological conditions in order to identify possible therapeutic targets for ER stress in astrocytes. We show that ER stress in astrocytes shares UPR activation pathways during both obesity and neurodegenerative diseases, demonstrating that UPR related proteins like ER chaperone GRP 78/Bip, PERK pathway and other exogenous molecules ameliorate UPR response and promote neuroprotection. Copyright © 2017 Elsevier Ltd. All rights reserved.

34 CFR Appendix A to Subpart C of... - Grants for Access and Persistence Program (GAP) State Grant Allotment Case Study

Code of Federal Regulations, 2010 CFR

2010-07-01

... 34 Education 3 2010-07-01 2010-07-01 false Grants for Access and Persistence Program (GAP) State Grant Allotment Case Study A Appendix A to Subpart C of Part 692 Education Regulations of the Offices of...) State Grant Allotment Case Study ER29OC09.010 ER29OC09.011 ER29OC09.012 ER29OC09.013 ER29OC09.014...

Evaluating the potential bioactivity of a novel compound ER1626.

PubMed

Wang, Lijun; Zeng, Yanyan; Wang, Tianling; Liu, Hongyi; Xiao, Hong; Xiang, Hua

2014-01-01

ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626. MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and chicken embryos. The expression of estrogen receptor protein was investigated with western-blot analysis. ER1626 down-regulated the expression of estrogen receptor α protein and up-regulated β protein in MCF-7 and Ishikawa cells. The value of IC50 of ER1626 on MCF-7 and Ishikawa cells were respectively 8.52 and 3.08 µmol/L. Meanwhile, ER1626 decreased VEGF secretion of MCF-7 and Ishikawa cells, disturbed the formation of VEGF-stimulated tubular structure in HUVEC cells, and inhibited the angiogenesis on the chicken chorioallantoic membrane. Scratch assay revealed that ER1626 suppressed the migration of MCF-7, Ishikawa and HUVEC cells. In addition to induction tumor cell apoptosis, ER1626 arrested cell cycle in G1/G0 phase in MCF-7 cells and G2/M phase in Ishikawa cells. In conclusion, our results demonstrated that ER1626 has favorable bioactivities to be a potential candidate against breast cancer and angiogenesis.

40 CFR 86.1360-2007 - Supplemental emission test; test cycle and procedures.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) * (MZ-MRS) / (MTU-MRS) ETU = ET + (EU-ET) * (nZ-nRT) / (nSU-nRT) ERS = ER + (ES-ER) * (nZ-nRT) / (nSU-n..., ET, EU = for each regulated pollutant, brake specific gaseous emissions of the enveloping modes...

Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.

PubMed

Terrill, Philip I; Edwards, Bradley A; Nemati, Shamim; Butler, James P; Owens, Robert L; Eckert, Danny J; White, David P; Malhotra, Atul; Wellman, Andrew; Sands, Scott A

2015-02-01

Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p<0.001), detected the known reduction in loop gain with oxygen (n=11; mean±sem change in loop gain (ΔLG) -0.23±0.08, p=0.02) and acetazolamide (n=11; ΔLG -0.20±0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control. Copyright ©ERS 2015.

ER-mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem-like cells.

PubMed

Bassoy, Esen Yonca; Kasahara, Atsuko; Chiusolo, Valentina; Jacquemin, Guillaume; Boydell, Emma; Zamorano, Sebastian; Riccadonna, Cristina; Pellegatta, Serena; Hulo, Nicolas; Dutoit, Valérie; Derouazi, Madiha; Dietrich, Pierre Yves; Walker, Paul R; Martinvalet, Denis

2017-06-01

Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. © 2017 The Authors.

Creatine phosphate disodium salt protects against Dox-induced cardiotoxicity by increasing calumenin.

PubMed

Wang, Yu; Sun, Ying; Guo, Xin; Fu, Yao; Long, Jie; Wei, Cheng-Xi; Zhao, Ming

2018-06-01

Inhibiting endoplasmic reticulum stress (ERS)-induced apoptosis may be a new therapeutic target in cardiovascular diseases. Creatine phosphate disodium salt (CP) has been reported to have cardiovascular protective effect, but its effects on ERS are unknown. The aim of this study was to identify the mechanism by which CP exerts its cardioprotection in doxorubicin (Dox)-induced cardiomyocytes injury. In our study, neonatal rats cardiomyocytes (NRC) was randomly divided into control group, model group, and treatment group. The cell viability and apoptosis were detected. grp78, grp94, and calumenin of the each group were monitored. To investigate the role of calumenin, Dox-induced ERS was compared in control and down-regulated calumenin cardiomyocytes. Our results showed that CP decreased Dox-induced apoptosis and relieved ERS. We found calumenin increased in Dox-induced apoptosis with CP. ERS effector C/EBP homologous protein was down-regulated by CP and it was influenced by calumenin. CP could protect NRC by inhibiting ERS, this mechanisms may be associated with its increasing of calumenin.

Impaired down-regulation of negative emotion in self-referent social situations in bipolar disorder: A pilot study of a novel experimental paradigm.

PubMed

Kjærstad, Hanne L; Vinberg, Maj; Goldin, Philippe R; Køster, Nicolai; Støttrup, Mette Marie D; Knorr, Ulla; Kessing, Lars V; Miskowiak, Kamilla W

2016-04-30

Emotion dysregulation is a core feature of bipolar disorder (BD) that persists into periods of remission. Neuroimaging studies show aberrant neural responses during emotion regulation (ER) in patients with BD relative to healthy controls, but behavioural evidence for ER deficits is sparse and conflicting. This study aimed to explore ER in BD using a novel, personally relevant experimental paradigm. Twenty patients with BD and 20 patients with unipolar disorder (UD), in full or partial remission, and 20 healthy controls were given a novel computerised test. Participants were instructed to react naturally or dampen their emotional response to positive and negative social scenarios and associated self-beliefs. They were also given an established experimental task for comparison, involving reappraisal of negative affective picture stimuli, as well as a questionnaire of habitual ER strategies. BD patients showed reduced ability to down-regulate emotional responses in negative, but not positive, social scenarios relative to healthy controls and UD patients. In contrast, there were no between-group differences in the established ER task or in self-reported habitual reappraisal strategies. Findings highlight the novel social scenario paradigm as a sensitive test for detection of ER difficulties in BD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Eucommia ulmoides Oliver Extract, Aucubin, and Geniposide Enhance Lysosomal Activity to Regulate ER Stress and Hepatic Lipid Accumulation

PubMed Central

Lee, Hwa-Young; Lee, Geum-Hwa; Lee, Mi-Rin; Kim, Hye-Kyung; Kim, Nan-young; Kim, Seung-Hyun; Lee, Yong-Chul; Kim, Hyung-Ryong; Chae, Han-Jung

2013-01-01

Eucommia ulmoides Oliver is a natural product widely used as a dietary supplement and medicinal plant. Here, we examined the potential regulatory effects of Eucommia ulmoides Oliver extracts (EUE) on hepatic dyslipidemia and its related mechanisms by in vitro and in vivo studies. EUE and its two active constituents, aucubin and geniposide, inhibited palmitate-induced endoplasmic reticulum (ER) stress, reducing hepatic lipid accumulation through secretion of apolipoprotein B and associated triglycerides and cholesterol in human HepG2 hepatocytes. To determine how EUE diminishes the ER stress response, lysosomal and proteasomal protein degradation activities were analyzed. Although proteasomal activity was not affected, lysosomal enzyme activities including V-ATPase were significantly increased by EUE as well as aucubin and geniposide in HepG2 cells. Treatment with the V-ATPase inhibitor, bafilomycin, reversed the inhibition of ER stress, secretion of apolipoprotein B, and hepatic lipid accumulation induced by EUE or its component, aucubin or geniposide. In addition, EUE was determined to regulate hepatic dyslipidemia by enhancing lysosomal activity and to regulate ER stress in rats fed a high-fat diet. Together, these results suggest that EUE and its active components enhance lysosomal activity, resulting in decreased ER stress and hepatic dyslipidemia. PMID:24349058

Up-regulation of K{sub ir}2.1 by ER stress facilitates cell death of brain capillary endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kito, Hiroaki; Yamazaki, Daiju; Department of Biological Chemistry, Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto

Highlights: {yields} We found that application of endoplasmic reticulum (ER) stress with tunicamycin to brain capillary endothelial cells (BCECs) induced cell death. {yields} The ER stress facilitated the expression of inward rectifier K{sup +} channel (K{sub ir}2.1) and induced sustained membrane hyperpolarization. {yields} The membrane hyperpolarization induced sustained Ca{sup 2+} entry through voltage-independent nonspecific cation channels and consequently facilitated cell death. {yields} The K{sub ir}2.1 up-regulation by ER stress is, at least in part, responsible for cell death of BCECs under pathological conditions. -- Abstract: Brain capillary endothelial cells (BCECs) form blood brain barrier (BBB) to maintain brain homeostasis. Cellmore » turnover of BCECs by the balance of cell proliferation and cell death is critical for maintaining the integrity of BBB. Here we found that stimuli with tunicamycin, endoplasmic reticulum (ER) stress inducer, up-regulated inward rectifier K{sup +} channel (K{sub ir}2.1) and facilitated cell death in t-BBEC117, a cell line derived from bovine BCECs. The activation of K{sub ir} channels contributed to the establishment of deeply negative resting membrane potential in t-BBEC117. The deep resting membrane potential increased the resting intracellular Ca{sup 2+} concentration due to Ca{sup 2+} influx through non-selective cation channels and thereby partly but significantly regulated cell death in t-BBEC117. The present results suggest that the up-regulation of K{sub ir}2.1 is, at least in part, responsible for cell death/cell turnover of BCECs induced by a variety of cellular stresses, particularly ER stress, under pathological conditions.« less

An emotion regulation intervention to reduce risk behaviors among at-risk early adolescents

PubMed Central

Houck, Christopher D.; Hadley, Wendy; Barker, David; Brown, Larry K.; Hancock, Evan; Almy, Brandon

2015-01-01

This study aimed to evaluate an intervention designed to enhance early adolescents’ emotion regulation skill use and to decrease risk behaviors. Adolescents 12 to 14 years old (N = 420; 53% male) with mental health symptoms were referred for participation in either an Emotion Regulation (ER) or Health Promotion (HP) intervention consisting of twelve after-school sessions. Participants completed baseline and follow-up questionnaires on laptop computers. Using a generalized analysis of covariance controlling for baseline scores, participants in the ER intervention were less likely to be sexually active and engage in other risk behaviors, such as fighting, at the conclusion of the program. Additionally, participants in the ER intervention reported greater use of emotion regulation strategies and more favorable attitudes toward abstinence. Interventions directly targeting emotion regulation may be useful in addressing health risk behaviors of adolescents with mental health symptoms. PMID:26297499

Dissecting and engineering of the TetR family regulator SACE_7301 for enhanced erythromycin production in Saccharopolyspora erythraea.

PubMed

Wu, Hang; Chen, Meng; Mao, Yongrong; Li, Weiwei; Liu, Jingtao; Huang, Xunduan; Zhou, Ying; Ye, Bang-Ce; Zhang, Lixin; Weaver, David T; Zhang, Buchang

2014-11-13

Saccharopolyspora erythraea was extensively utilized for the industrial-scale production of erythromycin A (Er-A), a macrolide antibiotic commonly used in human medicine. Yet, S. erythraea lacks regulatory genes in the erythromycin biosynthetic gene (ery) cluster, hampering efforts to enhance Er-A production via the engineering of regulatory genes. By the chromosome gene inactivation technique based on homologous recombination with linearized DNA fragments, we have inactivated a number of candidate TetR family transcriptional regulators (TFRs) and identified one TFR (SACE_7301) positively controlling erythromycin biosynthesis in S. erythraea A226. qRT-PCR and EMSA analyses demonstrated that SACE_7301 activated the transcription of erythromycin biosynthetic gene eryAI and the resistance gene ermE by interacting with their promoter regions with low affinities, similar to BldD (SACE_2077) previously identified to regulate erythromycin biosynthesis and morphological differentiation. Therefore, we designed a strategy for overexpressing SACE_7301 with 1 to 3 extra copies under the control of PermE* in A226. Following up-regulated transcriptional expression of SACE_7301, eryAI and ermE, the SACE_7301-overexpressed strains all increased Er-A production over A226 proportional to the number of copies. Likewise, when SACE_7301 was overexpressed in an industrial S. erythraea WB strain, Er-A yields of the mutants WB/7301, WB/2×7301 and WB/3×7301 were respectively increased by 17%, 29% and 42% relative to that of WB. In a 5 L fermentor, Er-A accumulation increased to 4,230 mg/L with the highest-yield strain WB/3×7301, an approximately 27% production improvement over WB (3,322 mg/L). We have identified and characterized a TFR, SACE_7301, in S. erythraea that positively regulated erythromycin biosynthesis, and overexpression of SACE_7301 in wild-type and industrial S. erythraea strains enhanced Er-A yields. This study markedly improves our understanding of the unusual regulatory mechanism of erythromycin biosynthesis, and provides a novel strategy towards Er-A overproduction by engineering transcriptional regulators of S. erythraea.

Homeobox A7 stimulates breast cancer cell proliferation by up-regulating estrogen receptor-alpha

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yu; Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4; Cheng, Jung-Chien

2013-11-01

Highlights: •HOXA7 regulates MCF7 cell proliferation. •HOXA7 up-regulates ERα expression. •HOXA7 mediates estrogen-induced MCF7 cell proliferation. -- Abstract: Breast cancer is the most common hormone-dependent malignancy in women. Homeobox (HOX) transcription factors regulate many cellular functions, including cell migration, proliferation and differentiation. The aberrant expression of HOX genes has been reported to be associated with human reproductive cancers. Estradiol (E2) and its nuclear receptors, estrogen receptor (ER)-alpha and ER-beta, are known to play critical roles in the regulation of breast cancer cell growth. However, an understanding of the potential relationship between HOXA7 and ER in breast cancer cells is limited.more » In this study, our results demonstrate that knockdown of HOXA7 in MCF7 cells significantly decreased cell proliferation and ERα expression. In addition, HOXA7 knockdown attenuated E2-induced cell proliferation as well as progesterone receptor (PR) expression. The stimulatory effects of E2 on cell proliferation and PR expression were abolished by co-treatment with ICI 182780, a selective ERα antagonist. In contrast, overexpression of HOXA7 significantly stimulated cell proliferation and ERα expression. Moreover, E2-induced cell proliferation, as well as PR expression, was enhanced by the overexpression of HOXA7. Neither knockdown nor overexpression of HOXA7 affected the ER-beta levels. Our results demonstrate a novel mechanistic role for HOXA7 in modulating breast cancer cell proliferation via regulation of ERα expression. This finding contributes to our understanding of the role HOXA7 plays in regulating the proliferation of ER-positive cancer cells.« less

Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me–induced apoptosis in breast cancer cells

PubMed Central

Lee, A Reum; Yoon, Mi Jin; Cho, Hyeseong; Lee, Jong-Soo; Choi, Kyeong Sook

2015-01-01

The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me–induced increases in intracellular Ca2+ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca2+ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIPL (cellular FLICE-inhibitory protein) and overexpression of c-FLIPL blocked CDDO-Me–induced cell death, but not vacuolation. These results suggest that c-FLIPL downregulation is a key contributor to CDDO-Me–induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca2+ influx and ROS generation as well as caspase activation via c-FLIPL downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells. PMID:26053096

Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me-induced apoptosis in breast cancer cells.

PubMed

Jeong, Soo Ah; Kim, In Young; Lee, A Reum; Yoon, Mi Jin; Cho, Hyeseong; Lee, Jong-Soo; Choi, Kyeong Sook

2015-08-28

The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me-induced increases in intracellular Ca2+ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca2+ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIPL (cellular FLICE-inhibitory protein) and overexpression of c-FLIPL blocked CDDO-Me-induced cell death, but not vacuolation. These results suggest that c-FLIPL downregulation is a key contributor to CDDO-Me-induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca2+ influx and ROS generation as well as caspase activation via c-FLIPL downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells.

48 CFR 53.301-1423 - Inventory Verification Survey.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Inventory Verification Survey. 53.301-1423 Section 53.301-1423 Federal Acquisition Regulations System FEDERAL ACQUISITION... Survey. ER05AP04.000 [69 FR 17752, Apr. 5, 2004] ER02JA97.015 [62 FR 249, Jan. 2, 1997] ...

Brief Report: Emotion Regulation and Respiratory Sinus Arrhythmia in Autism Spectrum Disorder

ERIC Educational Resources Information Center

Guy, Lisa; Souders, Margaret; Bradstreet, Lauren; DeLussey, Christine; Herrington, John D.

2014-01-01

Emotion regulation (ER) may be an important transdiagnostic factor for understanding mental and behavioral health given its association with several psychiatric disorders, including autism spectrum disorder (ASD). However, there is limited research on ER in ASD, particularly using biomarkers such as respiratory sinus arrhythmia (RSA). The aim of…

48 CFR 53.302-312 - Small Disadvantaged Business (SDB) Participation Report.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 2 2013-10-01 2013-10-01 false Small Disadvantaged Business (SDB) Participation Report. 53.302-312 Section 53.302-312 Federal Acquisition Regulations System... Disadvantaged Business (SDB) Participation Report. ER26JY00.003 ER26JY00.004 [65 FR 46062, July 26, 2000] ...

48 CFR 53.302-312 - Small Disadvantaged Business (SDB) Participation Report.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 2 2012-10-01 2012-10-01 false Small Disadvantaged Business (SDB) Participation Report. 53.302-312 Section 53.302-312 Federal Acquisition Regulations System... Disadvantaged Business (SDB) Participation Report. ER26JY00.003 ER26JY00.004 [65 FR 46062, July 26, 2000] ...

48 CFR 53.302-312 - Small Disadvantaged Business (SDB) Participation Report.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 false Small Disadvantaged Business (SDB) Participation Report. 53.302-312 Section 53.302-312 Federal Acquisition Regulations System... Disadvantaged Business (SDB) Participation Report. ER26JY00.003 ER26JY00.004 [65 FR 46062, July 26, 2000] ...

48 CFR 53.302-312 - Small Disadvantaged Business (SDB) Participation Report.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 2 2014-10-01 2014-10-01 false Small Disadvantaged Business (SDB) Participation Report. 53.302-312 Section 53.302-312 Federal Acquisition Regulations System... Disadvantaged Business (SDB) Participation Report. ER26JY00.003 ER26JY00.004 [65 FR 46062, July 26, 2000] ...

48 CFR 53.302-312 - Small Disadvantaged Business (SDB) Participation Report.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Small Disadvantaged Business (SDB) Participation Report. 53.302-312 Section 53.302-312 Federal Acquisition Regulations System... Disadvantaged Business (SDB) Participation Report. ER26JY00.003 ER26JY00.004 [65 FR 46062, July 26, 2000] ...

The Role of the Family Context in the Development of Emotion Regulation

ERIC Educational Resources Information Center

Morris, Amanda Sheffield; Silk, Jennifer S.; Steinberg, Laurence; Myers, Sonya S.; Robinson, Lara Rachel

2007-01-01

This article reviews current literature examining associations between components of the family context and children and adolescents' emotion regulation (ER). The review is organized around a tripartite model of familial influence. Firstly, it is posited that children learn about ER through observational learning, modeling and social referencing.…

Dynamic Regulation of FoxA1 by Steroid Receptors | Center for Cancer Research

Cancer.gov

The estrogen receptor (ER) is a key regulator in breast cancer initiation and progression. A widely discussed model proposes that forkhead box protein A1 (FoxA1) acts as a pioneer factor in cancer by binding and penetrating closed chromatin to allow access by transcription factors (TFs), including ER.

ICI 182,780 has agonistic effects and synergizes with estradiol-17 beta in fish liver, but not in testis.

PubMed

Pinto, Patrícia I S; Singh, Pratap B; Condeça, João B; Teodósio, Helena R; Power, Deborah M; Canário, Adelino V M

2006-12-27

ICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species. In the present study, the effects and mechanism of action of ICI were investigated in the teleost fish, sea bream (Sparus auratus). Three independent in vivo experiments were performed in which mature male tilapia (Oreochromis mossambicus) or sea bream received intra-peritoneal implants containing estradiol-17 beta (E2), ICI or a combination of both compounds. The effects of E2 and ICI on plasma calcium levels were measured and hepatic and testicular gene expression of the three ER subtypes, ER alpha, ER beta a and ER beta b, and the estrogen-responsive genes, vitellogenin II and choriogenin L, were analyzed by semi-quantitative RT-PCR in sea bream. E2 treatment caused an increase in calcium levels in tilapia, while ICI alone had no noticeable effect, as expected. However, pretreatment with ICI synergistically potentiated the effect of E2 on plasma calcium in both species. ICI mimicked some E2 actions in gene expression in sea bream liver upregulating ER alpha, vitellogenin II and choriogenin L, although, unlike E2, it did not downregulate ER beta a and ER beta b. In contrast, no effects of E2 or ICI alone were detected in the expression of ERs in testis, while vitellogenin II and choriogenin L were upregulated by E2 but not ICI. Finally, pretreatment with ICI had a synergistic effect on the hepatic E2 down-regulation of ER beta b, but apparently blocked the ER alpha up-regulation by E2. These results demonstrate that ICI has agonistic effects on several typical estrogenic responses in fish, but its actions are tissue-specific. The mechanisms for the ICI agonistic activity are still unknown; although the ICI induced up-regulation of ER alpha mRNA could be one of the factors contributing to the cellular response.

ICI 182,780 has agonistic effects and synergizes with estradiol-17 beta in fish liver, but not in testis

PubMed Central

Pinto, Patrícia IS; Singh, Pratap B; Condeça, João B; Teodósio, Helena R; Power, Deborah M; Canário, Adelino VM

2006-01-01

Background ICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species. In the present study, the effects and mechanism of action of ICI were investigated in the teleost fish, sea bream (Sparus auratus). Methods Three independent in vivo experiments were performed in which mature male tilapia (Oreochromis mossambicus) or sea bream received intra-peritoneal implants containing estradiol-17 beta (E2), ICI or a combination of both compounds. The effects of E2 and ICI on plasma calcium levels were measured and hepatic and testicular gene expression of the three ER subtypes, ER alpha, ER beta a and ER beta b, and the estrogen-responsive genes, vitellogenin II and choriogenin L, were analyzed by semi-quantitative RT-PCR in sea bream. Results E2 treatment caused an increase in calcium levels in tilapia, while ICI alone had no noticeable effect, as expected. However, pretreatment with ICI synergistically potentiated the effect of E2 on plasma calcium in both species. ICI mimicked some E2 actions in gene expression in sea bream liver upregulating ER alpha, vitellogenin II and choriogenin L, although, unlike E2, it did not downregulate ER beta a and ER beta b. In contrast, no effects of E2 or ICI alone were detected in the expression of ERs in testis, while vitellogenin II and choriogenin L were upregulated by E2 but not ICI. Finally, pretreatment with ICI had a synergistic effect on the hepatic E2 down-regulation of ER beta b, but apparently blocked the ER alpha up-regulation by E2. Conclusion These results demonstrate that ICI has agonistic effects on several typical estrogenic responses in fish, but its actions are tissue-specific. The mechanisms for the ICI agonistic activity are still unknown; although the ICI induced up-regulation of ER alpha mRNA could be one of the factors contributing to the cellular response. PMID:17192186

Roles for Ca2+ mobilization and its regulation in mast cell functions: recent progress.

PubMed

Holowka, David; Wilkes, Marcus; Stefan, Christopher; Baird, Barbara

2016-04-15

Ca(2+)mobilization in response to cross-linking of IgE bound to its high affinity receptor, FcεRI, on mast cells is central to immune allergic responses. Stimulated tyrosine phosphorylation caused by this cross-linking activates store-operated Ca(2+)entry that results in sustained Ca(2+)oscillations dependent on Rho family GTPases and phosphoinositide synthesis. Coupling of the endoplasmic reticulum (ER) Ca(2+)sensor, stromal interaction molecule 1 (STIM1), to the Ca(2+)-selective channel, Orai1, is regulated by these elements and depends on membrane organization, both at the plasma membrane and at the ER. Mitochondria also contribute to the regulation of Ca(2+)mobilization, and we describe recent evidence that the ER membrane protein vesicle-associated membrane protein-associated protein (VAP) plays a significant role in the coupling between ER and mitochondria in this process. In addition to granule exocytosis, Ca(2+)mobilization in these cells also contributes to stimulated outward trafficking of recycling endosomes and to antigen-stimulated chemotaxis, and it is pathologically regulated by protozoan parasitic invasion. © 2016 Authors; published by Portland Press Limited.

Generation of ER{alpha}-floxed and knockout mice using the Cre/LoxP system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Antonson, P., E-mail: per.antonson@ki.se; Omoto, Y.; Humire, P.

2012-08-10

Highlights: Black-Right-Pointing-Pointer ER{alpha} floxed and knockout mice were generated. Black-Right-Pointing-Pointer Disruption of the ER{alpha} gene results in sterility in both male and female mice. Black-Right-Pointing-Pointer ER{alpha}{sup -/-} mice have ovaries with hemorrhagic follicles and hypoplastic uterus. Black-Right-Pointing-Pointer Female ER{alpha}{sup -/-} mice develop obesity. -- Abstract: Estrogen receptor alpha (ER{alpha}) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a floxed ER{alpha} mouse line that can be used to knock out ER{alpha} in selected tissues by using the Cre/LoxP system. In this study, we established amore » new ER{alpha} knockout mouse line by crossing the floxed ER{alpha} mice with Cre deleter mice. Here we show that genetic disruption of the ER{alpha} gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4 months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ER{alpha} is necessary for reproductive tract development and has important functions as a regulator of metabolism in females.« less

Form follows function: the importance of endoplasmic reticulum shape.

PubMed

Westrate, L M; Lee, J E; Prinz, W A; Voeltz, G K

2015-01-01

The endoplasmic reticulum (ER) has a remarkably complex structure, composed of a single bilayer that forms the nuclear envelope, along with a network of sheets and dynamic tubules. Our understanding of the biological significance of the complex architecture of the ER has improved dramatically in the last few years. The identification of proteins and forces required for maintaining ER shape, as well as more advanced imaging techniques, has allowed the relationship between ER shape and function to come into focus. These studies have also revealed unexpected new functions of the ER and novel ER domains regulating alterations in ER dynamics. The importance of ER structure has become evident as recent research has identified diseases linked to mutations in ER-shaping proteins. In this review, we discuss what is known about the maintenance of ER architecture, the relationship between ER structure and function, and diseases associated with defects in ER structure.

Down-Regulation of Glucose-Regulated Protein (GRP) 78 Potentiates Cytotoxic Effect of Celecoxib in Human Urothelial Carcinoma Cells

PubMed Central

Huang, Kuo-How; Kuo, Kuan-Lin; Chen, Shyh-Chyan; Weng, Te-I; Chuang, Yuan-Ting; Tsai, Yu-Chieh; Pu, Yeong-Shiau; Chiang, Chih-Kang; Liu, Shing-Hwa

2012-01-01

Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor that has been reported to elicit anti-proliferative response in various tumors. In this study, we aim to investigate the antitumor effect of celecoxib on urothelial carcinoma (UC) cells and the role endoplasmic reticulum (ER) stress plays in celecoxib-induced cytotoxicity. The cytotoxic effects were measured by MTT assay and flow cytometry. The cell cycle progression and ER stress-associated molecules were examined by Western blot and flow cytometry. Moreover, the cytotoxic effects of celecoxib combined with glucose-regulated protein (GRP) 78 knockdown (siRNA), (−)-epigallocatechin gallate (EGCG) or MG132 were assessed. We demonstrated that celecoxib markedly reduces the cell viability and causes apoptosis in human UC cells through cell cycle G1 arrest. Celecoxib possessed the ability to activate ER stress-related chaperones (IRE-1α and GRP78), caspase-4, and CCAAT/enhancer binding protein homologous protein (CHOP), which were involved in UC cell apoptosis. Down-regulation of GRP78 by siRNA, co-treatment with EGCG (a GRP78 inhibitor) or with MG132 (a proteasome inhibitor) could enhance celecoxib-induced apoptosis. We concluded that celecoxib induces cell cycle G1 arrest, ER stress, and eventually apoptosis in human UC cells. The down-regulation of ER chaperone GRP78 by siRNA, EGCG, or proteosome inhibitor potentiated the cytotoxicity of celecoxib in UC cells. These findings provide a new treatment strategy against UC. PMID:22438966

Spatial Reorganization of the Endoplasmic Reticulum during Mitosis Relies on Mitotic Kinase Cyclin A in the Early Drosophila Embryo

PubMed Central

Bergman, Zane J.; Mclaurin, Justin D.; Eritano, Anthony S.; Johnson, Brittany M.; Sims, Amanda Q.; Riggs, Blake

2015-01-01

Mitotic cyclin-dependent kinase with their cyclin partners (cyclin:Cdks) are the master regulators of cell cycle progression responsible for regulating a host of activities during mitosis. Nuclear mitotic events, including chromosome condensation and segregation have been directly linked to Cdk activity. However, the regulation and timing of cytoplasmic mitotic events by cyclin:Cdks is poorly understood. In order to examine these mitotic cytoplasmic events, we looked at the dramatic changes in the endoplasmic reticulum (ER) during mitosis in the early Drosophila embryo. The dynamic changes of the ER can be arrested in an interphase state by inhibition of either DNA or protein synthesis. Here we show that this block can be alleviated by micro-injection of Cyclin A (CycA) in which defined mitotic ER clusters gathered at the spindle poles. Conversely, micro-injection of Cyclin B (CycB) did not affect spatial reorganization of the ER, suggesting CycA possesses the ability to initiate mitotic ER events in the cytoplasm. Additionally, RNAi-mediated simultaneous inhibition of all 3 mitotic cyclins (A, B and B3) blocked spatial reorganization of the ER. Our results suggest that mitotic ER reorganization events rely on CycA and that control and timing of nuclear and cytoplasmic events during mitosis may be defined by release of CycA from the nucleus as a consequence of breakdown of the nuclear envelope. PMID:25689737

Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells

PubMed Central

MacVicar, Thomas D. B.; Mannack, Lilith V. J. C.; Lees, Robert M.; Lane, Jon D.

2015-01-01

Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial autophagy (mitophagy), mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER) and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1), as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT) and the IP3-receptors (IP3Rs) as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R-mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU) primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R-mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis. PMID:26110381

Mitochondrial metabolic regulation by GRP78

PubMed Central

Prasad, Manoj; Pawlak, Kevin J.; Burak, William E.; Perry, Elizabeth E.; Marshall, Brendan; Whittal, Randy M.; Bose, Himangshu S.

2017-01-01

Steroids, essential for mammalian survival, are initiated by cholesterol transport by steroidogenic acute regulatory protein (StAR). Appropriate protein folding is an essential requirement of activity. Endoplasmic reticulum (ER) chaperones assist in folding of cytoplasmic proteins, whereas mitochondrial chaperones fold only mitochondrial proteins. We show that glucose regulatory protein 78 (GRP78), a master ER chaperone, is also present at the mitochondria-associated ER membrane (MAM), where it folds StAR for delivery to the outer mitochondrial membrane. StAR expression and activity are drastically reduced following GRP78 knockdown. StAR folding starts at the MAM region; thus, its cholesterol fostering capacity is regulated by GRP78 long before StAR reaches the mitochondria. In summary, GRP78 is an acute regulator of steroidogenesis at the MAM, regulating the intermediate folding of StAR that is crucial for its activity. PMID:28275724

MicroRNAs meet calcium: joint venture in ER proteostasis.

PubMed

Finger, Fabian; Hoppe, Thorsten

2014-11-04

The endoplasmic reticulum (ER) is a cellular compartment that has a key function in protein translation and folding. Maintaining its integrity is of fundamental importance for organism's physiology and viability. The dynamic regulation of intraluminal ER Ca(2+) concentration directly influences the activity of ER-resident chaperones and stress response pathways that balance protein load and folding capacity. We review the emerging evidence that microRNAs play important roles in adjusting these processes to frequently changing intracellular and environmental conditions to modify ER Ca(2+) handling and storage and maintain ER homeostasis. Copyright © 2014, American Association for the Advancement of Science.

The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise.

PubMed

Cai, Ming; Wang, Hong; Li, Jing-Jing; Zhang, Yun-Li; Xin, Lei; Li, Feng; Lou, Shu-Jie

2016-10-01

High fat diet (HFD)-induced obesity has been shown to reduce the levels of neuronal plasticity-related proteins, specifically brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN), in the hippocampus. However, the underlying mechanisms are not fully clear. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating gene expression and protein production by affecting stress signaling pathways and ER functions of protein folding and post-translational modification in peripheral tissues of obese rodent models. Additionally, HFD that is associated with hyperglycemia could induce hippocampal ERS, thus impairing insulin signaling and cognitive health in HFD mice. One goal of this study was to determine whether hyperglycemia and hyperlipidemia could cause hippocampal ERS in HFD-induced obese SD rats, and explore the potential mechanisms of ERS regulating hippocampal BDNF and SYN proteins production. Additionally, although regular aerobic exercise could reduce central inflammation and elevate hippocampal BDNF and SYN levels in obese rats, the regulated mechanisms are poorly understood. Nrf2-HO-1 pathways play roles in anti-ERS, anti-inflammation and anti-apoptosis in peripheral tissues. Therefore, the other goal of this study was to determine whether aerobic exercise could activate Nrf2-HO-1 in hippocampus to alleviate obesity-induced hippocampal ERS, which would lead to increased BDNF and SYN levels. Male SD rats were fed on HFD for 8weeks to establish the obese model. Then, 8weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that HFD-induced obesity caused hyperglycemia and hyperlipidemia, and significantly promoted hippocampal glucose transporter 3 (GLUT3) and fatty acid transport protein 1 (FATP1) protein expression. These results were associated with the activation of hippocampal ERS and ERS-mediated apoptosis. At the same time, we found that excessive hippocampal ERS not only significantly decreased proBDNF-the precursor of mature BDNF, but also attenuated p38/ERK-CREB signaling pathways and activated NLRP3-IL-1β pathways in obese rats. These results were associated with reduced BDNF and SYN protein production. However, these adverse changes were obviously reversed by aerobic exercise intervention through activating the Nrf2-HO-1 pathways. These results suggest that dietary obesity could induce hippocampal ERS in male SD rats, and excessive hippocampal ERS plays a critical role in decreasing the levels of BDNF and SYN. Moreover, aerobic exercise could activate hippocampal Nrf2 and HO-1 to relieve ERS and heighten BDNF and SYN production in obese rats. Copyright © 2016 Elsevier Inc. All rights reserved.

miRNA-148a regulates the expression of the estrogen receptor through DNMT1-mediated DNA methylation in breast cancer cells

PubMed Central

Xu, Yurui; Chao, Lin; Wang, Jianyu; Sun, Yonghong

2017-01-01

Breast cancer remains the most prevalent cancer among women worldwide. The expression of estrogen receptor-α (ER-α) is an important marker for prognosis. ER-α status may be positive or negative in breast cancer cells, although the cause of negative or positive status is not yet fully characterized. In the present study, the expression of ER-α and miRNA-148a was assessed in two breast cancer cell lines, HCC1937 and MCF7. An association between ER-α and miRNA-148a expression was identified. It was then demonstrated that DNA methyltransferase 1 (DNMT1) is a target of miRNA-148a, which may suppress the expression of ER-α via DNA methylation. Finally, an miRNA-148a mimic or inhibitor was transfected into MCF7 cells; the miRNA-148a mimic increased ER-α expression whereas the miRNA-148a inhibitor decreased ER-α expression. In conclusion, it was identified that miRNA-148a regulates ER-α expression through DNMT1-mediated DNA methylation in breast cancer cells. This may represent a potential miRNA-based strategy to modulate the expression of ER-α and provide a novel perspective for investigating the role of miRNAs in treating breast cancer. PMID:29085474

Endoplasmic reticulum-plasma membrane contact sites integrate sterol and phospholipid regulation.

PubMed

Quon, Evan; Sere, Yves Y; Chauhan, Neha; Johansen, Jesper; Sullivan, David P; Dittman, Jeremy S; Rice, William J; Chan, Robin B; Di Paolo, Gilbert; Beh, Christopher T; Menon, Anant K

2018-05-01

Tether proteins attach the endoplasmic reticulum (ER) to other cellular membranes, thereby creating contact sites that are proposed to form platforms for regulating lipid homeostasis and facilitating non-vesicular lipid exchange. Sterols are synthesized in the ER and transported by non-vesicular mechanisms to the plasma membrane (PM), where they represent almost half of all PM lipids and contribute critically to the barrier function of the PM. To determine whether contact sites are important for both sterol exchange between the ER and PM and intermembrane regulation of lipid metabolism, we generated Δ-super-tether (Δ-s-tether) yeast cells that lack six previously identified tethering proteins (yeast extended synatotagmin [E-Syt], vesicle-associated membrane protein [VAMP]-associated protein [VAP], and TMEM16-anoctamin homologues) as well as the presumptive tether Ice2. Despite the lack of ER-PM contacts in these cells, ER-PM sterol exchange is robust, indicating that the sterol transport machinery is either absent from or not uniquely located at contact sites. Unexpectedly, we found that the transport of exogenously supplied sterol to the ER occurs more slowly in Δ-s-tether cells than in wild-type (WT) cells. We pinpointed this defect to changes in sterol organization and transbilayer movement within the PM bilayer caused by phospholipid dysregulation, evinced by changes in the abundance and organization of PM lipids. Indeed, deletion of either OSH4, which encodes a sterol/phosphatidylinositol-4-phosphate (PI4P) exchange protein, or SAC1, which encodes a PI4P phosphatase, caused synthetic lethality in Δ-s-tether cells due to disruptions in redundant PI4P and phospholipid regulatory pathways. The growth defect of Δ-s-tether cells was rescued with an artificial "ER-PM staple," a tether assembled from unrelated non-yeast protein domains, indicating that endogenous tether proteins have nonspecific bridging functions. Finally, we discovered that sterols play a role in regulating ER-PM contact site formation. In sterol-depleted cells, levels of the yeast E-Syt tether Tcb3 were induced and ER-PM contact increased dramatically. These results support a model in which ER-PM contact sites provide a nexus for coordinating the complex interrelationship between sterols, sphingolipids, and phospholipids that maintain PM composition and integrity.

Conditional expression of constitutively active estrogen receptor {alpha} in chondrocytes impairs longitudinal bone growth in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ikeda, Kazuhiro; Tsukui, Tohru; Imazawa, Yukiko

2012-09-07

Highlights: Black-Right-Pointing-Pointer Conditional transgenic mice expressing constitutively active estrogen receptor {alpha} (caER{alpha}) in chondrocytes were developed. Black-Right-Pointing-Pointer Expression of caER{alpha} in chondrocytes impaired longitudinal bone growth in mice. Black-Right-Pointing-Pointer caER{alpha} affects chondrocyte proliferation and differentiation. Black-Right-Pointing-Pointer This mouse model is useful for understanding the physiological role of ER{alpha}in vivo. -- Abstract: Estrogen plays important roles in the regulation of chondrocyte proliferation and differentiation, which are essential steps for longitudinal bone growth; however, the mechanisms of estrogen action on chondrocytes have not been fully elucidated. In the present study, we generated conditional transgenic mice, designated as caER{alpha}{sup ColII}, expressing constitutively activemore » mutant estrogen receptor (ER) {alpha} in chondrocytes, using the chondrocyte-specific type II collagen promoter-driven Cre transgenic mice. caER{alpha}{sup ColII} mice showed retardation in longitudinal growth, with short bone lengths. BrdU labeling showed reduced proliferation of hypertrophic chondrocytes in the proliferating layer of the growth plate of tibia in caER{alpha}{sup ColII} mice. In situ hybridization analysis of type X collagen revealed that the maturation of hypertrophic chondrocytes was impaired in caER{alpha}{sup ColII} mice. These results suggest that ER{alpha} is a critical regulator of chondrocyte proliferation and maturation during skeletal development, mediating longitudinal bone growth in vivo.« less

The novel white spot syndrome virus-induced gene, PmERP15, encodes an ER stress-responsive protein in black tiger shrimp, Penaeus monodon.

PubMed

Leu, Jiann-Horng; Liu, Kuan-Fu; Chen, Kuan-Yu; Chen, Shu-Hwa; Wang, Yu-Bin; Lin, Chung-Yen; Lo, Chu-Fang

2015-04-01

By microarray screening, we identified a white spot syndrome virus (WSSV)-strongly induced novel gene in gills of Penaeus monodon. The gene, PmERP15, encodes a putative transmembrane protein of 15 kDa, which only showed some degree of similarity (54-59%) to several unknown insect proteins, but had no hits to shrimp proteins. RT-PCR showed that PmERP15 was highly expressed in the hemocytes, heart and lymphoid organs, and that WSSV-induced strong expression of PmERP15 was evident in all tissues examined. Western blot analysis likewise showed that WSSV strongly up-regulated PmERP15 protein levels. In WSSV-infected hemocytes, immunofluorescence staining showed that PmERP15 protein was colocalized with an ER enzyme, protein disulfide isomerase, and in Sf9 insect cells, PmERP15-EGFP fusion protein colocalized with ER -Tracker™ Red dye as well. GRP78, an ER stress marker, was found to be up-regulated in WSSV-infected P. monodon, and both PmERP15 and GRP78 were up-regulated in shrimp injected with ER stress inducers tunicamycin and dithiothreitol. Silencing experiments showed that although PmERP15 dsRNA-injected shrimp succumbed to WSSV infection more rapidly, the WSSV copy number had no significant changes. These results suggest that PmERP15 is an ER stress-induced, ER resident protein, and its induction in WSSV-infected shrimp is caused by the ER stress triggered by WSSV infection. Furthermore, although PmERP15 has no role in WSSV multiplication, its presence is essential for the survival of WSSV-infected shrimp. Copyright © 2014 Elsevier Ltd. All rights reserved.

Excessive endoplasmic reticulum stress and decreased neuroplasticity-associated proteins in prefrontal cortex of obese rats and the regulatory effects of aerobic exercise.

PubMed

Li, Feng; Liu, Bei Bei; Cai, Ming; Li, Jing Jing; Lou, Shu-Jie

2018-04-06

Studies have shown high fat diet induced obesity may cause cognition impairment and down-regulation of neuroplasticity-associated proteins, while aerobic exercise could improve that damage. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating neuroplasticity-associated proteins expression, folding and post-translational modification in hippocampus of obese rodent models, however, the effects of ERS on neuroplasticity-associated proteins and possible underlying mechanisms in prefrontal cortex are not fully clear. In order to clarify changes of neuroplasticity-associated proteins and ERS in the prefrontal cortex of obese rats, male SD rats were fed on high fat diet for 8 weeks to establish the obese model. Then, 8 weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that high fat diet induced obesity caused hyperlipidemia, and significantly promoted FATP1 expression in the prefrontal cortex, meanwhile, we found up-regulation of GRP78, p-PERK, p-eIF2α, caspase-12, CHOP, and Bax/Bcl-2, reflecting the activation of ERS and ERS-mediated apoptosis. Moreover, reduced BDNF and SYN was found in obese rats. However, FATP1, GRP78, p-PERK, p-eIF2α, caspase-12, CHOP, and Bax/Bcl-2 expressions were obviously reversed by aerobic exercise intervention. These results suggested that dietary obesity could induce Prefrontal ERS in SD rats and excessive ERS may play a critical role in decreasing the levels of neuroplasticity-associated proteins. Moreover, aerobic exercise could relieve ERS, thus promoted the expression of neuroplasticity-associated proteins. Copyright © 2018. Published by Elsevier Inc.

Don't worry, be happy: The role of positive emotionality and adaptive emotion regulation strategies for youth depressive symptoms.

PubMed

Van Beveren, Marie-Lotte; Harding, Kaitlin; Beyers, Wim; Braet, Caroline

2018-03-01

Low positive emotionality (PE) represents a temperamental vulnerability to depression in youth. Until now, little research has examined the mechanisms linking PE to depressive symptoms. Starting from integrated cognitive-affective models of depression, we aimed to study adaptive emotion regulation (ER) as a key underlying mechanism in the temperament-depression relationship. This study investigated whether adaptive ER strategies mediate the association between PE and depressive symptoms in a large community-based sample of youth, using a cross-sectional design. Participants were 1,655 youth (54% girls; 7-16 years, M = 11.41, SD = 1.88) who filled out a set of questionnaires assessing temperament, adaptive ER strategies, and depressive symptoms. Results revealed that low PE was significantly related to higher depressive symptoms among youth and that a lack of total adaptive ER abilities mediated this relationship. More specifically, the infrequent use of problem-solving appeared to be of significant importance. Problems in positive refocusing and a deficient use of forgetting mediated the relationships between low PE and high negative emotionality (NE) in predicting depressive symptoms. Reappraisal and distraction were not significant mediators. Results highlight the need to account for temperamental PE and adaptive ER strategies when studying youth depression. The findings contribute to a more nuanced understanding on the differential role of temperamental risk factors for developing depressive symptoms at an early stage and advocate for greater attention to adaptive ER strategies. Clinical interventions for youth depression may be improved by incorporating adaptive emotion regulation (ER) strategies and enhancing positive emotions. Youth low in positive emotionality (PE) may especially benefit from learning adaptive ER skills. Clinical practitioners should focus on alleviating negative emotions and enhancing positive emotions, especially among youth low in PE. © 2017 The British Psychological Society.

Distinct intracellular sAC-cAMP domains regulate ER Ca2+ signaling and OXPHOS function.

PubMed

Valsecchi, Federica; Konrad, Csaba; D'Aurelio, Marilena; Ramos-Espiritu, Lavoisier S; Stepanova, Anna; Burstein, Suzanne R; Galkin, Alexander; Magranè, Jordi; Starkov, Anatoly; Buck, Jochen; Levin, Lonny R; Manfredi, Giovanni

2017-11-01

cAMP regulates a wide variety of physiological functions in mammals. This single second messenger can regulate multiple, seemingly disparate functions within independently regulated cell compartments. We have previously identified one such compartment inside the matrix of the mitochondria, where soluble adenylyl cyclase (sAC) regulates oxidative phosphorylation (OXPHOS). We now show that sAC knockout fibroblasts have a defect in OXPHOS activity and attempt to compensate for this defect by increasing OXPHOS proteins. Importantly, sAC knockout cells also exhibit decreased probability of endoplasmic reticulum (ER) Ca 2+ release associated with diminished phosphorylation of the inositol 3-phosphate receptor. Restoring sAC expression exclusively in the mitochondrial matrix rescues OXPHOS activity and reduces mitochondrial biogenesis, indicating that these phenotypes are regulated by intramitochondrial sAC. In contrast, Ca 2+ release from the ER is only rescued when sAC expression is restored throughout the cell. Thus, we show that functionally distinct, sAC-defined, intracellular cAMP signaling domains regulate metabolism and Ca 2+ signaling. © 2017. Published by The Company of Biologists Ltd.

ER quality control components UGGT and STT3a are required for activation of defense responses in bir1-1.

PubMed

Zhang, Qian; Sun, Tongjun; Zhang, Yuelin

2015-01-01

The receptor-like kinase SUPPRESSOR OF BIR1, 1 (SOBIR1) functions as a critical regulator in plant immunity. It is required for activation of cell death and defense responses in Arabidopsis bak1-interacting receptor-like kinase 1,1 (bir1-1) mutant plants. Here we report that the ER quality control component UDP-glucose:glycoprotein glucosyltransferase (UGGT) is required for the biogenesis of SOBIR1 and mutations in UGGT suppress the spontaneous cell death and constitutive defense responses in bir1-1. Loss of function of STT3a, which encodes a subunit of the oligosaccharyltransferase complex, also suppresses the autoimmune phenotype in bir1-1. However, it has no effect on the accumulation of SOBIR1, suggesting that additional signaling components other than SOBIR1 may be regulated by ER quality control. Our study provides clear evidence that ER quality control play critical roles in regulating defense activation in bir1-1.

USP19-Mediated Deubiquitination Facilitates the Stabilization of HRD1 Ubiquitin Ligase.

PubMed

Harada, Kumi; Kato, Masako; Nakamura, Nobuhiro

2016-11-02

In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell homeostasis. In the ERAD pathway, several ER-localized E3 ubiquitin ligases target ERAD substrate proteins for ubiquitination and subsequent proteasomal degradation. However, little is known about how the functions of the ERAD ubiquitin ligases are regulated. Recently, USP19, an ER-anchored deubiquitinating enzyme (DUB), has been suggested to be involved in the regulation of ERAD. In this study, HRD1, an ERAD ubiquitin ligase, is shown to be a novel substrate for USP19. We demonstrate that USP19 rescues HRD1 from proteasomal degradation by deubiquitination of K48-linked ubiquitin chains. In addition, the altered expression of USP19 affects the steady-state levels of HRD1. These results suggest that USP19 regulates the stability of HRD1 and provide insight into the regulatory mechanism of the ERAD ubiquitin ligases.

Identification of SNPs involved in regulating a novel alternative transcript of P450 CYP6ER1 in the brown planthopper.

PubMed

Liang, Zhi-Kun; Pang, Rui; Dong, Yi; Sun, Zhong-Xiang; Ling, Yan; Zhang, Wen-Qing

2017-04-29

Cytochrome P450-mediated metabolic resistance is one of the major mechanisms involved in insecticide resistance. Although the up-regulation of cytochrome P450 plays a vital role in insecticide metabolism, the molecular basis for the transcriptional regulation of cytochrome P450 remains largely unknown. The P450 gene CYP6ER1, has been reported to confer imidacloprid resistance to the brown planthopper, Nilaparvata lugens. Here, we identified a novel alternative transcript of CYP6ER1 (transcript A2) that had different expression patterns between resistant and susceptible populations, and was more stable after insecticide induction. The promoter of this transcript was sequenced and multiple single nucleotide polymorphisms (SNPs) were detected in individuals from susceptible and resistant field-collected populations. Resistant alleles of four SNPs were found to significantly enhance the promoter activity of the CYP6ER1 transcript A2. Electrophoretic mobility shift assays (EMSAs) revealed that these SNPs might regulate the binding of transcription factors to the promoter. Our findings provide novel evidence regarding the transcriptional regulation of a metabolic resistance-related gene and may be useful to understand the resistance mechanism of N. lugens in the field. © 2017 Institute of Zoology, Chinese Academy of Sciences.

Refined molecular hinge between allosteric and catalytic domain determines allosteric regulation and stability of fungal chorismate mutase

PubMed Central

Helmstaedt, Kerstin; Heinrich, Gabriele; Lipscomb, William N.; Braus, Gerhard H.

2002-01-01

The yeast chorismate mutase is regulated by tyrosine as feedback inhibitor and tryptophan as crosspathway activator. The monomer consists of a catalytic and a regulatory domain covalently linked by the loop L220s (212–226), which functions as a molecular hinge. Two monomers form the active dimeric enzyme stabilized by hydrophobic interactions in the vicinity of loop L220s. The role of loop L220s and its environment for enzyme regulation, dimerization, and stability was analyzed. Substitution of yeast loop L220s in place of the homologous loop from the corresponding and similarly regulated Aspergillus enzyme (and the reverse substitution) changed tyrosine inhibition to activation. Yeast loop L220s substituted into the Aspergillus enzyme resulted in a tryptophan-inhibitable enzyme. Monomeric yeast chorismate mutases could be generated by substituting two hydrophobic residues in and near the hinge region. The resulting Thr-212→Asp–Phe-28→Asp enzyme was as stable as wild type, but lost allosteric regulation and showed reduced catalytic activity. These results underline the crucial role of this molecular hinge for inhibition, activation, quaternary structure, and stability of yeast chorismate mutase. PMID:11997452

Glyceollin, a novel regulator of mTOR/p70S6 in estrogen receptor positive breast cancer

USDA-ARS?s Scientific Manuscript database

An estimated 70% of breast cancer tumors utilize estrogen receptor (ER) signaling to maintain tumorigenesis, and targeting of the estrogen receptor is a common method of treatment for these tumor types. However, ER-positive (+) breast cancers often acquire drug resistant or altered ER activity in r...

A Systems Biological View of Life-and-Death Decision with Respect to Endoplasmic Reticulum Stress-The Role of PERK Pathway.

PubMed

Márton, Margita; Kurucz, Anita; Lizák, Beáta; Margittai, Éva; Bánhegyi, Gábor; Kapuy, Orsolya

2017-01-05

Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try to drive back the system to the former or a new homeostatic state by self-eating dependent autophagy, while excessive level of ER stress results in apoptotic cell death. Our study focuses on the role of PERK- and IRE-1-induced arms of UPR in life-or-death decision. Here we confirm that silencing of PERK extends autophagy-dependent survival, whereas the IRE-1-controlled apoptosis inducer is downregulated during ER stress. We also claim that the proper order of surviving and self-killing mechanisms is controlled by a positive feedback loop between PERK and IRE-1 branches. This regulatory network makes possible a smooth, continuous activation of autophagy with respect to ER stress, while the induction of apoptosis is irreversible and switch-like. Using our knowledge of molecular biological techniques and systems biological tools we give a qualitative description about the dynamical behavior of PERK- and IRE-1-controlled life-or-death decision. Our model claims that the two arms of UPR accomplish an altered upregulation of autophagy and apoptosis inducers during ER stress. Since ER stress is tightly connected to aging and age-related degenerative disorders, studying the signaling pathways of UPR and their role in maintaining ER proteostasis have medical importance.

Intraventricular administration of Tenebrio molitor larvae extract regulates food intake and body weight in mice with high-fat diet-induced obesity.

PubMed

Seo, Minchul; Kim, Jongwan; Moon, Seong-Su; Hwang, Jae-Sam; Kim, Mi-Ae

2017-08-01

We recently reported the in vitro and in vivo antiobesity effects of Tenebrio molitor larvae, a traditional food in many countries, but it remains unknown how the larvae affect appetite regulation in mice with diet-induced obesity. We hypothesized that the extract of T molitor larvae mediates appetite by regulating neuropeptide expression. We investigated T molitor larvae extract's (TME's) effects on anorexigenesis and endoplasmic reticulum (ER) stress-induced orexigenic neuropeptide expression in the hypothalami of obese mice. Intracerebroventricular TME administration suppressed feeding by down-regulating the expression of the orexigenic neuropeptides neuropeptide Y and agouti-related protein. T molitor larvae extract significantly reduced the expression of ER stress response genes. These results suggest that TME and its bioactive components are potential therapeutics for obesity and ER stress-driven disease states. Copyright © 2017 Elsevier Inc. All rights reserved.

Do People With Psychosis Have Specific Difficulties Regulating Emotions?

PubMed

Lincoln, Tania M; Hartmann, Maike; Köther, Ulf; Moritz, Steffen

2015-01-01

Difficulties in emotion regulation (ER) are present in psychotic disorders, but their precise nature is not yet fully understood and it is unclear which difficulties are unique to psychosis compared with other disorders. This study investigated whether ER difficulties in psychosis are more prominent for the ability to modify emotions or for the ability to tolerate and accept them. Furthermore, it investigated whether ER difficulties occur for sadness, anxiety, anger and shame likewise. ER skills were assessed in participants with psychotic disorders (n = 37), participants with depression (n = 30) and healthy controls (n = 28) using the Emotion Regulation Skill Questionnaire that asks participants to rate the intensity of different emotions over the past week and the skills employed to handle each of them. Compared with healthy controls, participants with psychosis showed reduced skills related to awareness, understanding and acceptance of potentially distressing emotions, but not in the ability to modify them. These differences remained significant after controlling for depression. Participants with psychosis showed reduced ER skills in regard to all of the assessed emotions compared with the healthy controls, despite the fact that they only reported sadness as being significantly more intense. The participants with depression showed a similar pattern of ER skills to the psychosis sample, although with a tendency towards even more pronounced difficulties. It is concluded that psychosis is characterized by difficulties in using specific ER skills related to awareness, understanding and acceptance to regulate anger, shame, anxiety and sadness. These difficulties are not unique to psychosis but nevertheless present a promising treatment target. The participants with psychosis found it more difficult to be aware of their emotions, to understand them and to accept them than the healthy control group. However, they reported equal skills when it came to actively modifying emotions. The difficulties in emotion regulation reported by the participants with psychosis were comparable with those reported by the participants with depression, and they occurred for all types of negative emotions likewise. The difficulties in using specific ER skills related to awareness, understanding and acceptance are a promising target for psychological treatment of psychosis. Interventions that are aimed specifically at increasing these skills need to be further developed. Copyright © 2014 John Wiley & Sons, Ltd.

HER4 selectively coregulates estrogen stimulated genes associated with breast tumor cell proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Wen; Jones, Frank E., E-mail: fjones3@tulane.edu

2014-01-10

Highlights: •HER4/4ICD is an obligate coactivator for 37% of estrogen regulated genes. •HER4/4ICD coactivated genes selectively regulate estrogen stimulated proliferation. •Estrogen stimulated tumor cell migration occurs independent of HER4/4ICD. •Disrupting HER4/4ICD and ER coactivated gene expression may suppress breast cancer. -- Abstract: The EGFR-family member HER4 undergoes regulated intramembrane proteolysis (RIP) to generate an intracellular domain (4ICD) that functions as a transcriptional coactivator. Accordingly, 4ICD coactivates the estrogen receptor (ER) and associates with ER at target gene promoters in breast tumor cells. However, the extent of 4ICD coactivation of ER and the functional significance of the 4ICD/ER transcriptional complex ismore » unclear. To identify 4ICD coactivated genes we performed a microarray gene expression analysis of β-estradiol treated cells comparing control MCF-7 breast cancer cells to MCF-7 cells where HER4 expression was stably suppressed using a shRNA. In the MCF-7 cell line, β-estradiol significantly stimulated or repressed by 2-fold or more 726 or 53 genes, respectively. Significantly, HER4/4ICD was an obligate coactivator for 277 or 38% of the β-estradiol stimulated genes. Ingenuity Pathway Analysis of β-estradiol regulated genes identified significant associations with multiple cellular functions regulating cellular growth and proliferation, cell cycle progression, cancer metastasis, decreased hypoplasia, tumor cell migration, apoptotic resistance of tumor cells, and increased transcription. Genes coactivated by 4ICD displayed functional specificity by only significantly contributing to cellular growth and proliferation, cell cycle progression, and decreased hypoplasia. In direct concordance with these in situ results we show that HER4 knockdown in MCF-7 cells results in a loss of estrogen stimulated tumor cell proliferation and cell cycle progression, whereas, estrogen stimulated tumor cell migration was unaffected by loss of HER4 expression. In summary, we demonstrate for the first time that a cell surface receptor functions as an obligate ER coactivator with functional specificity associated with breast tumor cell proliferation and cell cycle progression. Nearly 90% of ER positive tumors coexpress HER4, therefore we predict that the majority of breast cancer patients would benefit from a strategy to therapeutic disengage ER/4ICD coregulated tumor cell proliferation.« less

Emotion Regulation Mediates the Association Between ADHD and Depressive Symptoms in a Community Sample of Youth

PubMed Central

Seymour, Karen E.; Chronis-Tuscano, Andrea; Iwamoto, Derek K.; Kurdziel, Gretchen; MacPherson, Laura

2014-01-01

The purpose of this study was to examine the longitudinal relationship between attention-deficit/ hyperactivity disorder (ADHD) symptoms, emotion regulation (ER) ability, and depressive symptoms within a diverse community sample of 277 youth, ages 9–12 (56 % male). Participants were drawn from a larger study examining adolescent risk behaviors, and completed annual assessments over 3 years. Youth ADHD symptoms were assessed at Time 1 (T1) using the parent-reported Disruptive Behavior Disorders Rating Scale, ER was assessed with the parent-reported Emotion Regulation Checklist at Time 2 (T2), and youth depressive symptoms were assessed using the self-reported Revised Child Anxiety and Depression Scales at Time 3 (T3). Analyses examined T2 ER as a mediator between T1 ADHD symptoms (including the unique contributions of inattentive [IA] versus hyperactive/impulsive [HI] symptoms) and T3 depressive symptoms. Structural equation modeling (SEM) indicated the path model specified provided an excellent fit to the data. Tests of indirect effects suggested that T2 ER appears to be a significant mechanism that underlies the relationship between T1 ADHD and T3 depression, even when accounting for T1 oppositional defiant and depressive symptoms. Furthermore, while both T1 IA and HI symptoms had significant indirect effects on T3 depression through the mechanism T2 ER, HI proved a more robust predictor of T2 ER than IA. Results of this prospective study support cross-sectional findings pointing to ER as a potential mechanism linking ADHD and depressive symptoms in youth. Clinical implications and future directions are discussed. PMID:24221724

Molecular characterization of estrogen receptor genes in Gobiocypris rarus and their expression upon endocrine disrupting chemicals exposure in juveniles.

PubMed

Wang, Houpeng; Wang, Jingjing; Wu, Tingting; Qin, Fang; Hu, Xiaoqi; Wang, Lihong; Wang, Zaizhao

2011-01-17

Estrogens play an important role in many physiological processes of vertebrates, mediated by estrogen receptors (ERs). The full length of the cDNAs for ERα, ERβ1, and ERβ2 were isolated and characterized from Gobiocypris rarus. G. rarus ERs shared the highest amino acid identities with counterparts of three cyprinidae species (Pimephales promelas ERα: 91.1%, Rutilus rutilus ERβ1: 92.9%, Tanichthy albonubes ERβ2: 93.5%). The phylogenic tree of vertebrate ERs indicates G. rarus ER isoforms are more related to counterparts of cyprinidae species. The expression of ERα mRNA was high in gonad and liver. The ERβ1 transcript was the highest in the liver of female fish and was evenly high in the liver, testis and intestine in male. The ERβ2 transcript was high in liver, gonad, and intestine. G. rarus juvenile at 34 days post fertilization were exposed for 3 days to endocrine disrupting chemicals including 17α-ethynylestradiol (EE2), 4-nonylphenol (NP) and bisphenol A (BPA). ER mRNA expression following the xenoestrogens' exposure was analyzed by quantitative real-time PCR. EE2 exposure at 0.01, 0.1 and 1 nM significantly up-regulated ERα transcript. ERβ1 mRNA expression was suppressed by EE2 at all concentrations. However ERβ2 transcript had opposite response to EE2 at low and high concentrations (up-regulation at 0.1 nM, down-regulation at 1 nM). Except a weak increase of ERα at 10 nM EE2, varying decrease of three ER transcripts was resulted in by NP at 10, 100 and 1000 nM. ERα transcript was significantly up-regulated by BPA at 10 nM. A non-significant weak increase in ERβ1 mRNA expression was caused by 1 nM BPA. However 1 nM and 10 nM BPA exposures resulted in significant and non-significant decrease of ERβ2 transcript, respectively. The BPA exposures at other concentrations almost had no effect on the ER transcripts. Vitellogenin (Vtg) mRNA expression profiling following exposure to three xenoestrogens indicated that Vtg transcript is a sensitive biomarker of the juvenile G. rarus at 34 dpf to the EDCs, especially to EE2. These results combined suggest that the ER genes are not modulated in the same manner by EE2, NP, and BPA and that ERs may not contribute equally to the transcriptional regulation of genes involved in fish development and reproduction. Copyright © 2010 Elsevier B.V. All rights reserved.

Glutathione S-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

PubMed Central

Ye, Zhi-Wei; Zhang, Jie; Ancrum, Tiffany; Manevich, Yefim; Townsend, Danyelle M.

2017-01-01

Abstract Aims: S-glutathionylation of cysteine residues, catalyzed by glutathione S-transferase Pi (GSTP), alters structure/function characteristics of certain targeted proteins. Our goal is to characterize how S-glutathionylation of proteins within the endoplasmic reticulum (ER) impact cell sensitivity to ER-stress inducing drugs. Results: We identify GSTP to be an ER-resident protein where it demonstrates both chaperone and catalytic functions. Redox based proteomic analyses identified a cluster of proteins cooperatively involved in the regulation of ER stress (immunoglobulin heavy chain-binding protein [BiP], protein disulfide isomerase [PDI], calnexin, calreticulin, endoplasmin, sarco/endoplasmic reticulum Ca2+-ATPase [SERCA]) that individually co-immunoprecipitated with GSTP (implying protein complex formation) and were subject to reactive oxygen species (ROS) induced S-glutathionylation. S-glutathionylation of each of these six proteins was attenuated in cells (liver, embryo fibroblasts or bone marrow dendritic) from mice lacking GSTP (Gstp1/p2−/−) compared to wild type (Gstp1/p2+/+). Moreover, Gstp1/p2−/− cells were significantly more sensitive to the cytotoxic effects of the ER-stress inducing drugs, thapsigargin (7-fold) and tunicamycin (2-fold). Innovation: Within the family of GST isozymes, GSTP has been ascribed the broadest range of catalytic and chaperone functions. Now, for the first time, we identify it as an ER resident protein that catalyzes S-glutathionylation of critical ER proteins within this organelle. Of note, this can provide a nexus for linkage of redox based signaling and pathways that regulate the unfolded protein response (UPR). This has novel importance in determining how some drugs kill cancer cells. Conclusions: Contextually, these results provide mechanistic evidence that GSTP can exert redox regulation in the oxidative ER environment and indicate that, within the ER, GSTP influences the cellular consequences of the UPR through S-glutathionylation of a series of key interrelated proteins. Antioxid. Redox Signal. 26, 247–261. PMID:26838680

REEPs Are Membrane Shaping Adapter Proteins That Modulate Specific G Protein-Coupled Receptor Trafficking by Affecting ER Cargo Capacity

PubMed Central

Ho, Vincent K.; Angelotti, Timothy

2013-01-01

Receptor expression enhancing proteins (REEPs) were identified by their ability to enhance cell surface expression of a subset of G protein-coupled receptors (GPCRs), specifically GPCRs that have proven difficult to express in heterologous cell systems. Further analysis revealed that they belong to the Yip (Ypt-interacting protein) family and that some REEP subtypes affect ER structure. Yip family comparisons have established other potential roles for REEPs, including regulation of ER-Golgi transport and processing/neuronal localization of cargo proteins. However, these other potential REEP functions and the mechanism by which they selectively enhance GPCR cell surface expression have not been clarified. By utilizing several REEP family members (REEP1, REEP2, and REEP6) and model GPCRs (α2A and α2C adrenergic receptors), we examined REEP regulation of GPCR plasma membrane expression, intracellular processing, and trafficking. Using a combination of immunolocalization and biochemical methods, we demonstrated that this REEP subset is localized primarily to ER, but not plasma membranes. Single cell analysis demonstrated that these REEPs do not specifically enhance surface expression of all GPCRs, but affect ER cargo capacity of specific GPCRs and thus their surface expression. REEP co-expression with α2 adrenergic receptors (ARs) revealed that this REEP subset interacts with and alter glycosidic processing of α2C, but not α2A ARs, demonstrating selective interaction with cargo proteins. Specifically, these REEPs enhanced expression of and interacted with minimally/non-glycosylated forms of α2C ARs. Most importantly, expression of a mutant REEP1 allele (hereditary spastic paraplegia SPG31) lacking the carboxyl terminus led to loss of this interaction. Thus specific REEP isoforms have additional intracellular functions besides altering ER structure, such as enhancing ER cargo capacity, regulating ER-Golgi processing, and interacting with select cargo proteins. Therefore, some REEPs can be further described as ER membrane shaping adapter proteins. PMID:24098485

Genomic organization of the human mi-er1 gene and characterization of alternatively spliced isoforms: regulated use of a facultative intron determines subcellular localization.

PubMed

Paterno, Gary D; Ding, Zhihu; Lew, Yuan-Y; Nash, Gord W; Mercer, F Corinne; Gillespie, Laura L

2002-07-24

mi-er1 (previously called er1) is a fibroblast growth factor-inducible early response gene activated during mesoderm induction in Xenopus embryos and encoding a nuclear protein that functions as a transcriptional activator. The human orthologue of mi-er1 was shown to be upregulated in breast carcinoma cell lines and breast tumours when compared to normal breast cells. In this report, we investigate the structure of the human mi-er1 (hmi-er1) gene and characterize the alternatively spliced transcripts and protein isoforms. hmi-er1 is a single copy gene located at 1p31.2 and spanning 63 kb. It contains 17 exons and includes one skipped exon, a facultative intron and three polyadenylation signals to produce 12 transcripts encoding six distinct proteins. hmi-er1 transcripts were expressed at very low levels in most human adult tissues and the mRNA isoform pattern varied with the tissue. The 12 transcripts encode proteins containing a common internal sequence with variable N- and C-termini. Three distinct N- and two distinct C-termini were identified, giving rise to six protein isoforms. The two C-termini differ significantly in size and sequence and arise from alternate use of a facultative intron to produce hMI-ER1alpha and hMI-ER1beta. In all tissues except testis, transcripts encoding the beta isoform were predominant. hMI-ER1alpha lacks the predicted nuclear localization signal and transfection assays revealed that, unlike hMI-ER1beta, it is not a nuclear protein, but remains in the cytoplasm. Our results demonstrate that alternate use of a facultative intron regulates the subcellular localization of hMI-ER1 proteins and this may have important implications for hMI-ER1 function.

48 CFR 53.301-1094A - SF 1094A, Tax Exemption Certificates Accountability Record.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false SF 1094A, Tax Exemption Certificates Accountability Record. 53.301-1094A Section 53.301-1094A Federal Acquisition Regulations System... 1094A, Tax Exemption Certificates Accountability Record. ER02JA97.013 ER02JA97.014 [62 FR 247, Jan. 2...

Methodological Implications of the Affect Revolution: A 35-Year Review of Emotion Regulation Assessment in Children

ERIC Educational Resources Information Center

Adrian, Molly; Zeman, Janice; Veits, Gina

2011-01-01

This investigation analyzed the methods used over the past 35 years to study emotion regulation (ER) in children. Articles published from 1975 through 2010 were identified in 42 child clinical, developmental, and emotion psychology journals. Overall, 61.1% of published ER articles relied on one method and 23.6% used two methods. Analyses revealed…

The Multifaceted Role of Attachment during Preschool: Moderator of Its Indirect Effect on Empathy through Emotion Regulation

ERIC Educational Resources Information Center

Stefan, Catrinel A.; Avram, Julia

2018-01-01

The aims of the current study were (1) to replicate findings regarding the mediator role of emotion regulation (ER) between attachment and empathy; (2) to extend current knowledge by testing the moderator effect of ER on the relationship between attachment and empathy; and (3) to test an integrative moderated mediation model in which attachment…

Improving Emotion Regulation and Sibling Relationship Quality: The More Fun with Sisters and Brothers Program

ERIC Educational Resources Information Center

Kennedy, Denise E.; Kramer, Laurie

2008-01-01

We examined the role of emotion regulation (ER) in improving sibling relationship quality (SRQ) by evaluating the More Fun With Sisters and Brothers Program where 4- to 8-year-old siblings from 95 families were taught emotional and social competencies. Parents reported on SRQ and ER, and sibling interactions were observed in homes. SRQ and ER…

Brainstem Regions Involved in the Expiration Reflex. A c-fos Study in Anesthetized Cats

PubMed Central

Poliacek, Ivan; Halasova, Erika; Jakus, Jan; Murin, Peter; Barani, Helena; Stransky, Albert; Bolser, Donald C

2009-01-01

Expression of the immediate-early gene c-fos, a marker of neuronal activation, was employed to localize brainstem neuronal populations functionally related to the expiration reflex (ER). Twelve spontaneously breathing, non-decerebrate, pentobarbital anesthetized cats were used. The level of Fos-like immunoreactivity (FLI) in 6 animals with repetitive ERs mechanically induced from the glottis (296±9 ERs) was compared to FLI in 6 control non-stimulated cats. Respiratory rate, arterial blood pressure, and end tidal CO2 concentration remained stable during the experiment. In the medulla, increased FLI was found in the region of nucleus tractus solitarii (p<0.001), in the ventrolateral medulla along with the lateral tegmental field (p<0.01), and in the vestibular nuclei (p<0.01). In the pons, increased FLI was detected in the caudal extensions of the lateral parabrachial and Kölliker-Fuse nuclei (p<0.05). Within the rostral mesencephalon FLI was enhanced in the midline area (p<0.05). A lower level of ER-related FLI compared to control animals was detected in the pontine raphe region (p<0.05) and the lateral division of mesencephalic periaqueductal gray (p<0.05). The results suggest that the ER is coordinated by a complex long loop of medullary-pontine-mesencephalic neuronal circuits, some of which may differ from those of other respiratory reflexes. The FLI related to the expulsive behavior ER differs from that induced by laryngeal stimulation and laryngeal adductor responses, particularly in ventrolateral medulla and mesencephalon. PMID:17964550

Estradiol agonists inhibit human LoVo colorectal-cancer cell proliferation and migration through p53.

PubMed

Hsu, Hsi-Hsien; Kuo, Wei-Wen; Ju, Da-Tong; Yeh, Yu-Lan; Tu, Chuan-Chou; Tsai, Ying-Lan; Shen, Chia-Yao; Chang, Sheng-Huang; Chung, Li-Chin; Huang, Chih-Yang

2014-11-28

To investigate the effects of 17β-estradiol via estrogen receptors (ER) or direct administration of ER agonists on human colorectal cancer. LoVo cells were established from the Bioresource Collection and Research Center and cultured in phenol red-free DMEM (Sigma, United States). To investigate the effects of E2 and/or ER selective agonists on cellular proliferation, LoVo colorectal cells were treated with E2 or ER-selective agonists for 24 h and 48 h and subjected to the MTT (Sigma) assay to find the concentration. And investigate the effects of E2 and/or ER selective agonists on cell used western immunoblotting to find out the diversification of signaling pathways. In order to observe motility and migration the wound healing assay and a transwell chamber (Neuro Probe) plate were tased. For a quantitative measure, we counted the number of migrating cells to the wound area post-wounding for 24 h. We further examined the cellular migration-regulating factors urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and matrix metalloproteinase (MMP)-9 in human LoVo cells so gelatin zymography that we used and gelatinolytic activity was visualized by Coomassie blue staining. And these results are presented as means ± SE, and statistical comparisons were made using Student's t-test. The structure was first compared with E2 and ER agonists. We then treated the LoVo cells with E2 and ER agonists (10(-8) mol/L) for 24 h and 48 h and subsequently measured the cell viability using MTT assay. Our results showed that treatment with 17β-estradiol and/or ER agonists in human LoVo colorectal cancer cells activated p53 and then up-regulated p21 and p27 protein levels, subsequently inhibiting the downstream target gene, cyclin D1, which regulates cell proliferation. Taken together, our findings demonstrate the anti-tumorigenesis effects of 17β-estradiol and/or ER agonists and suggest that these compounds may prove to be a potential alternative therapy in the treatment of human colorectal cancer. These results demonstrate that 17β-estradiol and/or ER agonists downregulate migration-related proteins through the p53 signaling pathway in human LoVo colorectal cancer cells. These findings suggest that p53 plays a critical role in the 17β-estradiol and/or ER agonist-mediated protective activity against colorectal cancer progression. In addition, 17β-estradiol and/or ER agonists dramatically inhibited cell migration and reduced the expression of u-PA, t-PA and MMP-9 as well as MMP-2/9 activity in LoVo cells, which regulate cell metastasis. Moreover, we observed that pretreatment with a p53 inhibitor significantly blocked the anti-migration effects of E2 and/or ER agonists on LoVo cells. That E2 and/or ER agonists may impair LoVo cell migration by modulating migration-related factors via the p53 tumor suppressor gene. Direct ER treatment may prove to be an attractive alternative therapy in the treatment of human colorectal tumors in the future.

The dynamic changes of endoplasmic reticulum stress pathway markers GRP78 and CHOP in the hippocampus of diabetic mice.

PubMed

Zhao, Yongmei; Yan, Ying; Zhao, Zhiwei; Li, Sen; Yin, Jie

2015-02-01

Diabetic encephalopathy has recently been recognized late complication of diabetes resulting in progressive cognitive deficits. Emerging evidence has indicated that endoplasmic reticulum (ER) stress-mediated apoptosis is involved in the pathogenesis of diabetic eye and kidney as well as non-diabetic neurodegeneration. However, there was little direct evidence for the involvement of ER stress in diabetic encephalopathy up to now. In the present work, we investigated the role of ER stress in the pathogenesis of diabetic encephalopathy. Our results have demonstrated the existence of ER stress in the hippocampus of streptozotocin (STZ)-induced diabetic mice. STZ injection i.p. rapidly induced up-regulation of the ER stress marker, the prosurvival chaperone glucose-regulated protein 78 (GRP78), as early as 6-24h and persisted at least for up to 72h in the hippocampus of mice, indicating the UPR activation soon after STZ administration. The increased expression of GRP78 in hippocampal cells is to relieve the ER stress. With the development of diabetes, the expression of GRP78 decreases while the expression of UPR-associated proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) increases significantly in the hippocampal neurons of diabetic mice from 1 week after STZ administration to 12 weeks/the end of the study. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells in the hippocampus of diabetic mice were largely colocalized with NeuN- and CHOP-positive cells, indicating that the up-regulation of CHOP in hippocampal neurons of diabetic mice may promote neuronal apoptosis and account for the damaged learning and memory ability of diabetic mice. Therefore, our study provides evidence that ER stress may play an important role in the pathogenesis of neuronal degeneration and may contribute to cognitive dysfunction of diabetic encephalopathy. Copyright © 2014 Elsevier Inc. All rights reserved.

Fluid cognitive ability is a resource for successful emotion regulation in older and younger adults

PubMed Central

Opitz, Philipp C.; Lee, Ihno A.; Gross, James J.; Urry, Heather L.

2014-01-01

The Selection, Optimization, and Compensation with Emotion Regulation (SOC-ER) framework suggests that (1) emotion regulation (ER) strategies require resources and that (2) higher levels of relevant resources may increase ER success. In the current experiment, we tested the specific hypothesis that individual differences in one internal class of resources, namely cognitive ability, would contribute to greater success using cognitive reappraisal (CR), a form of ER in which one reinterprets the meaning of emotion-eliciting situations. To test this hypothesis, 60 participants (30 younger and 30 older adults) completed standardized neuropsychological tests that assess fluid and crystallized cognitive ability, as well as a CR task in which participants reinterpreted the meaning of sad pictures in order to alter (increase or decrease) their emotions. In a control condition, they viewed the pictures without trying to change how they felt. Throughout the task, we indexed subjective emotional experience (self-reported ratings of emotional intensity), expressive behavior (corrugator muscle activity), and autonomic physiology (heart rate and electrodermal activity) as measures of emotional responding. Multilevel models were constructed to explain within-subjects variation in emotional responding as a function of ER contrasts comparing increase or decrease conditions with the view control condition and between-subjects variation as a function of cognitive ability and/or age group (older, younger). As predicted, higher fluid cognitive ability—indexed by perceptual reasoning, processing speed, and working memory—was associated with greater success using reappraisal to alter emotional responding. Reappraisal success did not vary as a function of crystallized cognitive ability or age group. Collectively, our results provide support for a key tenet of the SOC-ER framework that higher levels of relevant resources may confer greater success at emotion regulation. PMID:24987387

Glucose Regulation of Load‐Induced mTOR Signaling and ER Stress in Mammalian Heart

PubMed Central

Sen, Shiraj; Kundu, Bijoy K.; Wu, Henry Cheng‐Ju; Hashmi, S. Shahrukh; Guthrie, Patrick; Locke, Landon W.; Roy, R. Jack; Matherne, G. Paul; Berr, Stuart S.; Terwelp, Matthew; Scott, Brian; Carranza, Sylvia; Frazier, O. Howard; Glover, David K.; Dillmann, Wolfgang H.; Gambello, Michael J.; Entman, Mark L.; Taegtmeyer, Heinrich

2013-01-01

Background Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose‐6‐phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6‐phosphate (G6P) accumulation. Methods and Results We subjected the working rat heart ex vivo to a high workload in the presence of different energy‐providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4‐phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2‐deoxy‐d‐glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro‐PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. Conclusions We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load‐induced mTOR activation and ER stress. PMID:23686371

Fluid cognitive ability is a resource for successful emotion regulation in older and younger adults.

PubMed

Opitz, Philipp C; Lee, Ihno A; Gross, James J; Urry, Heather L

2014-01-01

The Selection, Optimization, and Compensation with Emotion Regulation (SOC-ER) framework suggests that (1) emotion regulation (ER) strategies require resources and that (2) higher levels of relevant resources may increase ER success. In the current experiment, we tested the specific hypothesis that individual differences in one internal class of resources, namely cognitive ability, would contribute to greater success using cognitive reappraisal (CR), a form of ER in which one reinterprets the meaning of emotion-eliciting situations. To test this hypothesis, 60 participants (30 younger and 30 older adults) completed standardized neuropsychological tests that assess fluid and crystallized cognitive ability, as well as a CR task in which participants reinterpreted the meaning of sad pictures in order to alter (increase or decrease) their emotions. In a control condition, they viewed the pictures without trying to change how they felt. Throughout the task, we indexed subjective emotional experience (self-reported ratings of emotional intensity), expressive behavior (corrugator muscle activity), and autonomic physiology (heart rate and electrodermal activity) as measures of emotional responding. Multilevel models were constructed to explain within-subjects variation in emotional responding as a function of ER contrasts comparing increase or decrease conditions with the view control condition and between-subjects variation as a function of cognitive ability and/or age group (older, younger). As predicted, higher fluid cognitive ability-indexed by perceptual reasoning, processing speed, and working memory-was associated with greater success using reappraisal to alter emotional responding. Reappraisal success did not vary as a function of crystallized cognitive ability or age group. Collectively, our results provide support for a key tenet of the SOC-ER framework that higher levels of relevant resources may confer greater success at emotion regulation.

Autophagy-related direct membrane import from ER/cytoplasm into the vacuole or apoplast: a hidden gateway also for secondary metabolites and phytohormones?

PubMed

Kulich, Ivan; Žárský, Viktor

2014-04-29

Transportation of low molecular weight cargoes into the plant vacuole represents an essential plant cell function. Several lines of evidence indicate that autophagy-related direct endoplasmic reticulum (ER) to vacuole (and also, apoplast) transport plays here a more general role than expected. This route is regulated by autophagy proteins, including recently discovered involvement of the exocyst subcomplex. Traffic from ER into the vacuole bypassing Golgi apparatus (GA) acts not only in stress-related cytoplasm recycling or detoxification, but also in developmentally-regulated biopolymer and secondary metabolite import into the vacuole (or apoplast), exemplified by storage proteins and anthocyanins. We propose that this pathway is relevant also for some phytohormones' (e.g., auxin, abscisic acid (ABA) and salicylic acid (SA)) degradation. We hypothesize that SA is not only an autophagy inducer, but also a cargo for autophagy-related ER to vacuole membrane container delivery and catabolism. ER membrane localized enzymes will potentially enhance the area of biosynthetic reactive surfaces, and also, abundant ER localized membrane importers (e.g., ABC transporters) will internalize specific molecular species into the autophagosome biogenesis domain of ER. Such active ER domains may create tubular invaginations of tonoplast into the vacuoles as import intermediates. Packaging of cargos into the ER-derived autophagosome-like containers might be an important mechanism of vacuole and exosome biogenesis and cytoplasm protection against toxic metabolites. A new perspective on metabolic transformations intimately linked to membrane trafficking in plants is emerging.

A systematic review on the neural effects of music on emotion regulation: implications for music therapy practice.

PubMed

Moore, Kimberly Sena

2013-01-01

Emotion regulation (ER) is an internal process through which a person maintains a comfortable state of arousal by modulating one or more aspects of emotion. The neural correlates underlying ER suggest an interplay between cognitive control areas and areas involved in emotional reactivity. Although some studies have suggested that music may be a useful tool in ER, few studies have examined the links between music perception/production and the neural mechanisms that underlie ER and resulting implications for clinical music therapy treatment. Objectives of this systematic review were to explore and synthesize what is known about how music and music experiences impact neural structures implicated in ER, and to consider clinical implications of these findings for structuring music stimuli to facilitate ER. A comprehensive electronic database search resulted in 50 studies that met predetermined inclusion and exclusion criteria. Pertinent data related to the objective were extracted and study outcomes were analyzed and compared for trends and common findings. Results indicated there are certain music characteristics and experiences that produce desired and undesired neural activation patterns implicated in ER. Desired activation patterns occurred when listening to preferred and familiar music, when singing, and (in musicians) when improvising; undesired activation patterns arose when introducing complexity, dissonance, and unexpected musical events. Furthermore, the connection between music-influenced changes in attention and its link to ER was explored. Implications for music therapy practice are discussed and preliminary guidelines for how to use music to facilitate ER are shared.

Autophagy-Related Direct Membrane Import from ER/Cytoplasm into the Vacuole or Apoplast: A Hidden Gateway also for Secondary Metabolites and Phytohormones?

PubMed Central

Kulich, Ivan; Žárský, Viktor

2014-01-01

Transportation of low molecular weight cargoes into the plant vacuole represents an essential plant cell function. Several lines of evidence indicate that autophagy-related direct endoplasmic reticulum (ER) to vacuole (and also, apoplast) transport plays here a more general role than expected. This route is regulated by autophagy proteins, including recently discovered involvement of the exocyst subcomplex. Traffic from ER into the vacuole bypassing Golgi apparatus (GA) acts not only in stress-related cytoplasm recycling or detoxification, but also in developmentally-regulated biopolymer and secondary metabolite import into the vacuole (or apoplast), exemplified by storage proteins and anthocyanins. We propose that this pathway is relevant also for some phytohormones’ (e.g., auxin, abscisic acid (ABA) and salicylic acid (SA)) degradation. We hypothesize that SA is not only an autophagy inducer, but also a cargo for autophagy-related ER to vacuole membrane container delivery and catabolism. ER membrane localized enzymes will potentially enhance the area of biosynthetic reactive surfaces, and also, abundant ER localized membrane importers (e.g., ABC transporters) will internalize specific molecular species into the autophagosome biogenesis domain of ER. Such active ER domains may create tubular invaginations of tonoplast into the vacuoles as import intermediates. Packaging of cargos into the ER-derived autophagosome-like containers might be an important mechanism of vacuole and exosome biogenesis and cytoplasm protection against toxic metabolites. A new perspective on metabolic transformations intimately linked to membrane trafficking in plants is emerging. PMID:24786101

The Conundrum of Estrogen Receptor Oscillatory Activity in the Search for an Appropriate Hormone Replacement Therapy

PubMed Central

Della Torre, Sara; Biserni, Andrea; Rando, Gianpaolo; Monteleone, Giuseppina; Ciana, Paolo; Komm, Barry

2011-01-01

By the use of in vivo imaging, we investigated the dynamics of estrogen receptor (ER) activity in intact, ovariectomized, and hormone-replaced estrogen response element-luciferase reporter mice. The study revealed the existence of a long-paced, noncircadian oscillation of ER transcriptional activity. Among the ER-expressing organs, this oscillation was asynchronous and its amplitude and period were tissue dependent. Ovariectomy affected the amplitude but did not suppress ER oscillations, suggesting the presence of tissue endogenous oscillators. Long-term administration of raloxifene, bazedoxifene, combined estrogens alone or with basedoxifene to ovariectomized estrogen response element-luciferase mice showed that each treatment induced a distinct spatiotemporal profile of ER activity, demonstrating that the phasing of ER activity among tissues may be regulated by the chemical nature and the concentration of circulating estrogen. This points to the possibility of a hierarchical organization of the tissue-specific pacemakers. Conceivably, the rhythm of ER transcriptional activity translates locally into the activation of specific gene networks enabling ER to significantly change its physiological activity according to circulating estrogens. In reproductive and nonreproductive organs this hierarchical regulation may provide ER with the signaling plasticity necessary to drive the complex metabolic changes occurring at each female reproductive status. We propose that the tissue-specific oscillatory activity here described is an important component of ER signaling necessary for the full hormone action including the beneficial effects reported for nonreproductive organs. Thus, this mechanism needs to be taken in due consideration to develop novel, more efficacious, and safer hormone replacement therapies. PMID:21505049

Uncovering a Dual Regulatory Role for Caspases During Endoplasmic Reticulum Stress-induced Cell Death

PubMed Central

Anania, Veronica G.; Yu, Kebing; Gnad, Florian; Pferdehirt, Rebecca R.; Li, Han; Ma, Taylur P.; Jeon, Diana; Fortelny, Nikolaus; Forrest, William; Ashkenazi, Avi; Overall, Christopher M.; Lill, Jennie R.

2016-01-01

Many diseases are associated with endoplasmic reticulum (ER) stress, which results from an accumulation of misfolded proteins. This triggers an adaptive response called the “unfolded protein response” (UPR), and prolonged exposure to ER stress leads to cell death. Caspases are reported to play a critical role in ER stress-induced cell death but the underlying mechanisms by which they exert their effect continue to remain elusive. To understand the role caspases play during ER stress, a systems level approach integrating analysis of the transcriptome, proteome, and proteolytic substrate profile was employed. This quantitative analysis revealed transcriptional profiles for most human genes, provided information on protein abundance for 4476 proteins, and identified 445 caspase substrates. Based on these data sets many caspase substrates were shown to be downregulated at the protein level during ER stress suggesting caspase activity inhibits their cellular function. Additionally, RNA sequencing revealed a role for caspases in regulation of ER stress-induced transcriptional pathways and gene set enrichment analysis showed expression of multiple gene targets of essential transcription factors to be upregulated during ER stress upon inhibition of caspases. Furthermore, these transcription factors were degraded in a caspase-dependent manner during ER stress. These results indicate that caspases play a dual role in regulating the cellular response to ER stress through both post-translational and transcriptional regulatory mechanisms. Moreover, this study provides unique insight into progression of the unfolded protein response into cell death, which may help identify therapeutic strategies to treat ER stress-related diseases. PMID:27125827

Uncovering a Dual Regulatory Role for Caspases During Endoplasmic Reticulum Stress-induced Cell Death.

PubMed

Anania, Veronica G; Yu, Kebing; Gnad, Florian; Pferdehirt, Rebecca R; Li, Han; Ma, Taylur P; Jeon, Diana; Fortelny, Nikolaus; Forrest, William; Ashkenazi, Avi; Overall, Christopher M; Lill, Jennie R

2016-07-01

Many diseases are associated with endoplasmic reticulum (ER) stress, which results from an accumulation of misfolded proteins. This triggers an adaptive response called the "unfolded protein response" (UPR), and prolonged exposure to ER stress leads to cell death. Caspases are reported to play a critical role in ER stress-induced cell death but the underlying mechanisms by which they exert their effect continue to remain elusive. To understand the role caspases play during ER stress, a systems level approach integrating analysis of the transcriptome, proteome, and proteolytic substrate profile was employed. This quantitative analysis revealed transcriptional profiles for most human genes, provided information on protein abundance for 4476 proteins, and identified 445 caspase substrates. Based on these data sets many caspase substrates were shown to be downregulated at the protein level during ER stress suggesting caspase activity inhibits their cellular function. Additionally, RNA sequencing revealed a role for caspases in regulation of ER stress-induced transcriptional pathways and gene set enrichment analysis showed expression of multiple gene targets of essential transcription factors to be upregulated during ER stress upon inhibition of caspases. Furthermore, these transcription factors were degraded in a caspase-dependent manner during ER stress. These results indicate that caspases play a dual role in regulating the cellular response to ER stress through both post-translational and transcriptional regulatory mechanisms. Moreover, this study provides unique insight into progression of the unfolded protein response into cell death, which may help identify therapeutic strategies to treat ER stress-related diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Synaptotagmin SYTA forms ER-plasma membrane junctions that are recruited to plasmodesmata for plant virus movement.

PubMed

Levy, Amit; Zheng, Judy Y; Lazarowitz, Sondra G

2015-08-03

Metazoan synaptotagmins are Ca(2+) sensors that regulate exocytosis and endocytosis in various cell types, notably in nerve and neuroendocrine cells [1, 2]. Recently, the structurally related extended synaptotagmins were shown to tether the cortical ER to the plasma membrane in human and yeast cells to maintain ER morphology and stabilize ER-plasma membrane (ER-PM) contact sites for intracellular lipid and Ca(2+) signaling [3, 4]. The Arabidopsis synaptotagmin SYTA regulates endocytosis and the ability of plant virus movement proteins (MPs) to alter plasmodesmata to promote virus cell-to-cell transport [5, 6]. Yet how MPs modify plasmodesmata, the cellular functions of SYTA and how these aid MP activity, and the proteins essential to form plant cell ER-PM contact sites remain unknown. We addressed these questions using an Arabidopsis SYTA knockdown line syta-1 and a Tobamovirus movement protein MP(TVCV) [5, 7]. We report here that SYTA localized to ER-PM contact sites. These sites were depleted and the ER network collapsed in syta-1, and both reformed upon rescue with SYTA. MP(TVCV) accumulation in plasmodesmata, but not secretory trafficking, was also inhibited in syta-1. During infection, MP(TVCV) recruited SYTA to plasmodesmata, and SYTA and the cortical ER were subsequently remodeled to form viral replication sites adjacent to plasmodesmata in which MP(TVCV) and SYTA directly interacted caged within ER membrane. SYTA also accumulated in plasmodesmata active in MP(TVCV) transport. Our findings show that SYTA is essential to form ER-PM contact sites and suggest that MPs interact with SYTA to recruit these sites to alter plasmodesmata for virus cell-to-cell movement. Copyright © 2015 Elsevier Ltd. All rights reserved.

Loss of Mitofusin 2 Promotes Endoplasmic Reticulum Stress*

PubMed Central

Ngoh, Gladys A.; Papanicolaou, Kyriakos N.; Walsh, Kenneth

2012-01-01

The outer mitochondrial membrane GTPase mitofusin 2 (Mfn2) is known to regulate endoplasmic reticulum (ER) shape in addition to its mitochondrial fusion effects. However, its role in ER stress is unknown. We report here that induction of ER stress with either thapsigargin or tunicamycin in mouse embryonic fibroblasts leads to up-regulation of Mfn2 mRNA and protein levels with no change in the expression of the mitochondrial shaping factors Mfn1, Opa1, Drp1, and Fis1. Genetic deletion of Mfn2 but not Mfn1 in mouse embryonic fibroblasts or cardiac myocytes in mice led to an increase in the expression of the ER chaperone proteins. Genetic ablation of Mfn2 in mouse embryonic fibroblasts amplified ER stress and exacerbated ER stress-induced apoptosis. Deletion of Mfn2 delayed translational recovery through prolonged eIF2α phosphorylation associated with decreased GADD34 and p58IPK expression and elevated C/EBP homologous protein induction at late time points. These changes in the unfolded protein response were coupled to increased cell death reflected by augmented caspase 3/7 activity, lactate dehydrogenase release from cells, and an increase in propidium iodide-positive nuclei in response to thapsigargin or tunicamycin treatment. In contrast, genetic deletion of Mfn1 did not affect ER stress-mediated increase in ER chaperone synthesis or eIF2α phosphorylation. Additionally, ER stress-induced C/EBP homologous protein, GADD34, and p58IPK induction and cell death were not affected by loss of Mfn1. We conclude that Mfn2 but not Mfn1 is an ER stress-inducible protein that is required for the proper temporal sequence of the ER stress response. PMID:22511781

Teachers' Emotion Regulation Skills Facilitate Implementation of Health-related Intentions.

PubMed

Eckert, Marcus; Ebert, David D; Lehr, Dirk; Sieland, Bernhard; Jazaieri, Hooria; Berking, Matthias

2015-11-01

Many teachers report high levels of job-related stress. Successful outcomes in stress-management trainings depend on participants actively engaging in skill-building exercises. However, despite good intentions to engage in such exercises on a regular basis, many participants ultimately fail to do so. The present study seeks to understand whether general emotion regulation (ER) skills moderate the relation between the intention to engage in skill-building exercises and actually engaging in these exercises. ER skills, the intention to engage in autonomous skill-building exercises, and the extent to which individuals actually engaged in such exercises were assessed in a sample of 119 teachers participating in stress-management training. ER skills significantly moderated the association between the intention and engagement in skill-building practice. The greater the ER skills, the more coupled was the relation between the intention and actual practices. Findings are consistent with the hypotheses. Thus, skill-building trainings should support participants scoring low in ER skills in effectively coping with aversive affective states cued through skill-building exercises.

49 CFR Appendix E to Part 599 - Disposal Facility Certification Form

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Disposal Facility Certification Form E Appendix E to Part 599 Transportation Other Regulations Relating to Transportation (Continued) NATIONAL HIGHWAY... Facility Certification Form ER05AU09.020 ER05AU09.021 ER05AU09.022 [74 FR 38976, Aug. 5, 2009] ...

Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

PubMed Central

Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E.; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F.G.; Rothermel, Beverly A.; Lavandero, Sergio

2014-01-01

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER–mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245

Predictive Rotation Profile Control for the DIII-D Tokamak

NASA Astrophysics Data System (ADS)

Wehner, W. P.; Schuster, E.; Boyer, M. D.; Walker, M. L.; Humphreys, D. A.

2017-10-01

Control-oriented modeling and model-based control of the rotation profile are employed to build a suitable control capability for aiding rotation-related physics studies at DIII-D. To obtain a control-oriented model, a simplified version of the momentum balance equation is combined with empirical representations of the momentum sources. The control approach is rooted in a Model Predictive Control (MPC) framework to regulate the rotation profile while satisfying constraints associated with the desired plasma stored energy and/or βN limit. Simple modifications allow for alternative control objectives, such as maximizing the plasma rotation while maintaining a specified input torque. Because the MPC approach can explicitly incorporate various types of constraints, this approach is well suited to a variety of control objectives, and therefore serves as a valuable tool for experimental physics studies. Closed-loop TRANSP simulations are presented to demonstrate the effectiveness of the control approach. Supported by the US DOE under DE-SC0010661 and DE-FC02-04ER54698.

ER-to-plasma membrane tethering proteins regulate cell signaling and ER morphology.

PubMed

Manford, Andrew G; Stefan, Christopher J; Yuan, Helen L; Macgurn, Jason A; Emr, Scott D

2012-12-11

Endoplasmic reticulum-plasma membrane (ER-PM) junctions are conserved structures defined as regions of the ER that tightly associate with the plasma membrane. However, little is known about the mechanisms that tether these organelles together and why such connections are maintained. Using a quantitative proteomic approach, we identified three families of ER-PM tethering proteins in yeast: Ist2 (related to mammalian TMEM16 ion channels), the tricalbins (Tcb1/2/3, orthologs of the extended synaptotagmins), and Scs2 and Scs22 (vesicle-associated membrane protein-associated proteins). Loss of all six tethering proteins results in the separation of the ER from the PM and the accumulation of cytoplasmic ER. Importantly, we find that phosphoinositide signaling is misregulated at the PM, and the unfolded protein response is constitutively activated in the ER in cells lacking ER-PM tether proteins. These results reveal critical roles for ER-PM contacts in cell signaling, organelle morphology, and ER function. Copyright © 2012 Elsevier Inc. All rights reserved.

Regulation of Cancer Stem Cell Self-Renewal by HOXB9 Antagonizes Endoplasmic Reticulum Stress-Induced Melanoma Cell Apoptosis via the miR-765-FOXA2 Axis.

PubMed

Lin, Jingrong; Zhang, Dongmei; Fan, Yongsheng; Chao, Yulin; Chang, Jinming; Li, Na; Han, Linlin; Han, Chuanchun

2018-07-01

Adaptation to endoplasmic reticulum (ER) stress has been indicated as a driver of malignancy and resistance to therapy in human melanoma. However, the relationship between cancer stem cells and adaptation to ER stress remains unclear. Here, we show that the ratio of cancer stem cells is increased in ER stress-resistant melanoma cells, which inhibit ER stress-induced apoptosis and promote tumorigenesis. Further mechanistic studies showed that HOXB9 triggered by ER stress favors cancer stem cell self-renewal and enhances ER stress resistance. HOXB9 directly binds to the promoter of microRNA-765 and facilitates its transcription, which in turn targets FOXA2, resulting in a FOXA2 decrease and cancer stem cell increase. Additionally, an increase in HOXB9 promotes melanoma growth and inhibits cell apoptosis in a mouse xenograft model. Elevated HOXB9 is found in human melanoma tissues, which is associated with microRNA-765 up-regulation and FOXA2 decreases. Thus, our data showed that the HOXB9-dependent, microRNA-765-mediated FOXA2 pathway contributes to the survival of melanoma under ER stress by maintaining the properties of cancer stem cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Endothelial NOS activation induces the blood-brain barrier disruption via ER stress following status epilepticus.

PubMed

Ko, Ah-Reum; Kim, Ji Yang; Hyun, Hye-Won; Kim, Ji-Eun

2015-10-05

The blood-brain barrier (BBB) maintains the unique brain microenvironment, which is separated from the systemic circulating system. Since the endoplasmic reticulum (ER) is an important cell organelle that is responsible for protein synthesis, the correct folding and sorting of proteins contributing to cell survivals, ER stress is a potential cause of cell damage in various diseases. Therefore, it would be worthy to explore the the relationship between the ER stress and BBB disruption during vasogenic edema formation induced by epileptogenic insults. In the present study, we investigated the roles of ER stress in vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced status epilepticus (SE). SE-induced eNOS activation induces BBB breakdown via up-regulation of GRP78 expression and dysfunction of SMI-71 (an endothelial BBB marker) in the piriform cortex (PC). In addition, caveolin-1 peptide (an eNOS inhibitor) effectively attenuated GRP78 expression and down-regulation of SMI-71. Taken together, our findings suggest that eNOS-mediated ER stress may participate in SE-induced vasogenic edema formation. Therefore, the modulation of ER stress may be a considerable strategy for therapy in impairments of endothelial cell function. Copyright © 2015 Elsevier B.V. All rights reserved.

Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

PubMed Central

Basseri, Sana; Austin, Richard C.

2012-01-01

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis. PMID:22195283

Efficient carrier-envelope offset frequency stabilization through gain modulation via stimulated emission.

PubMed

Karlen, Lauriane; Buchs, Gilles; Portuondo-Campa, Erwin; Lecomte, Steve

2016-01-15

A novel scheme for intracavity control of the carrier-envelope offset (CEO) frequency of a 100 MHz mode-locked Er:Yb:glass diode-pumped solid-state laser (DPSSL) based on the modulation of the laser gain via stimulated emission of the excited Er(3+) ions is demonstrated. This method allows us to bypass the ytterbium system few-kHz low-pass filter in the f(CEO) stabilization loop and thus to push the phase lock bandwidth up to a limit close to the relaxation oscillations frequency of the erbium system. A phase lock bandwidth above 70 kHz has been achieved with the fully stabilized laser, leading to an integrated phase noise [1 Hz-1 MHz] of 120 mrad.

Self- and Co-Regulation of Anger and Fear in Preschoolers with Autism Spectrum Disorders: The Role of Maternal Parenting Style and Temperament

ERIC Educational Resources Information Center

Hirschler-Guttenberg, Yael; Feldman, Ruth; Ostfeld-Etzion, Sharon; Laor, Nathaniel; Golan, Ofer

2015-01-01

Emotion regulation (ER) difficulties are a major concern in children with autism spectrum disorder (ASD). Maternal temperament and parenting style have significant effects on children's ER. However, these effects have not been studied in children with ASD. Forty preschoolers with ASD and their mothers and forty matched controls engaged in fear and…

A Limited Repertoire of Emotion Regulation Strategies Is Associated with Internalizing Problems in Adolescence

ERIC Educational Resources Information Center

Lougheed, Jessica P.; Hollenstein, Tom

2012-01-01

The present study was designed to test whether the beneficial effects of emotion regulation (ER) have less to do with the use of singular, "adaptive" strategies and more to do with using a range of strategies. Using a community sample of adolescents (N = 177, M = 13.6 years), groups based on five measures of ER (reappraisal, suppression,…

GLP-1 promotes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum-mitochondria coupling.

PubMed

Morales, Pablo E; Torres, Gloria; Sotomayor-Flores, Cristian; Peña-Oyarzún, Daniel; Rivera-Mejías, Pablo; Paredes, Felipe; Chiong, Mario

2014-03-28

Incretin GLP-1 has important metabolic effects on several tissues, mainly through the regulation of glucose uptake and usage. One mechanism for increasing cell metabolism is modulating endoplasmic reticulum (ER)-mitochondria communication, as it allows for a more efficient transfer of Ca(2+) into the mitochondria, thereby increasing activity. Control of glucose metabolism is essential for proper vascular smooth muscle cell (VSMC) function. GLP-1 has been shown to produce varied metabolic actions, but whether it regulates glucose metabolism in VSMC remains unknown. In this report, we show that GLP-1 increases mitochondrial activity in the aortic cell line A7r5 by increasing ER-mitochondria coupling. GLP-1 increases intracellular glucose and diminishes glucose uptake without altering glycogen content. ATP, mitochondrial potential and oxygen consumption increase at 3h of GLP-1 treatment, paralleled by increased Ca(2+) transfer from the ER to the mitochondria. Furthermore, GLP-1 increases levels of Mitofusin-2 (Mfn2), an ER-mitochondria tethering protein, via a PKA-dependent mechanism. Accordingly, PKA inhibition and Mfn2 down-regulation prevented mitochondrial Ca(2+) increases in GLP-1 treated cells. Inhibiting both Ca(2+) release from the ER and Ca(2+) entry into mitochondria as well as diminishing Mfn2 levels blunted the increase in mitochondrial activity in response to GLP-1. Altogether, these results strongly suggest that GLP-1 increases ER-mitochondria communication in VSMC, resulting in higher mitochondrial activity. Copyright © 2014 Elsevier Inc. All rights reserved.

Elucidation of Chromatin Remodeling Machinery Involved in Regulation of Estrogen Receptor Alpha Expression in Human Breast Cancer Cells

DTIC Science & Technology

2005-08-01

encoded by different genes (26, 27)), can act as transcriptional repressors by using their ATRX domain to recruit HDAC1 (28, 29). Heterochromatic...ER-positive MCF-7 cells with an unmethylated ER promoter were used as our model system. Using antibodies against acetylated H4, acetylated H3...MBD1, and anti MBD2 antibodies revealed that these proteins are associated with the silenced ER promoter in MDA-MB-231 cells whereas the active ER

The SANT domain of human MI-ER1 interacts with Sp1 to interfere with GC box recognition and repress transcription from its own promoter.

PubMed

Ding, Zhihu; Gillespie, Laura L; Mercer, F Corinne; Paterno, Gary D

2004-07-02

To gain insight into the regulation of hmi-er1 expression, we cloned a human genomic DNA fragment containing one of the two hmi-er1 promoters and consisting of 1460 bp upstream of the translation initiation codon of hMI-ER1. Computer-assisted sequence analysis revealed that the hmi-er1 promoter region contains a CpG island but lacks an identifiable TATA element, initiator sequence and downstream promoter element. This genomic DNA was able to direct transcription of a luciferase reporter gene in a variety of human cell lines, and the minimal promoter was shown to be located within-68/+144 bp. Several putative Sp1 binding sites were identified, and we show that Sp1 can bind to the hmi-er1 minimal promoter and increase transcription, suggesting that the level of hmi-er1 expression may depend on the availability of Sp1 protein. Functional analysis revealed that hMI-ER1 represses Sp1-activated transcription from the minimal promoter by a histone deacetylase-independent mechanism. Chromatin immunoprecipitation analysis demonstrated that both Sp1 and hMI-ER1 are associated with the chromatin of the hmi-er1 promoter and that overexpression of hMI-ER1 in cell lines that allow Tet-On-inducible expression resulted in loss of detectable Sp1 from the endogenous hmi-er1 promoter. The mechanism by which this occurs does not involve binding of hMI-ER1 to cis-acting elements. Instead, we show that hMI-ER1 physically associates with Sp1 and that endogenous complexes containing the two proteins could be detected in vivo. Furthermore, hMI-ER1 specifically interferes with binding of Sp1 to the hmi-er1 minimal promoter as well as to an Sp1 consensus oligonucleotide. Deletion analysis revealed that this interaction occurs through a region containing the SANT domain of hMI-ER1. Together, these data reveal a functional role for the SANT domain in the action of co-repressor regulatory factors and suggest that the association of hMI-ER1 with Sp1 represents a novel mechanism for the negative regulation of Sp1 target promoters.

Dominant gain-of-function mutations in transmembrane domain III of ERS1 and ETR1 suggest a novel role for this domain in regulating the magnitude of ethylene response in Arabidopsis.

PubMed

Deslauriers, Stephen D; Alvarez, Ashley A; Lacey, Randy F; Binder, Brad M; Larsen, Paul B

2015-10-01

Prior work resulted in identification of an Arabidopsis mutant, eer5-1, with extreme ethylene response in conjunction with failure to induce a subset of ethylene-responsive genes, including AtEBP. EER5, which is a TREX-2 homolog that is part of a nucleoporin complex, functions as part of a cryptic aspect of the ethylene signaling pathway that is required for regulating the magnitude of ethylene response. A suppressor mutagenesis screen was carried out to identify second site mutations that could restore the growth of ethylene-treated eer5-1 to wild-type levels. A dominant gain-of-function mutation in the ethylene receptor ETHYLENE RESPONSE SENSOR 1 (ERS1) was identified, with the ers1-4 mutation being located in transmembrane domain III at a point nearly equivalent to the previously described etr1-2 mutation in the other Arabidopsis subfamily I ethylene receptor, ETHYLENE RESPONSE 1 (ETR1). Although both ers1-4 and etr1-2 partially suppress the ethylene hypersensitivity of eer5-1 and are at least in part REVERSION TO ETHYLENE SENSITIVITY 1 (RTE1)-dependent, ers1-4 was additionally found to restore the expression of AtEBP in ers1-4;eer5-1 etiolated seedlings after ethylene treatment in an EIN3-dependent manner. Our work indicates that ERS1-regulated expression of a subset of ethylene-responsive genes is related to controlling the magnitude of ethylene response, with hyperinduction of these genes correlated with reduced ethylene-dependent growth inhibition. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

The Lifetime of UDP-galactose:Ceramide Galactosyltransferase Is Controlled by a Distinct Endoplasmic Reticulum-associated Degradation (ERAD) Regulated by Sigma-1 Receptor Chaperones*

PubMed Central

Hayashi, Teruo; Hayashi, Eri; Fujimoto, Michiko; Sprong, Hein; Su, Tsung-Ping

2012-01-01

The glycosphingolipid biosynthesis is initiated by monoglycosylation of ceramides, the action of which is catalyzed either by UDP-glucose:ceramide glucosyltransferase or by UDP-galactose:ceramide galactosyltransferase (CGalT). CGalT is expressed predominantly at the endoplasmic reticulum (ER) of oligodendrocytes and is responsible for synthesizing galactosylceramides (GalCer) that play an important role in regulation of axon conductance. However, despite the importance of ceramide monoglycosylation enzymes in a spectrum of cellular functions, the mechanism that fine tunes activities of those enzymes is largely unknown. In the present study, we demonstrated that the sigma-1 receptor (Sig-1R) chaperone, the mammalian homologue of a yeast C8-C7 sterol isomerase, controls the protein level and activity of the CGalT enzyme via a distinct ER-associated degradation system involving Insig. The Sig-1R forms a complex with Insig via its transmembrane domain partly in a sterol-dependent manner and associates with CGalT at the ER. The knockdown of Sig-1Rs dramatically prolonged the lifetime of CGalT without affecting the trimming of N-linked oligosaccharides at CGalT. The increased lifetime leads to the up-regulation of CGalT protein as well as elevated enzymatic activity in CHO cells stably expressing CGalT. Knockdown of Sig-1Rs also decreased CGalT degradation endogenously expressed in D6P2T-schwannoma cells. Our data suggest that Sig-1Rs negatively regulate the activity of GalCer synthesis under physiological conditions by enhancing the degradation of CGalT through regulation of the dynamics of Insig in the lipid-activated ER-associated degradation system. The GalCer synthesis may thus be influenced by sterols at the ER. PMID:23105111

The Golgi apparatus regulates cGMP-dependent protein kinase I compartmentation and proteolysis.

PubMed

Kato, Shin; Chen, Jingsi; Cornog, Katherine H; Zhang, Huili; Roberts, Jesse D

2015-06-01

cGMP-dependent protein kinase I (PKGI) is an important effector of cGMP signaling that regulates vascular smooth muscle cell (SMC) phenotype and proliferation. PKGI has been detected in the perinuclear region of cells, and recent data indicate that proprotein convertases (PCs) typically resident in the Golgi apparatus (GA) can stimulate PKGI proteolysis and generate a kinase fragment that localizes to the nucleus and regulates gene expression. However, the role of the endomembrane system in PKGI compartmentation and processing is unknown. Here, we demonstrate that PKGI colocalizes with endoplasmic reticulum (ER), ER-Golgi intermediate compartment, GA cisterna, and trans-Golgi network proteins in pulmonary artery SMC and cell lines. Moreover, PKGI localizes with furin, a trans-Golgi network-resident PC known to cleave PKGI. ER protein transport influences PKGI localization because overexpression of a constitutively inactive Sar1 transgene caused PKGI retention in the ER. Additionally, PKGI appears to reside within the GA because PKGI immunoreactivity was determined to be resistant to cytosolic proteinase K treatment in live cells. The GA appears to play a role in PKGI proteolysis because overexpression of inositol 1,4,5-trisphosphate receptor-associated cGMP kinase substrate, not only tethered heterologous PKGI-β to the ER and decreased its localization to the GA, but also diminished PKGI proteolysis and nuclear translocation. Also, inhibiting intra-GA protein transport with monensin was observed to decrease PKGI cleavage. These studies detail a role for the endomembrane system in regulating PKGI compartmentation and proteolysis. Moreover, they support the investigation of mechanisms regulating PKGI-dependent nuclear cGMP signaling in the pulmonary vasculature with Golgi dysfunction. Copyright © 2015 the American Physiological Society.

Induced ER-chaperones regulate a novel receptor-like kinase to mediate a viral innate immune response

PubMed Central

Caplan, Jeffrey L.; Zhu, Xiaohong; Mamillapalli, Padmavathi; Marathe, Rajendra; Anandalakshmi, Radhamani; Dinesh-Kumar, S. P.

2009-01-01

Summary The plant innate immune response requires a rapid, global reprogramming of cellular processes. Here we employed two complementary proteomic methods, two-dimensional differential in-gel electrophoresis (2D-DIGE) and iTRAQ, to identify differentially regulated proteins early during a defense response. Besides defense-related proteins, the constituents of the largest category of up-regulated proteins were cytoplasmic- and endoplasmic reticulum (ER)-residing molecular chaperones. Silencing of ER-resident protein disulfide isomerases, NbERp57 and NbP5, and the calreticulins, NbCRT2 and NbCRT3, lead to a partial loss of N immune receptor-mediated defense against Tobacco mosaic virus (TMV). Furthermore, NbCRT2 and NbCRT3 are required for the expression of a novel induced receptor-like kinase (IRK). IRK is a plasma membrane-localized protein required for the N-mediated hypersensitive response programmed cell death (HR-PCD) and resistance to TMV. These data support a model in which ER-resident chaperones are required for the accumulation of membrane bound or secreted proteins that are necessary for innate immunity. PMID:19917500

ER-plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI3P synthesis.

PubMed

Nascimbeni, Anna Chiara; Giordano, Francesca; Dupont, Nicolas; Grasso, Daniel; Vaccaro, Maria I; Codogno, Patrice; Morel, Etienne

2017-07-14

The double-membrane-bound autophagosome is formed by the closure of a structure called the phagophore, origin of which is still unclear. The endoplasmic reticulum (ER) is clearly implicated in autophagosome biogenesis due to the presence of the omegasome subdomain positive for DFCP1, a phosphatidyl-inositol-3-phosphate (PI3P) binding protein. Contribution of other membrane sources, like the plasma membrane (PM), is still difficult to integrate in a global picture. Here we show that ER-plasma membrane contact sites are mobilized for autophagosome biogenesis, by direct implication of the tethering extended synaptotagmins (E-Syts) proteins. Imaging data revealed that early autophagic markers are recruited to E-Syt-containing domains during autophagy and that inhibition of E-Syts expression leads to a reduction in autophagosome biogenesis. Furthermore, we demonstrate that E-Syts are essential for autophagy-associated PI3P synthesis at the cortical ER membrane via the recruitment of VMP1, the stabilizing ER partner of the PI3KC3 complex. These results highlight the contribution of ER-plasma membrane tethers to autophagosome biogenesis regulation and support the importance of membrane contact sites in autophagy. © 2017 The Authors.

Characterization of an estrogen-responsive element implicated in regulation of the rainbow trout estrogen receptor gene.

PubMed

Le Dréan, Y; Lazennec, G; Kern, L; Saligaut, D; Pakdel, F; Valotaire, Y

1995-08-01

We previously reported that the expression of the rainbow trout estrogen receptor (rtER) gene is markedly increased by estradiol (E2). In this paper, we have used transient transfection assays with reporter plasmids expressing chloramphenicol acetyl transferase (CAT), linked to 5' flanking regions of the rtER gene promoter, to identify cis-elements responsible for E2 inducibility. Deletion analysis localized an estrogen-responsive element (ERE), at position +242, with one mutation on the first base compared with the consensus sequence. This element confers estrogen responsiveness to CAT reporter linked to both the herpes simplex virus thymidine kinase promoter and the homologous rtER promoter. Moreover, using a 0.2 kb fragment of the rtER promoter encompassing the ERE and the rtER DNA binding domain obtained from a bacterial expression system, DNase I footprinting experiments demonstrated a specific protection covering 20 bp (+240/+260) containing the ERE sequence. Based on these studies, we believe that this ERE sequence, identified in the rtER gene promoter, may be a major cis-acting element involved in the regulation of the gene by estrogen.

Can we link emotional eating with the emotion regulation skills of adolescents?

PubMed

Vandewalle, Julie; Moens, Ellen; Beyers, Wim; Braet, Caroline

2016-07-01

A recent cross-sectional study showed that maternal rejection is associated with emotional eating of obese youngsters seeking treatment, and that this relation is mediated by maladaptive emotion regulation (ER) of the youngsters. We wanted to build on this study and investigate the relation between parental rejection, maladaptive ER and emotional eating in a community sample using longitudinal data. Participants were 81 youngsters between the ages of 10 and 16 years. Participants completed questionnaires assessing maternal and paternal rejection, ER strategies and emotional eating, at two time moments (M = 71 days between time moments). Latent change models were used to estimate level and change of each variable. Results showed that the levels of maternal rejection, maladaptive ER and emotional eating were related. The indirect effect of the level of maternal rejection on the level of emotional eating through the level of maladaptive ER was marginally significant. On average, maternal rejection showed no change over time, whereas the other variables decreased. The changes in the variables were not related. The findings highlight the importance of assessing the emotional bond between mother and youngster and the ER of youngsters with an emotional eating style.

The ER-mitochondria interface: the social network of cell death.

PubMed

Grimm, Stefan

2012-02-01

When cellular organelles communicate bad things can happen. Recent findings uncovered that the junction between the endoplasmic reticulum (ER) and the mitochondria holds a crucial role for cell death regulation. Not only does this locale connect the two best-known organelles in apoptosis, numerous regulators of cell death are concentrated at this spot, providing a terrain for intense signal transfers. Ca2+ is the most prominent signalling factor that is released from the ER and, at high concentration, mediates the transfer of an apoptosis signal to mitochondria as the executioner organelle for cell death. An elaborate array of checks and balances is fine-tuning this process including Bcl-2 family members. Moreover, MAMs, "mitochondria-associated membranes", are distinct membrane sections at the ER that are in close contact with mitochondria and have been found to exchange lipids and lipid-derived molecules such as ceramide for apoptosis induction. Recent work has also described a reverse transfer of apoptosis signals, from mitochondria to the ER, via cytochrome c release and prolonged IP3R opening or through the mitochondrial fission factor Fis1 and Bap31 at the ER, which form the ARCosome, a novel caspase-activation complex. Copyright © 2011 Elsevier B.V. All rights reserved.

Regulation of endoplasmic reticulum turnover by selective autophagy.

PubMed

Khaminets, Aliaksandr; Heinrich, Theresa; Mari, Muriel; Grumati, Paolo; Huebner, Antje K; Akutsu, Masato; Liebmann, Lutz; Stolz, Alexandra; Nietzsche, Sandor; Koch, Nicole; Mauthe, Mario; Katona, Istvan; Qualmann, Britta; Weis, Joachim; Reggiori, Fulvio; Kurth, Ingo; Hübner, Christian A; Dikic, Ivan

2015-06-18

The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.

Getting in (and out of) the loop: regulating higher order telomere structures.

PubMed

Luke-Glaser, Sarah; Poschke, Heiko; Luke, Brian

2012-01-01

The DNA at the ends of linear chromosomes (the telomere) folds back onto itself and forms an intramolecular lariat-like structure. Although the telomere loop has been implicated in the protection of chromosome ends from nuclease-mediated resection and unscheduled DNA repair activities, it potentially poses an obstacle to the DNA replication machinery during S-phase. Therefore, the coordinated regulation of telomere loop formation, maintenance, and resolution is required in order to establish a balance between protecting the chromosome ends and promoting their duplication prior to cell division. Until recently, the only factor known to influence telomere looping in human cells was TRF2, a component of the shelterin complex. Recent work in yeast and mouse cells has uncovered additional regulatory factors that affect the loop structure at telomeres. In the following "perspective" we outline what is known about telomere looping and highlight the latest results regarding the regulation of this chromosome end structure. We speculate about how the manipulation of the telomere loop may have therapeutic implications in terms of diseases associated with telomere dysfunction and uncontrolled proliferation.

A family of membrane-shaping proteins at ER subdomains regulates pre-peroxisomal vesicle biogenesis.

PubMed

Joshi, Amit S; Huang, Xiaofang; Choudhary, Vineet; Levine, Tim P; Hu, Junjie; Prinz, William A

2016-11-21

Saccharomyces cerevisiae contains three conserved reticulon and reticulon-like proteins that help maintain ER structure by stabilizing high membrane curvature in ER tubules and the edges of ER sheets. A mutant lacking all three proteins has dramatically altered ER morphology. We found that ER shape is restored in this mutant when Pex30p or its homologue Pex31p is overexpressed. Pex30p can tubulate membranes both in cells and when reconstituted into proteoliposomes, indicating that Pex30p is a novel ER-shaping protein. In contrast to the reticulons, Pex30p is low abundance, and we found that it localizes to subdomains in the ER. We show that these ER subdomains are the sites where most preperoxisomal vesicles (PPVs) are generated. In addition, overproduction or deletion of Pex30p or Pex31p alters the size, shape, and number of PPVs. Our findings suggest that Pex30p and Pex31p help shape and generate regions of the ER where PPV biogenesis occurs.

A SAL1 Loss-of-Function Arabidopsis Mutant Exhibits Enhanced Cadmium Tolerance in Association with Alleviation of Endoplasmic Reticulum Stress.

PubMed

Xi, Hongmei; Xu, Hua; Xu, Wenxiu; He, Zhenyan; Xu, Wenzhong; Ma, Mi

2016-06-01

SAL1, as a negative regulator of stress response signaling, has been studied extensively for its role in plant response to environmental stresses. However, the role of SAL1 in cadmium (Cd) stress response and the underlying mechanism is still unclear. Using an Arabidopsis thaliana loss-of-function mutant of SAL1, we assessed Cd resistance and further explored the Cd toxicity mechanism through analysis of the endoplasmic reticulum (ER) stress response. The loss of SAL1 function greatly improved Cd tolerance and significantly attenuated ER stress in Arabidopsis. Exposure to Cd induced an ER stress response in Arabidopsis as evidenced by unconventional splicing of AtbZIP60 and up-regulation of ER stress-responsive genes. Damage caused by Cd was markedly reduced in the ER stress response double mutant bzip28 bzip60 or by application of the ER stress-alleviating chemical agents, tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (4-PBA), in wild-type plants. The Cd-induced ER stress in Arabidopsis was also alleviated by loss of function of SAL1. These results identified SAL1 as a new component mediating Cd toxicity and established the role of the ER stress response in Cd toxicity. Additionally, the attenuated ER stress in the sal1 mutant might also shed new light on the mechanism of diverse abiotic stress resistance in the SAL1 loss-of-function mutants. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Deletion of protein tyrosine phosphatase 1B obliterates endoplasmic reticulum stress-induced myocardial dysfunction through regulation of autophagy.

PubMed

Wang, Shuyi; Chen, Xiyao; Nair, Sreejayan; Sun, Dongdong; Wang, Xiaoming; Ren, Jun

2017-12-01

Endoplasmic reticulum (ER) stress has been demonstrated to prompt various cardiovascular risks although the underlying mechanism remains elusive. Protein tyrosine phosphatase-1B (PTP1B) serves as an essential negative regulator for insulin signaling. This study examined the role of PTP1B in ER stress-induced myocardial anomalies and underlying mechanism involved with a focus on autophagy. WT and PTP1B knockout mice were subjected to the ER stress inducer tunicamycin (1mg/kg). Cardiac function was evaluated with echocardiography and an Ion-Optix MyoCam system. Western blot analysis was used to monitor the levels of ER stress, autophagy and insulin signaling including insulin receptor substrate (IRS), tribbles homolog 3 (TRIB3), Atg5/7, p62 and LC3-II. Our results showed that ER stress resulted in compromised echocardiographic and cardiomyocyte contractile function, intracellular Ca 2+ mishandling, ER stress, O 2 - production, apoptosis, the effects of which (with the exception of ER stress) were significantly attenuated or negated by PTP1B ablation. Levels of serine phosphorylation of IRS-1, TRIB3, Atg5/7, LC3B and the autophagy adaptor p62 were significantly upregulated while IRS-1 tyrosine phosphorylation was reduced by tunicamycin, the effect of which were obliterated by PTP1B ablation. In vitro study revealed that the autophagy inducer rapamycin and TRIB3 overexpression cancelled PTP1B ablation-offered beneficial effects on cardiomyocyte function or O 2 - production in murine cardiomyocytes or H9C2 myoblasts. Antioxidant or gene silencing of TRIB3 mimicked PTP1B ablation-induced protective effects. These findings collectively suggested that PTP1B ablation protects against ER stress-induced cardiac anomalies through regulation of autophagy. Copyright © 2017 Elsevier B.V. All rights reserved.

Stromal Clues in Endometrial Carcinoma: Loss of Expression of β-Catenin, Epithelial-Mesenchymal Transition Regulators, and Estrogen-Progesterone Receptor.

PubMed

Senol, Serkan; Sayar, Ilyas; Ceyran, Ayse B; Ibiloglu, Ibrahim; Akalin, Ibrahim; Firat, Ugur; Kosemetin, Duygu; Engin Zerk, Pinar; Aydin, Abdullah

2016-05-01

Epithelial-stroma interactions in the endometrium are known to be responsible for physiological functions and emergence of several pathologic lesions. Periglandular stromal cells act on endometrial cells in a paracrine manner through sex hormones. In this study, we immunohistochemically evaluated the expression of epithelial-mesenchymal transition regulators (SNAIL/SLUG, TWIST, ZEB1), adhesion molecules (β-catenin and E-cadhenin), estrogen (ER)-progesterone (PR) receptor and their correlation with each other in 30 benign, 148 hyperplastic (EH), and 101 endometrioid-type endometrial carcinoma (EC) endometria. In the epithelial component, loss of expression in E-cadherin, ER and PR, and overexpression of TWIST and ZEB1 were significantly higher in EC than in EH (P<0.01). In the periglandular stromal component, β-catenin and SNAIL/SLUG expression were significantly higher in normal endometrium and simple without atypical EH compared with complex atypical EH and EC (P<0.01). In addition, periglandular stromal TWIST expression was significantly higher in EH group compared with EC (P<0.05). There was significantly negative correlation between β-catenin and ER, TWIST and ER, and TWIST and PR in hyperplastic and carcinomatous glandular epithelium, whereas there was a significantly positive correlation between β-catenin and SNAIL-SLUG, β-catenin and TWIST, β-catenin and ER, β-catenin and PR, SNAIL-SLUG and ER, SNAIL-SLUG and PR, TWIST and ER, TWIST and PR, in periglandular/cancer-associated stromal cells (P<0.01). In conclusion, the pattern of positive and negative correlations in the expression of epithelial-mesenchymal transition regulators (SNAIL-SLUG and TWIST), sex hormone receptors (ER and PR), and β-catenin between ECs and hyperplasia, as well as between epithelium and stroma herein, is suggestive of a significant role for these proteins and their underlying molecular processes in the development of endometrial carcinomas.

Stromal Clues in Endometrial Carcinoma: Loss of Expression of β-Catenin, Epithelial-Mesenchymal Transition Regulators, and Estrogen-Progesterone Receptor

PubMed Central

Sayar, Ilyas; Ceyran, Ayse B.; Ibiloglu, Ibrahim; Akalin, Ibrahim; Firat, Ugur; Kosemetin, Duygu; Engin Zerk, Pinar; Aydin, Abdullah

2016-01-01

Epithelial-stroma interactions in the endometrium are known to be responsible for physiological functions and emergence of several pathologic lesions. Periglandular stromal cells act on endometrial cells in a paracrine manner through sex hormones. In this study, we immunohistochemically evaluated the expression of epithelial-mesenchymal transition regulators (SNAIL/SLUG, TWIST, ZEB1), adhesion molecules (β-catenin and E-cadhenin), estrogen (ER)-progesterone (PR) receptor and their correlation with each other in 30 benign, 148 hyperplastic (EH), and 101 endometrioid-type endometrial carcinoma (EC) endometria. In the epithelial component, loss of expression in E-cadherin, ER and PR, and overexpression of TWIST and ZEB1 were significantly higher in EC than in EH (P<0.01). In the periglandular stromal component, β-catenin and SNAIL/SLUG expression were significantly higher in normal endometrium and simple without atypical EH compared with complex atypical EH and EC (P<0.01). In addition, periglandular stromal TWIST expression was significantly higher in EH group compared with EC (P<0.05). There was significantly negative correlation between β-catenin and ER, TWIST and ER, and TWIST and PR in hyperplastic and carcinomatous glandular epithelium, whereas there was a significantly positive correlation between β-catenin and SNAIL-SLUG, β-catenin and TWIST, β-catenin and ER, β-catenin and PR, SNAIL-SLUG and ER, SNAIL-SLUG and PR, TWIST and ER, TWIST and PR, in periglandular/cancer-associated stromal cells (P<0.01). In conclusion, the pattern of positive and negative correlations in the expression of epithelial-mesenchymal transition regulators (SNAIL-SLUG and TWIST), sex hormone receptors (ER and PR), and β-catenin between ECs and hyperplasia, as well as between epithelium and stroma herein, is suggestive of a significant role for these proteins and their underlying molecular processes in the development of endometrial carcinomas. PMID:26367784

Endoplasmic reticulum stress responses function in the HRT-mediated hypersensitive response in Nicotiana benthamiana.

PubMed

Moon, Ju Yeon; Lee, Jeong Hee; Oh, Chang-Sik; Kang, Hong-Gu; Park, Jeong Mee

2016-12-01

HRT is a plant coiled-coil, nucleotide-binding and leucine-rich repeat (CC-NB-LRR) disease resistance protein that triggers the hypersensitive response (HR) on recognition of Turnip crinkle virus (TCV) coat protein (CP). The molecular mechanism and significance of HR-mediated cell death for TCV resistance have not been fully elucidated. To identify the genes involved in HRT/TCV CP-mediated HR in Nicotiana benthamiana, we performed virus-induced gene silencing (VIGS) of 459 expressed sequence tags (ESTs) of pathogen-responsive Capsicum annuum genes. VIGS of CaBLP5, which encodes an endoplasmic reticulum (ER)-associated immunoglobulin-binding protein (BiP), silenced NbBiP4 and NbBiP5 and significantly reduced HRT-mediated HR. The induction of ER stress-responsive genes and the accumulation of ER-targeted BiPs in response to HRT-mediated HR suggest that ER is involved in HR in N. benthamiana. BiP4/5 silencing significantly down-regulated HRT at the mRNA and protein levels, and affected SGT1 and HSP90 expression. Co-expression of TCV CP in BiP4/5-silenced plants completely abolished HRT induction. Transient expression of TCV CP alone induced selected ER stress-responsive gene transcripts only in Tobacco rattle virus (TRV)-infected plants, and most of these genes were induced by HRT/TCV CP, except for bZIP60, which was induced specifically in response to HRT/TCV CP. TCV CP-mediated induction of ER stress-responsive genes still occurred in BiP4/5-silenced plants, but HRT/TCV CP-mediated induction of these genes was defective. Tunicamycin, a chemical that inhibits protein N-glycosylation, inhibited HRT-mediated HR, suggesting that ER has a role in HR regulation. These results indicate that BiP and ER, which modulate pattern recognition receptors in innate immunity, also regulate R protein-mediated resistance. © 2016 BSPP and John Wiley & Sons Ltd.

O-GlcNAcylation of eIF2α regulates the phospho-eIF2α-mediated ER stress response.

PubMed

Jang, Insook; Kim, Han Byeol; Seo, Hojoong; Kim, Jin Young; Choi, Hyeonjin; Yoo, Jong Shin; Kim, Jae-woo; Cho, Jin Won

2015-08-01

O-GlcNAcylation is highly involved in cellular stress responses including the endoplasmic reticulum (ER) stress response. For example, glucosamine-induced flux through the hexosamine biosynthetic pathway can promote ER stress and ER stress inducers can change the total cellular level of O-GlcNAcylation. However, it is largely unknown which component(s) of the unfolded protein response (UPR) is directly regulated by O-GlcNAcylation. In this study, eukaryotic translation initiation factor 2α (eIF2α), a major branch of the UPR, was O-GlcNAcylated at Ser 219, Thr 239, and Thr 241. Upon ER stress, eIF2α is phosphorylated at Ser 51 by phosphorylated PKR-like ER kinase and this inhibits global translation initiation, except for that of specific mRNAs, including activating transcription factor 4, that induce stress-responsive genes such as C/EBP homologous protein (CHOP). Hyper-O-GlcNAcylation induced by O-GlcNAcase inhibitor (thiamet-G) treatment or O-GlcNAc transferase (OGT) overexpression hindered phosphorylation of eIF2α at Ser 51. The level of O-GlcNAcylation of eIF2α was changed by dithiothreitol treatment dependent on its phosphorylation at Ser 51. Point mutation of the O-GlcNAcylation sites of eIF2α increased its phosphorylation at Ser 51 and CHOP expression and resulted in increased apoptosis upon ER stress. These results suggest that O-GlcNAcylation of eIF2α affects its phosphorylation at Ser 51 and influences CHOP-mediated cell death. This O-GlcNAcylation of eIF2α was reproduced in thiamet-G-injected mouse liver. In conclusion, proper regulation of O-GlcNAcylation and phosphorylation of eIF2α is important to maintain cellular homeostasis upon ER stress. Copyright © 2015 Elsevier B.V. All rights reserved.

BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakuci, Enkeleda; Mahner, Sven; DiRenzo, James

2006-10-01

The regulator of cell cycle progression, cyclin D1, is up-regulated in breast cancer cells; its expression is, in part, dependent on ER{alpha} signaling. However, many ER{alpha}-negative tumors and tumor cell lines (e.g., SKBR3) also show over-expression of cyclin D1. This suggests that, in addition to ER{alpha} signaling, cyclin D1 expression is under the control of other signaling pathways; these pathways may even be over-expressed in the ER{alpha}-negative cells. We previously noticed that both ER{alpha}-positive and -negative cell lines over-express BRCA1-IRIS mRNA and protein. Furthermore, the level of over-expression of BRCA1-IRIS in ER{alpha}-negative cell lines even exceeded its over-expression level inmore » ER{alpha}-positive cell lines. In this study, we show that: (1) BRCA1-IRIS forms complex with two of the nuclear receptor co-activators, namely, SRC1 and SRC3 (AIB1) in an ER{alpha}-independent manner. (2) BRCA1-IRIS alone, or in connection with co-activators, is recruited to the cyclin D1 promoter through its binding to c-Jun/AP1 complex; this binding activates the cyclin D1 expression. (3) Over-expression of BRCA1-IRIS in breast cells over-activates JNK/c-Jun; this leads to the induction of cyclin D1 expression and cellular proliferation. (4) BRCA1-IRIS activation of JNK/c-Jun/AP1 appears to account for this, because in cells that were depleted from BRCA1-IRIS, JNK remained inactive. However, depletion of SRC1 or SRC3 instead reduced c-Jun expression. Our data suggest that this novel signaling pathway links BRCA1-IRIS to cellular proliferation through c-Jun/AP1 nuclear pathway; finally, this culminates in the increased expression of the cyclin D1 gene.« less

Neuro Emotional Literacy Program: Does Teaching the Function of Affect and Affect Regulation Strategies Improve Affect Management and Well-Being?

ERIC Educational Resources Information Center

Patten, Kathryn E.; Campbell, Stephen R.

2016-01-01

Although research on Emotion Regulation (ER) is developing at a rapid rate, much of it lacks a clear theoretical framework and most focuses on a narrow set of ER strategies. This work presents the details of a pilot project, the Neuro Emotional Literacy Program (NELP), designed for parents and based on the Somatic Appraisal Model of Affect (SAMA).…

[Impact of Emotion Regulation and Emotional Arousal on Quality of Life and Adherence of Couples after Kidney Transplantation].

PubMed

Peters, Luisa; Franke, Laura; Tkachenko, Daria; Schiffer, Mario; Zimmermann, Tanja

2018-05-01

Nonadherence to immunosuppressive medication increases the risk of graft failure. Maladaptive emotion regulation strategies (ERS) seem to be a risk factor for nonadherence, whereas for patients in relationships spousal support appears as a protective resource. Emotional arousal, objectively measured by the fundamental frequency (f 0 ) during spousal supportive communication is associated with supportive behavior. This study examined the relationship between beliefs about immunosuppressive medication, quality of life, ERS, emotions and emotional arousal, assessed during social support interactions of both spouses of N=50 couples after kidney transplantation. Maladaptive ERS of the transplant recipient were associated with lower mental quality of life of the partner, marginally higher own negative affect and lower beliefs about medication. Maladaptive ERS of the partner showed negative correlations with own mental quality of life. Regarding f 0 , gender differences were found. Higher f 0 of the male transplant recipient were associated with more maladaptive ERS of the female partner. Marginally significate correlations were found with lower own beliefs about medication. Higher f 0 of the wife of the male transplant recipient showed correlations with lower own positive affect, more negative affect of the male patient and lower beliefs about medication. Higher f 0 of female transplant recipients were associated with lower own maladaptive ERS and lower maladaptive ERS of the husband. The findings support the relevance of early interventions focusing on identifying and modifying maladaptive ERS for both the patient and partner. © Georg Thieme Verlag KG Stuttgart · New York.

The role of emotion regulation in situational empathy-related responding and prosocial behaviour in the presence of negative affect.

PubMed

Hein, Sascha; Röder, Mandy; Fingerle, Michael

2016-12-15

Empathy and prosocial behaviour are crucial factors for children's positive social adjustment. Contemporary models of empathy highlight the capacity to regulate vicariously experienced emotions as a precursor to empathy-related responses (e.g., prosocial behaviour). The goal of this study was to examine the role of emotion regulation (ER) in situational empathy-related responding and prosocial behaviour. A sample of 157 children (76 boys and 81 girls; M age = 9.94 years) participated in a two-tiered interview procedure that utilised vignettes to assess empathy and prosocial behaviour. Between both phases of the interview, a negative affect was induced to investigate the influence of ER on the change between the two phases. Results from a latent change model showed that ER strategies positively predicted change scores, that is, children with higher abilities to regulate emotions showed a higher increase in empathy and prosocial behaviour. Implications for the promotion of social-emotional learning in school are discussed. © 2016 International Union of Psychological Science.

A Model-Based Cluster Analysis of Maternal Emotion Regulation and Relations to Parenting Behavior.

PubMed

Shaffer, Anne; Whitehead, Monica; Davis, Molly; Morelen, Diana; Suveg, Cynthia

2017-10-15

In a diverse community sample of mothers (N = 108) and their preschool-aged children (M age  = 3.50 years), this study conducted person-oriented analyses of maternal emotion regulation (ER) based on a multimethod assessment incorporating physiological, observational, and self-report indicators. A model-based cluster analysis was applied to five indicators of maternal ER: maternal self-report, observed negative affect in a parent-child interaction, baseline respiratory sinus arrhythmia (RSA), and RSA suppression across two laboratory tasks. Model-based cluster analyses revealed four maternal ER profiles, including a group of mothers with average ER functioning, characterized by socioeconomic advantage and more positive parenting behavior. A dysregulated cluster demonstrated the greatest challenges with parenting and dyadic interactions. Two clusters of intermediate dysregulation were also identified. Implications for assessment and applications to parenting interventions are discussed. © 2017 Family Process Institute.

Membrane Contact Sites: Complex Zones for Membrane Association and Lipid Exchange

PubMed Central

Quon, Evan; Beh, Christopher T.

2015-01-01

Lipid transport between membranes within cells involves vesicle and protein carriers, but as agents of nonvesicular lipid transfer, the role of membrane contact sites has received increasing attention. As zones for lipid metabolism and exchange, various membrane contact sites mediate direct associations between different organelles. In particular, membrane contact sites linking the plasma membrane (PM) and the endoplasmic reticulum (ER) represent important regulators of lipid and ion transfer. In yeast, cortical ER is stapled to the PM through membrane-tethering proteins, which establish a direct connection between the membranes. In this review, we consider passive and facilitated models for lipid transfer at PM–ER contact sites. Besides the tethering proteins, we examine the roles of an additional repertoire of lipid and protein regulators that prime and propagate PM–ER membrane association. We conclude that instead of being simple mediators of membrane association, regulatory components of membrane contact sites have complex and multilayered functions. PMID:26949334

Mitochondria-Associated Membranes (MAMs): Overview and Its Role in Parkinson's Disease.

PubMed

Rodríguez-Arribas, M; Yakhine-Diop, S M S; Pedro, J M Bravo-San; Gómez-Suaga, P; Gómez-Sánchez, R; Martínez-Chacón, G; Fuentes, J M; González-Polo, R A; Niso-Santano, M

2017-10-01

Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i.e., autophagy dysregulation, mitochondrial dysfunction, oxidative stress, and lately, neuronal death. Moreover,, ER stress and/or damaged mitochondria can be the cause of these disruptions. Therefore, ER-mitochondria contact structure and function are crucial to multiple cellular processes. This review is focused on the molecular interaction between ER and mitochondria indispensable to MAM formation and on MAM alteration-induced etiology of neurodegenerative diseases.

Theory of Self- vs. Externally-Regulated LearningTM: Fundamentals, Evidence, and Applicability.

PubMed

de la Fuente-Arias, Jesús

2017-01-01

The Theory of Self- vs. Externally-Regulated Learning TM has integrated the variables of SRL theory, the DEDEPRO model, and the 3P model. This new Theory has proposed: (a) in general, the importance of the cyclical model of individual self-regulation (SR) and of external regulation stemming from the context (ER), as two different and complementary variables, both in combination and in interaction; (b) specifically, in the teaching-learning context, the relevance of different types of combinations between levels of self-regulation (SR) and of external regulation (ER) in the prediction of self-regulated learning (SRL), and of cognitive-emotional achievement. This review analyzes the assumptions, conceptual elements, empirical evidence, benefits and limitations of SRL vs. ERL Theory . Finally, professional fields of application and future lines of research are suggested.

Role of ER Export Signals in Controlling Surface Potassium Channel Numbers

NASA Astrophysics Data System (ADS)

Ma, Dzwokai; Zerangue, Noa; Lin, Yu-Fung; Collins, Anthony; Yu, Mei; Jan, Yuh Nung; Yeh Jan, Lily

2001-01-01

Little is known about the identity of endoplasmic reticulum (ER) export signals and how they are used to regulate the number of proteins on the cell surface. Here, we describe two ER export signals that profoundly altered the steady-state distribution of potassium channels and were required for channel localization to the plasma membrane. When transferred to other potassium channels or a G protein-coupled receptor, these ER export signals increased the number of functional proteins on the cell surface. Thus, ER export of membrane proteins is not necessarily limited by folding or assembly, but may be under the control of specific export signals.

The ER in 3D: a multifunctional dynamic membrane network.

PubMed

Friedman, Jonathan R; Voeltz, Gia K

2011-12-01

The endoplasmic reticulum (ER) is a large, singular, membrane-bound organelle that has an elaborate 3D structure with a diversity of structural domains. It contains regions that are flat and cisternal, ones that are highly curved and tubular, and others adapted to form contacts with nearly every other organelle and with the plasma membrane. The 3D structure of the ER is determined by both integral ER membrane proteins and by interactions with the cytoskeleton. In this review, we describe some of the factors that are known to regulate ER structure and discuss how this structural organization and the dynamic nature of the ER membrane network allow it to perform its many different functions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Conditions for Stabilizability of Linear Switched Systems

NASA Astrophysics Data System (ADS)

Minh, Vu Trieu

2011-06-01

This paper investigates some conditions that can provide stabilizability for linear switched systems with polytopic uncertainties via their closed loop linear quadratic state feedback regulator. The closed loop switched systems can stabilize unstable open loop systems or stable open loop systems but in which there is no solution for a common Lyapunov matrix. For continuous time switched linear systems, we show that if there exists solution in an associated Riccati equation for the closed loop systems sharing one common Lyapunov matrix, the switched linear systems are stable. For the discrete time switched systems, we derive a Linear Matrix Inequality (LMI) to calculate a common Lyapunov matrix and solution for the stable closed loop feedback systems. These closed loop linear quadratic state feedback regulators guarantee the global asymptotical stability for any switched linear systems with any switching signal sequence.

Biochemical evidence that regulation of Ero1β activity in human cells does not involve the isoform-specific cysteine 262

PubMed Central

Hansen, Henning G.; Søltoft, Cecilie L.; Schmidt, Jonas D.; Birk, Julia; Appenzeller-Herzog, Christian; Ellgaard, Lars

2014-01-01

In the ER (endoplasmic reticulum) of human cells, disulfide bonds are predominantly generated by the two isoforms of Ero1 (ER oxidoreductin-1): Ero1α and Ero1β. The activity of Ero1α is tightly regulated through the formation of intramolecular disulfide bonds to help ensure balanced ER redox conditions. Ero1β is less tightly regulated, but the molecular details underlying control of activity are not as well characterized as for Ero1α. Ero1β contains an additional cysteine residue (Cys262), which has been suggested to engage in an isoform-specific regulatory disulfide bond with Cys100. However, we show that the two regulatory disulfide bonds in Ero1α are likely conserved in Ero1β (Cys90–Cys130 and Cys95–Cys100). Molecular modelling of the Ero1β structure predicted that the side chain of Cys262 is completely buried. Indeed, we found this cysteine to be reduced and partially protected from alkylation in the ER of living cells. Furthermore, mutation of Cys100–but not of Cys262–rendered Ero1β hyperactive in cells, as did mutation of Cys130. Ero1β hyperactivity induced the UPR (unfolded protein response) and resulted in oxidative perturbation of the ER redox state. We propose that features other than a distinct pattern of regulatory disulfide bonds determine the loose redox regulation of Ero1β relative to Ero1α. PMID:27919037

GILZ overexpression attenuates endoplasmic reticulum stress-mediated cell death via the activation of mitochondrial oxidative phosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

André, Fanny; Corazao-Rozas, Paola; Idziorek, Thierry

The Glucocorticoïd-induced leucine zipper (GILZ) protein has profound anti-inflammatory activities in haematopoietic cells. GILZ regulates numerous signal transduction pathways involved in proliferation and survival of normal and neoplastic cells. Here, we have demonstrated the potential of GILZ in alleviating apoptosis induced by ER stress inducers. Whereas the glucocorticoid, dexamethasone, protects from tunicamycin-induced cell death, silencing endogeneous GILZ in dexamethasone-treated cancer cells alter the capacity of glucocorticoids to protect from tunicamycin-mediated apoptosis. Under ER stress conditions, overexpression of GILZ significantly reduced activation of mitochondrial pathway of apoptosis by maintaining Bcl-xl level. GILZ protein affects the UPR signaling shifting the balance towardsmore » pro-survival signals as judged by down-regulation of CHOP, ATF4, XBP1s mRNA and increase in GRP78 protein level. Interestingly, GILZ sustains high mitochondrial OXPHOS during ER stress and cytoprotection mediated by GILZ is abolished in cells depleted of mitochondrial DNA, which are OXPHOS-deficient. These findings reveal a new role of GILZ, which acts as a cytoprotector against ER stress through a pathway involving mitochondrial OXPHOS. - Highlights: • GILZ attenuates apoptotic cell death induced by ER stress conditions. • GILZ promotes pro-survival signaling of the UPR. • GILZ overexpression sustains high mitochondrial activity under ER stress. • Mitochondrial OXPHOX is required for GILZ protective effects against ER stress-mediated apoptosis.« less

ER Stress-Mediated Signaling: Action Potential and Ca(2+) as Key Players.

PubMed

Bahar, Entaz; Kim, Hyongsuk; Yoon, Hyonok

2016-09-15

The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca(2+)) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca(2+) regulates cell death both at the early and late stages of apoptosis. Severe Ca(2+) dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca(2+) (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca(2+) and action potential in ER stress-mediated apoptosis.

Maternal emotion regulation during child distress, child anxiety accommodation, and links between maternal and child anxiety.

PubMed

Kerns, Caroline E; Pincus, Donna B; McLaughlin, Katie A; Comer, Jonathan S

2017-08-01

Environmental contributions are thought to play a primary role in the familial aggregation of anxiety, but parenting influences remain poorly understood. We examined dynamic relations between maternal anxiety, maternal emotion regulation (ER) during child distress, maternal accommodation of child distress, and child anxiety. Mothers (N=45) of youth ages 3-8 years (M=4.8) participated in an experimental task during which they listened to a standardized audio recording of a child in anxious distress pleading for parental intervention. Measures of maternal and child anxiety, mothers' affective states, mothers' ER strategies during the child distress, and maternal accommodation of child anxiety were collected. Mothers' resting respiratory sinus arrhythmia (RSA) reactivity during the recording was also acquired. Higher maternal negative affect and greater maternal ER switching (i.e., using multiple ER strategies in a short time without positive regulatory results) during child distress were associated with child anxiety. Sequential mediation modeling showed that maternal anxiety predicted ineffective maternal ER during child distress exposure, which in turn predicted greater maternal accommodation, which in turn predicted higher child anxiety. Findings support the mediating roles of maternal ER and accommodation in linking maternal and child anxiety, and suggest that ineffective maternal ER and subsequent attempts to accommodate child distress may act as mechanisms underlying the familial aggregation of anxiety. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL.

PubMed

Zhou, Yan; Kurukuti, Sreenivasulu; Saffrey, Peter; Vukovic, Milica; Michie, Alison M; Strogantsev, Ruslan; West, Adam G; Vetrie, David

2013-12-19

TAL1 is an important regulator of hematopoiesis and its expression is tightly controlled despite complexities in its genomic organization. It is frequently misregulated in T-cell acute lymphoblastic leukemia (T-ALL), often due to deletions between TAL1 and the neighboring STIL gene. To better understand the events that lead to TAL1 expression in hematopoiesis and in T-ALL, we studied looping interactions at the TAL1 locus. In TAL1-expressing erythroid cells, the locus adopts a looping "hub" which brings into close physical proximity all known TAL1 cis-regulatory elements including CTCF-bound insulators. Loss of GATA1 results in disassembly of the hub and loss of CTCF/RAD21 from one of its insulators. Genes flanking TAL1 are partly dependent on hub integrity for their transcriptional regulation. We identified looping patterns unique to TAL1-expressing T-ALL cells, and, intriguingly, loops occurring between the TAL1 and STIL genes at the common TAL1/STIL breakpoints found in T-ALL. These findings redefine how TAL1 and neighboring genes communicate within the nucleus, and indicate that looping facilitates both normal and aberrant TAL1 expression and may predispose to structural rearrangements in T-ALL. We also propose that GATA1-dependent looping mechanisms may facilitate the conservation of TAL1 regulation despite cis-regulatory remodeling during vertebrate evolution.

ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis.

PubMed

DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C; Guo, Deng-Fu; Gansemer, Erica R; Kaufman, Randal J; Rahmouni, Kamal; Gillum, Matthew P; Taylor, Eric B; Teesch, Lynn M; Rutkowski, D Thomas

2017-05-30

The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol

PubMed Central

Infante, Rodney Elwood; Radhakrishnan, Arun

2017-01-01

Cells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. To date, all inhibitors of cholesterol transport block steps in lysosomes, limiting our understanding of post-lysosomal transport steps. Here, we establish the cholesterol-binding domain 4 of anthrolysin O (ALOD4) as a reversible inhibitor of cholesterol transport from PM to endoplasmic reticulum (ER). Using ALOD4, we: (1) deplete ER cholesterol without altering PM or overall cellular cholesterol levels; (2) demonstrate that LDL-derived cholesterol travels from lysosomes first to PM to meet cholesterol needs, and subsequently from PM to regulatory domains of ER to suppress activation of SREBPs, halting cholesterol uptake and synthesis; and (3) determine that continuous PM-to-ER cholesterol transport allows ER to constantly monitor PM cholesterol levels, and respond rapidly to small declines in cellular cholesterol by activating SREBPs, increasing cholesterol uptake and synthesis. DOI: http://dx.doi.org/10.7554/eLife.25466.001 PMID:28414269

ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER.

PubMed

Costello, Joseph L; Castro, Inês G; Hacker, Christian; Schrader, Tina A; Metz, Jeremy; Zeuschner, Dagmar; Azadi, Afsoon S; Godinho, Luis F; Costina, Victor; Findeisen, Peter; Manner, Andreas; Islinger, Markus; Schrader, Michael

2017-02-01

Peroxisomes (POs) and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism and form tight structural associations, which were first observed in ultrastructural studies decades ago. PO-ER associations have been suggested to impact on a diverse number of physiological processes, including lipid metabolism, phospholipid exchange, metabolite transport, signaling, and PO biogenesis. Despite their fundamental importance to cell metabolism, the mechanisms by which regions of the ER become tethered to POs are unknown, in particular in mammalian cells. Here, we identify the PO membrane protein acyl-coenzyme A-binding domain protein 5 (ACBD5) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein B (VAPB). We show that ACBD5-VAPB interaction regulates PO-ER associations. Moreover, we demonstrate that loss of PO-ER association perturbs PO membrane expansion and increases PO movement. Our findings reveal the first molecular mechanism for establishing PO-ER associations in mammalian cells and report a new function for ACBD5 in PO-ER tethering. © 2017 Costello et al.

ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER

PubMed Central

Costello, Joseph L.; Hacker, Christian; Schrader, Tina A.; Zeuschner, Dagmar; Findeisen, Peter

2017-01-01

Peroxisomes (POs) and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism and form tight structural associations, which were first observed in ultrastructural studies decades ago. PO–ER associations have been suggested to impact on a diverse number of physiological processes, including lipid metabolism, phospholipid exchange, metabolite transport, signaling, and PO biogenesis. Despite their fundamental importance to cell metabolism, the mechanisms by which regions of the ER become tethered to POs are unknown, in particular in mammalian cells. Here, we identify the PO membrane protein acyl-coenzyme A–binding domain protein 5 (ACBD5) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein B (VAPB). We show that ACBD5–VAPB interaction regulates PO–ER associations. Moreover, we demonstrate that loss of PO–ER association perturbs PO membrane expansion and increases PO movement. Our findings reveal the first molecular mechanism for establishing PO–ER associations in mammalian cells and report a new function for ACBD5 in PO–ER tethering. PMID:28108524

ER-plasma membrane junctions: Why and how do we study them?

PubMed

Chang, Chi-Lun; Chen, Yu-Ju; Liou, Jen

2017-09-01

Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are membrane microdomains important for communication between the ER and the PM. ER-PM junctions were first reported in muscle cells in 1957, but mostly ignored in non-excitable cells due to their scarcity and lack of functional significance. In 2005, the discovery of stromal interaction molecule 1 (STIM1) mediating a universal Ca 2+ feedback mechanism at ER-PM junctions in mammalian cells led to a resurgence of research interests toward ER-PM junctions. In the past decade, several major advancements have been made in this emerging topic in cell biology, including the generation of tools for labeling ER-PM junctions and the unraveling of mechanisms underlying regulation and functions of ER-PM junctions. This review summarizes early studies, recently developed tools, and current advances in the characterization and understanding of ER-PM junctions. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann. Copyright © 2017 Elsevier B.V. All rights reserved.

Yif1 associates with Yip1 on Golgi and regulates dendrite pruning in sensory neurons during Drosophila metamorphosis.

PubMed

Wang, Qiwei; Wang, Yan; Yu, Fengwei

2018-05-16

Pruning that selectively removes unnecessary neurites without causing neuronal death is essential for sculpting the mature nervous system during development. In Drosophila , ddaC sensory neurons specifically prune their larval dendrites with intact axons during metamorphosis. However, it remains unknown about an important role of ER-to-Golgi transport in dendrite pruning. Here, in a clonal screen we identified Yif1, an uncharacterized Drosophila homologue of Yif1p that is known as a regulator of ER-to-Golgi transport in yeast. We show that Yif1 is required for dendrite pruning of ddaC neurons but not for apoptosis of ddaF neurons. We further identified the Yif1-binding partner Yip1 which is also crucial for dendrite pruning. Yif1 forms a protein complex with Yip1 in S2 cells and ddaC neurons. Yip1 and Yif1 colocalize on ER/Golgi and are required for the integrity of Golgi apparatus and outposts. Moreover, we show that two GTPases Rab1 and Sar1, known to regulate ER-to-Golgi transport, are essential for dendrite pruning of ddaC neurons. Finally, our data reveal that ER-to-Golgi transport promotes endocytosis and downregulation of cell adhesion molecule Neuroglian and thereby dendrite pruning. © 2018. Published by The Company of Biologists Ltd.

ER stress-mediated cell damage contributes to the release of EDA+ fibronectin from hepatocytes in nonalcoholic fatty liver disease.

PubMed

He, Lei; Yuan, Fa-Hu; Chen, Ting; Huang, Qiang; Wang, Yu; Liu, Zhi-Guo

2017-04-01

Fibronectin containing extra domain A (EDA + FN), a functional glycoprotein participating in several cellular processes, correlates with chronic liver disease. Herein, we aim to investigate the expression and secretion of EDA + FN from hepatocytes in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanisms. Circulating levels of EDA + FN were determined by ELISA in clinical samples. Western blotting and flow cytometry were performed on L02 and HepG2 cell lines to analyze whether the levels of EDA + FN were associated with endoplasmic reticulum (ER) stress-related cell death. Circulating levels of EDA + FN in NAFLD patients were significantly higher than those in control subjects, and positively related with severity of ultrasonographic steatosis score. In cultured hepatocytes, palmitate up-regulated the expression of EDA + FN in a dose-dependent manner. Conversely, when the cells were pretreated with 4-phenylbutyrate, a specific inhibitor of ER stress, up-regulation of EDA + FN could be abrogated. Moreover, silencing CHOP by shRNA enhanced the release of EDA + FN from hepatocytes following palmitate treatment, which was involved in ER stress-related cell damage. These findings suggest that the up-regulated level of EDA + FN is associated with liver damage in NAFLD, and ER stress-mediated cell damage contributes to the release of EDA + FN from hepatocytes.

SMILE, a new orphan nuclear receptor SHP-interacting protein, regulates SHP-repressed estrogen receptor transactivation.

PubMed

Xie, Yuan-Bin; Lee, Ok-Hee; Nedumaran, Balachandar; Seong, Hyun-A; Lee, Kyeong-Min; Ha, Hyunjung; Lee, In-Kyu; Yun, Yungdae; Choi, Hueng-Sik

2008-12-15

SHP (small heterodimer partner) is a well-known NR (nuclear receptor) co-regulator. In the present study, we have identified a new SHP-interacting protein, termed SMILE (SHP-interacting leucine zipper protein), which was previously designated as ZF (Zhangfei) via a yeast two-hybrid system. We have determined that the SMILE gene generates two isoforms [SMILE-L (long isoform of SMILE) and SMILE-S (short isoform of SMILE)]. Mutational analysis has demonstrated that the SMILE isoforms arise from the alternative usage of initiation codons. We have confirmed the in vivo interaction and co-localization of the SMILE isoforms and SHP. Domain-mapping analysis indicates that the entire N-terminus of SHP and the middle region of SMILE-L are involved in this interaction. Interestingly, the SMILE isoforms counteract the SHP repressive effect on the transactivation of ERs (estrogen receptors) in HEK-293T cells (human embryonic kidney cells expressing the large T-antigen of simian virus 40), but enhance the SHP-repressive effect in MCF-7, T47D and MDA-MB-435 cells. Knockdown of SMILE gene expression using siRNA (small interfering RNA) in MCF-7 cells increases ER-mediated transcriptional activity. Moreover, adenovirus-mediated overexpression of SMILE and SHP down-regulates estrogen-induced mRNA expression of the critical cell-cycle regulator E2F1. Collectively, these results indicate that SMILE isoforms regulate the inhibition of ER transactivation by SHP in a cell-type-specific manner and act as a novel transcriptional co-regulator in ER signalling.

Differential Regulation of Native Estrogen Receptor-Regulatory Elements by Estradiol, Tamoxifen, and Raloxifene

PubMed Central

Levy, Nitzan; Tatomer, Dierdre; Herber, Candice B.; Zhao, Xiaoyue; Tang, Hui; Sargeant, Toby; Ball, Lonnele J.; Summers, Jonathan; Speed, Terence P.; Leitman, Dale C.

2008-01-01

Estrogen receptors (ERs) regulate gene transcription by interacting with regulatory elements. Most information regarding how ER activates genes has come from studies using a small set of target genes or simple consensus sequences such as estrogen response element, activator protein 1, and Sp1 elements. However, these elements cannot explain the differences in gene regulation patterns and clinical effects observed with estradiol (E2) and selective estrogen receptor modulators. To obtain a greater understanding of how E2 and selective estrogen receptor modulators differentially regulate genes, it is necessary to investigate their action on a more comprehensive set of native regulatory elements derived from ER target genes. Here we used chromatin immunoprecipitation-cloning and sequencing to isolate 173 regulatory elements associated with ERα. Most elements were found in the introns (38%) and regions greater than 10 kb upstream of the transcription initiation site (38%); 24% of the elements were found in the proximal promoter region (<10 kb). Only 11% of the elements contained a classical estrogen response element; 23% of the elements did not have any known response elements, including one derived from the naked cuticle homolog gene, which was associated with the recruitment of p160 coactivators. Transfection studies found that 80% of the 173 elements were regulated by E2, raloxifene, or tamoxifen with ERα or ERβ. Tamoxifen was more effective than raloxifene at activating the elements with ERα, whereas raloxifene was superior with ERβ. Our findings demonstrate that E2, tamoxifen, and raloxifene differentially regulate native ER-regulatory elements isolated by chromatin immunoprecipitation with ERα and ERβ. PMID:17962382

Maternal Emotion Regulation Strategies, Internalizing Problems and Infant Negative Affect

PubMed Central

Edwards, Erin S.; Holzman, Jacob B.; Burt, Nicole M.; Rutherford, Helena J. V.; Mayes, Linda C.; Bridgett, David J.

2016-01-01

Recent work has identified links between mothers’ self-regulation and emotion regulation (ER) and children’s social-emotional outcomes. However, associations between maternal ER strategies (e.g., reappraisal, suppression), known to influence internalizing problems in adults, and children’s negative affect (NA) have not been considered. In the current study, the direct and indirect relationships, through maternal internalizing problems, between maternal use of ER strategies and infant NA are examined. The potential effects of infant NA on maternal internalizing difficulties are also considered. Ninety-nine mothers and their infants participated across three time points during the first year postpartum. Higher maternal suppression was indirectly related to higher infant NA, through maternal internalizing problems; lower maternal reappraisal also was indirectly related to higher infant NA through maternal internalizing problems. Infant NA at four months postpartum was related to mothers’ internalizing problems 6 months postpartum. The implications of these findings for future research and intervention are discussed. PMID:28785122

Identification of discrete sites in Yip1A necessary for regulation of endoplasmic reticulum structure.

PubMed

Dykstra, Kaitlyn M; Ulengin, Idil; Delrose, Nicholas; Lee, Tina H

2013-01-01

The endoplasmic reticulum (ER) of specialized cells can undergo dramatic changes in structural organization, including formation of concentric whorls. We previously reported that depletion of Yip1A, an integral membrane protein conserved between yeast and mammals, caused ER whorl formation reminiscent of that seen in specialized cells. Yip1A and its yeast homologue Yip1p cycle between the ER and early Golgi, have been implicated in a number of distinct trafficking steps, and interact with a conserved set of binding partners including Yif1p/Yif1A and the Ypt1/Ypt31 Rab GTPases. Here, we carried out a mutational analysis of Yip1A to obtain insight into how it regulates ER whorl formation. Most of the Yip1A cytoplasmic domain was dispensable, whereas the transmembrane (TM) domain, especially residues within predicted TM helices 3 and 4, were sensitive to mutagenesis. Comprehensive analysis revealed two discrete functionally required determinants. One was E95 and flanking residues L92 and L96 within the cytoplasmic domain; the other was K146 and nearby residue V152 within the TM domain. Notably, the identified determinants correspond closely to two sites previously found to be essential for yeast viability (E76 and K130 in Yip1p corresponding to E95 and K146 in Yip1A, respectively). In contrast, a third site (E89) also essential for yeast viability (E70 in Yip1p) was dispensable for regulation of whorl formation. Earlier work showed that E76 (E95) was dispensable for binding Yif1p or Ypt1p/Ypt31p, whereas E70 (E89) was required. Collectively, these findings suggest that the ability of Yip1A to bind its established binding partners may be uncoupled from its ability to control ER whorl formation. In support, Yif1A knockdown did not cause ER whorl formation. Thus Yip1A may use the sites identified herein to interact with a novel binding partner to regulate ER membrane organization.

Homeostatic Regulation of the PI(4,5)P2-Ca2+ Signaling System at ER-PM Junctions

PubMed Central

Chang, Chi-Lun; Liou, Jen

2016-01-01

The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-Ca2+ signaling system is important for cell activation in response to various extracellular stimuli. This signaling system is initiated by receptor-induced hydrolysis of PI(4,5)P2 in the plasma membrane (PM) to generate the soluble second messenger inositol 1,4,5-trisphosphate (IP3). IP3 subsequently triggers the release of Ca2+ from the endoplasmic reticulum (ER) store to the cytosol to activate Ca2+-mediated responses, such as secretion and proliferation. The consumed PM PI(4,5)P2 and ER Ca2+ must be quickly restored to sustain signaling responses, and to maintain the homeostasis of PI(4,5)P2 and Ca2+. Since phosphatidylinositol (PI), the precursor lipid for PM PI(4,5)P2, is synthesized in the ER membrane, and a Ca2+ influx across the PM is required to refill the ER Ca2+ store, efficient communications between the ER and the PM are critical for the homeostatic regulation of the PI(4,5)P2-Ca2+ signaling system. This review describes the major findings that established the framework of the PI(4,5)P2-Ca2+ signaling system, and recent discoveries on feedback control mechanisms at ER-PM junctions that sustain the PI(4,5)P2-Ca2+ signaling system. Particular emphasis is placed on the characterization of ER-PM junctions where efficient communications between the ER and the PM occurs, and the activation mechanisms of proteins that dynamically localize to ER-PM junctions to provide the feedback control during PI(4,5)P2-Ca2+ signaling, including the ER Ca2+ sensor STIM1, the extended synaptotagmin E-Syt1, and the PI transfer protein Nir2. This review is part of a Special Issue entitled The Cellular Lipid Landscape. PMID:26924250

The Endoplasmic Reticulum: A Central Player in Cell Signalling and Protein Synthesis

NASA Astrophysics Data System (ADS)

Llewelyn Roderick, H.; Berridge, Michael J.; Bootman, Martin D.

In addition to being the principle intracellular Ca 2+ store, the endoplasmic reticulum (ER) is the initial site of synthesis and folding of membrane and secretory proteins. These two roles of the ER are intimately linked. First, the function of many proteins involved in Ca 2+ handling are modulated by Ca 2+ and second, ER lumenal Ca 2+ modulates protein synthesis and folding. Within the ER, Ca 2+ is stored by low affinity high capacity Ca 2+ binding proteins and is maintained at a free concentration between 0.1 and 1 μM relative to 0.1 μM cytosolic Ca 2+. This concentration gradient is maintained by the action of the Sarco-Endoplasmic Reticulum ATPases (SERCa) which hydrolyse ATP to pump Ca 2+ into the ER. Following stimulation Ca 2+ is released from the ER through several classes of ligand gated channels. The most well characterized of these being the inositol 1,4,5-trisphosphate receptor ( IP 3 R) and the Ryanodine receptor (RyR) families of proteins. This release of Ca 2+ results in a drop of ER free Ca 2+ to levels as low as 10 μM. This decrease in lumenal Ca 2+ inhibits further release through the channels and increases the rate of re-sequestration of Ca 2+ into the ER by the SERCa pumps. Under these conditions, in addition to effects on Ca 2+ handling proteins, protein synthesis is inhibited, chaperones dissociate from their substrates, secondary modifications of proteins are inhibited and the retention of many proteins within the ER is lost. Furthermore, a signalling cascade resulting in the up-regulation of many proteins involved in protein folding and Ca 2+ homeostasis is initiated. This review will focus on the proteins involved in the regulation ER lumenal Ca 2+ and the role of ER lumenal Ca 2+ in cell signalling and protein synthesis.

Shifting the closed-loop spectrum in the optimal linear quadratic regulator problem for hereditary systems

NASA Technical Reports Server (NTRS)

Gibson, J. S.; Rosen, I. G.

1985-01-01

In the optimal linear quadratic regulator problem for finite dimensional systems, the method known as an alpha-shift can be used to produce a closed-loop system whose spectrum lies to the left of some specified vertical line; that is, a closed-loop system with a prescribed degree of stability. This paper treats the extension of the alpha-shift to hereditary systems. As infinite dimensions, the shift can be accomplished by adding alpha times the identity to the open-loop semigroup generator and then solving an optimal regulator problem. However, this approach does not work with a new approximation scheme for hereditary control problems recently developed by Kappel and Salamon. Since this scheme is among the best to date for the numerical solution of the linear regulator problem for hereditary systems, an alternative method for shifting the closed-loop spectrum is needed. An alpha-shift technique that can be used with the Kappel-Salamon approximation scheme is developed. Both the continuous-time and discrete-time problems are considered. A numerical example which demonstrates the feasibility of the method is included.

Shifting the closed-loop spectrum in the optimal linear quadratic regulator problem for hereditary systems

NASA Technical Reports Server (NTRS)

Gibson, J. S.; Rosen, I. G.

1987-01-01

In the optimal linear quadratic regulator problem for finite dimensional systems, the method known as an alpha-shift can be used to produce a closed-loop system whose spectrum lies to the left of some specified vertical line; that is, a closed-loop system with a prescribed degree of stability. This paper treats the extension of the alpha-shift to hereditary systems. As infinite dimensions, the shift can be accomplished by adding alpha times the identity to the open-loop semigroup generator and then solving an optimal regulator problem. However, this approach does not work with a new approximation scheme for hereditary control problems recently developed by Kappel and Salamon. Since this scheme is among the best to date for the numerical solution of the linear regulator problem for hereditary systems, an alternative method for shifting the closed-loop spectrum is needed. An alpha-shift technique that can be used with the Kappel-Salamon approximation scheme is developed. Both the continuous-time and discrete-time problems are considered. A numerical example which demonstrates the feasibility of the method is included.

CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.

PubMed

Tang, Juan; Guo, Yun-Shan; Yu, Xiao-Ling; Huang, Wan; Zheng, Ming; Zhou, Ying-Hui; Nan, Gang; Wang, Jian-Chao; Yang, Hai-Jiao; Yu, Jing-Min; Jiang, Jian-Li; Chen, Zhi-Nan

2015-10-27

Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.

CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma

PubMed Central

Zheng, Ming; Zhou, Ying-Hui; Nan, Gang; Wang, Jian-Chao; Yang, Hai-Jiao; Yu, Jing-Min; Jiang, Jian-Li; Chen, Zhi-Nan

2015-01-01

Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+ refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC. PMID:26498680

Loss-of-function PCSK9 mutants evade the unfolded protein response sensor GRP78 and fail to induce endoplasmic reticulum stress when retained.

PubMed

Lebeau, Paul; Platko, Khrystyna; Al-Hashimi, Ali A; Byun, Jae Hyun; Lhoták, Šárka; Holzapfel, Nicholas; Gyulay, Gabriel; Igdoura, Suleiman A; Cool, David R; Trigatti, Bernardo; Seidah, Nabil G; Austin, Richard C

2018-05-11

The proprotein convertase subtilisin/kexin type-9 (PCSK9) plays a central role in cardiovascular disease (CVD) by degrading hepatic low-density lipoprotein receptor (LDLR). As such, loss-of-function (LOF) PCSK9 variants that fail to exit the endoplasmic reticulum (ER) increase hepatic LDLR levels and lower the risk of developing CVD. The retention of misfolded protein in the ER can cause ER stress and activate the unfolded protein response (UPR). In this study, we investigated whether a variety of LOF PCSK9 variants that are retained in the ER can cause ER stress and hepatic cytotoxicity. Although overexpression of these PCSK9 variants caused an accumulation in the ER of hepatocytes, UPR activation or apoptosis was not observed. Furthermore, ER retention of endogenous PCSK9 via splice switching also failed to induce the UPR. Consistent with these in vitro studies, overexpression of PCSK9 in the livers of mice had no impact on UPR activation. To elucidate the cellular mechanism to explain these surprising findings, we observed that the 94-kDa glucose-regulated protein (GRP94) sequesters PCSK9 away from the 78-kDa glucose-regulated protein (GRP78), the major activator of the UPR. As a result, GRP94 knockdown increased the stability of GRP78-PCSK9 complex and resulted in UPR activation following overexpression of ER-retained PCSK9 variants relative to WT secreted controls. Given that overexpression of these LOF PCSK9 variants does not cause UPR activation under normal homeostatic conditions, therapeutic strategies aimed at blocking the autocatalytic cleavage of PCSK9 in the ER represent a viable strategy for reducing circulating PCSK9. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Emotion Regulation Protects Against Recurrence of Depressive Symptoms Following Inpatient Care for Major Depressive Disorder.

PubMed

Ebert, David D; Hopfinger, Lisa; Bockting, Claudi L H; Berking, Matthias

2017-11-01

Relapse following response in psychotherapy for major depressive disorder (MDD) is a major concern. Emotion regulation (ER) has been discussed as a putative emerging and maintaining factor for depression. The purpose of the present study was to examine whether ER protects against recurrence of depression over and above residual symptoms of depression following inpatient care for MDD. ER skills (ERSQ-ES) and depression (HEALTH-49) were assessed in 193 patients with MDD (age, M = 47.4, SD = 9.6, 75.1% female, 100% Caucasian) at treatment discontinuation, 3 and 12 months after treatment. Multiple hierarchical regressions were used to examine general and specific ER as predictors of depressive symptoms at follow-ups. Higher general ER predicted lower depression over and beyond residual symptoms of depression at 3-month follow-up among treatment responders but not among treatment nonresponders. With regard to specific ER skills, readiness to confront and acceptance of undesired emotions predicted lower depressive symptoms beyond residual symptoms of depression 12 months, respectively 3 and 12 months after treatment. Findings of the present study indicate that targeting general ER might be more important for remitted and less important for nonremitted patients. Enhancing ER should hence be realized in a sequential treatment design, in which a continuation phase treatment with a specific focus on ER directly follows, once patients sufficiently responded to treatment. Acceptance of undesired emotion and readiness to confront situations that cue these emotions appear to be particularly important for protecting against recurrence of depression. Future research should clarify whether findings can be generalized to outpatient care. Copyright © 2017. Published by Elsevier Ltd.

Muscadine Grape Skin Extract Induces an Unfolded Protein Response-Mediated Autophagy in Prostate Cancer Cells: A TMT-Based Quantitative Proteomic Analysis

PubMed Central

Burton, Liza J.; Rivera, Mariela; Hawsawi, Ohuod; Zou, Jin; Hudson, Tamaro; Wang, Guangdi; Zhang, Qiang; Cubano, Luis; Boukli, Nawal; Odero-Marah, Valerie

2016-01-01

Muscadine grape skin extract (MSKE) is derived from muscadine grape (Vitis rotundifolia), a common red grape used to produce red wine. Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) that serves as a survival mechanism to relieve ER stress and restore ER homeostasis. However, when persistent, ER stress can alter the cytoprotective functions of the UPR to promote autophagy and cell death. Although MSKE has been documented to induce apoptosis, it has not been linked to ER stress/UPR/autophagy. We hypothesized that MSKE may induce a severe ER stress response-mediated autophagy leading to apoptosis. As a model, we treated C4-2 prostate cancer cells with MSKE and performed a quantitative Tandem Mass Tag Isobaric Labeling proteomic analysis. ER stress response, autophagy and apoptosis were analyzed by western blot, acridine orange and TUNEL/Annexin V staining, respectively. Quantitative proteomics analysis indicated that ER stress response proteins, such as GRP78 were greatly elevated following treatment with MSKE. The up-regulation of pro-apoptotic markers PARP, caspase-12, cleaved caspase-3, -7, BAX and down-regulation of anti-apoptotic marker BCL2 was confirmed by Western blot analysis and apoptosis was visualized by increased TUNEL/Annexin V staining upon MSKE treatment. Moreover, increased acridine orange, and LC3B staining was detected in MSKE-treated cells, suggesting an ER stress/autophagy response. Finally, MSKE-mediated autophagy and apoptosis was antagonized by co-treatment with chloroquine, an autophagy inhibitor. Our results indicate that MSKE can elicit an UPR that can eventually lead to apoptosis in prostate cancer cells. PMID:27755556

The expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katayama, Seiichi; Ashizawa, Koji; Gohma, Hiroshi

2006-12-15

The objective of this study was to investigate the effects of estrogen receptor (ER) agonists and an ER antagonist on the expression of Hedgehog genes (Indian hedgehog: Ihh; Desert hedgehog: Dhh) and Hedgehog target genes (Patched 1: Ptc1; glioma-associated oncogene homolog 1: Gli1; chicken ovalbumin upstream promoter transcription factor II: Coup-TfII) in the rat uterus. Immature female rats were administered once with 17{alpha}-ethynyl estradiol (EE, an ER agonist), propyl pyrazole triole (PPT, an ER{alpha}-selective agonist), diarylpropionitrile (DPN, an ER{beta}-selective agonist), or ICI 182,780 (an ER antagonist). Expression of mRNA for Ihh, Dhh, and Ptc1 was dose-dependently downregulated by EE inmore » the uterus of immature rats, mediated by ER as confirmed by coadministration of ICI 182,780. The mRNA expression levels of Ptc1, Gli1, and Coup-TfII were simultaneously downregulated during the period in which the mRNA expression levels of Ihh and Dhh were downregulated in the uterus after administration of EE. PPT downregulated the transcription of Ihh, Dhh, Ptc1, Gli1, and Coup-TfII, indicating that expression of these genes was regulated by the ER{alpha}-dependent pathway. DPN also downregulated the transcription of Ihh and Dhh, although the effect was weaker than that of PPT, indicating that the regulation of uterine Ihh and Dhh transcription was also affected by the ER{beta}-dependent pathway. These results suggest that the expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats.« less

Muscadine Grape Skin Extract Induces an Unfolded Protein Response-Mediated Autophagy in Prostate Cancer Cells: A TMT-Based Quantitative Proteomic Analysis.

PubMed

Burton, Liza J; Rivera, Mariela; Hawsawi, Ohuod; Zou, Jin; Hudson, Tamaro; Wang, Guangdi; Zhang, Qiang; Cubano, Luis; Boukli, Nawal; Odero-Marah, Valerie

2016-01-01

Muscadine grape skin extract (MSKE) is derived from muscadine grape (Vitis rotundifolia), a common red grape used to produce red wine. Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) that serves as a survival mechanism to relieve ER stress and restore ER homeostasis. However, when persistent, ER stress can alter the cytoprotective functions of the UPR to promote autophagy and cell death. Although MSKE has been documented to induce apoptosis, it has not been linked to ER stress/UPR/autophagy. We hypothesized that MSKE may induce a severe ER stress response-mediated autophagy leading to apoptosis. As a model, we treated C4-2 prostate cancer cells with MSKE and performed a quantitative Tandem Mass Tag Isobaric Labeling proteomic analysis. ER stress response, autophagy and apoptosis were analyzed by western blot, acridine orange and TUNEL/Annexin V staining, respectively. Quantitative proteomics analysis indicated that ER stress response proteins, such as GRP78 were greatly elevated following treatment with MSKE. The up-regulation of pro-apoptotic markers PARP, caspase-12, cleaved caspase-3, -7, BAX and down-regulation of anti-apoptotic marker BCL2 was confirmed by Western blot analysis and apoptosis was visualized by increased TUNEL/Annexin V staining upon MSKE treatment. Moreover, increased acridine orange, and LC3B staining was detected in MSKE-treated cells, suggesting an ER stress/autophagy response. Finally, MSKE-mediated autophagy and apoptosis was antagonized by co-treatment with chloroquine, an autophagy inhibitor. Our results indicate that MSKE can elicit an UPR that can eventually lead to apoptosis in prostate cancer cells.

A meta-analytic study of event rate effects on Go/No-Go performance in attention-deficit/hyperactivity disorder.

PubMed

Metin, Baris; Roeyers, Herbert; Wiersema, Jan R; van der Meere, Jaap; Sonuga-Barke, Edmund

2012-12-15

According to the state regulation deficit model, event rate (ER) is an important determinant of performance of children with attention-deficit/hyperactivity disorder (ADHD). Fast ER is predicted to create overactivation and produce errors of commission, whereas slow ER is thought to create underactivation marked by slow and variable reaction times (RT) and errors of omission. To test these predictions, we conducted a systematic search of the literature to identify all reports of comparisons of ADHD and control individuals' performance on Go/No-Go tasks published between 2000 and 2011. In one analysis, we included all trials with at least two event rates and calculated the difference between ER conditions. In a second analysis, we used metaregression to test for the moderating role of ER on ADHD versus control differences seen across Go/No-Go studies. There was a significant and disproportionate slowing of reaction time in ADHD relative to controls on trials with slow event rates in both meta-analyses. For commission errors, the effect sizes were larger on trials with fast event rates. No ER effects were seen for RT variability. There were also general effects of ADHD on performance for all variables that persisted after effects of ER were taken into account. The results provide support for the state regulation deficit model of ADHD by showing the differential effects of fast and slow ER. The lack of an effect of ER on RT variability suggests that this behavioral characteristic may not be a marker of cognitive energetic effects in ADHD. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Reduction of Mitochondria-Endoplasmic Reticulum Interactions by Acetylcholine Protects Human Umbilical Vein Endothelial Cells From Hypoxia/Reoxygenation Injury.

PubMed

He, Xi; Bi, Xue-Yuan; Lu, Xing-Zhu; Zhao, Ming; Yu, Xiao-Jiang; Sun, Lei; Xu, Man; Wier, W Gil; Zang, Wei-Jin

2015-07-01

We explored the role of endoplasmic reticulum (ER)-mitochondria Ca(2+) cross talk involving voltage-dependent anion channel-1 (VDAC1)/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex and mitofusin 2 in endothelial cells during hypoxia/reoxygenation (H/R), and investigated the protective effects of acetylcholine. Acetylcholine treatment during reoxygenation prevented intracellular and mitochondrial Ca(2+) increases and alleviated ER Ca(2+) depletion during H/R in human umbilical vein endothelial cells. Consequently, acetylcholine enhanced mitochondrial membrane potential and inhibited proapoptotic cascades, thereby reducing cell death and preserving endothelial ultrastructure. This effect was likely mediated by the type-3 muscarinic acetylcholine receptor and the phosphatidylinositol 3-kinase/Akt pathway. In addition, interactions among members of the VDAC1/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex were increased after H/R and were associated with mitochondrial Ca(2+) overload and cell death. Inhibition of the partner of the Ca(2+) channeling complex (VDAC1 siRNA) or a reduction in ER-mitochondria tethering (mitofusin 2 siRNA) prevented the increased protein interaction within the complex and reduced mitochondrial Ca(2+) accumulation and subsequent endothelial cell death after H/R. Intriguingly, acetylcholine could modulate ER-mitochondria Ca(2+) cross talk by inhibiting the VDAC1/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex and mitofusin 2 expression. Phosphatidylinositol 3-kinase siRNA diminished acetylcholine-mediated inhibition of mitochondrial Ca(2+) overload and VDAC1/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex formation induced by H/R. Our data suggest that ER-mitochondria interplay plays an important role in reperfusion injury in the endothelium and may be a novel molecular target for endothelial protection. Acetylcholine attenuates both intracellular and mitochondrial Ca(2+) overload and protects endothelial cells from H/R injury, presumably by disrupting the ER-mitochondria interaction. © 2015 American Heart Association, Inc.

Breast Cancer Stem Cells in Antiestrogen Resistance

DTIC Science & Technology

2013-08-01

several flavonoid derivatives purified from the bark of the Paper Mulberry tree (Broussonetia papyrifera) (L.) were able to down-regulate ER- α36...that a flavonoid derivative Broussoflavonol B, inhibited the expression of ER-α36 and EGFR, attenuated growth of ER-negative breast cancer stem...2.00+.40 Recently, we reported that several flavonoid derivatives purified from the bark of the Paper Mulberry tree (Broussonetia papyrifera) (L.) were

Sex-specific neural circuits of emotion regulation in the centromedial amygdala.

PubMed

Wu, Yan; Li, Huandong; Zhou, Yuan; Yu, Jian; Zhang, Yuanchao; Song, Ming; Qin, Wen; Yu, Chunshui; Jiang, Tianzi

2016-03-23

Sex-related differences in emotion regulation (ER) in the frequency power distribution within the human amygdala, a brain region involved in emotion processing, have been reported. However, how sex differences in ER are manifested in the brain networks which are seeded on the amygdala subregions is unclear. The goal of this study was to investigate this issue from a brain network perspective. Utilizing resting-state functional connectivity (RSFC) analysis, we found that the sex-specific functional connectivity patterns associated with ER trait level were only seeded in the centromedial amygdala (CM). Women with a higher trait-level ER had a stronger negative RSFC between the right CM and the medial superior frontal gyrus (mSFG), and stronger positive RSFC between the right CM and the anterior insula (AI) and the superior temporal gyrus (STG). But men with a higher trait-level ER was associated with weaker negative RSFC of the right CM-mSFG and positive RSFCs of the right CM-left AI, right CM-right AI/STG, and right CM-left STG. These results provide evidence for the sex-related effects in ER based on CM and indicate that men and women may differ in the neural circuits associated with emotion representation and integration.

The comER Gene Plays an Important Role in Biofilm Formation and Sporulation in both Bacillus subtilis and Bacillus cereus.

PubMed

Yan, Fang; Yu, Yiyang; Wang, Luyao; Luo, Yuming; Guo, Jian-Hua; Chai, Yunrong

2016-01-01

Bacteria adopt alternative cell fates during development. In Bacillus subtilis, the transition from planktonic growth to biofilm formation and sporulation is controlled by a complex regulatory circuit, in which the most important event is activation of Spo0A, a transcription factor and a master regulator for genes involved in both biofilm formation and sporulation. In B. cereus, the regulatory pathway controlling biofilm formation and cell differentiation is much less clear. In this study, we show that a novel gene, comER, plays a significant role in biofilm formation as well as sporulation in both B. subtilis and B. cereus. Mutations in the comER gene result in defects in biofilm formation and a delay in spore formation in the two Bacillus species. Our evidence supports the idea that comER may be part of the regulatory circuit that controls Spo0A activation. comER likely acts upstream of sda, a gene encoding a small checkpoint protein for both sporulation and biofilm formation, by blocking the phosphor-relay and thereby Spo0A activation. In summary, our studies outlined a conserved, positive role for comER, a gene whose function was previously uncharacterized, in the regulation of biofilm formation and sporulation in the two Bacillus species.

The comER Gene Plays an Important Role in Biofilm Formation and Sporulation in both Bacillus subtilis and Bacillus cereus

PubMed Central

Yan, Fang; Yu, Yiyang; Wang, Luyao; Luo, Yuming; Guo, Jian-hua; Chai, Yunrong

2016-01-01

Bacteria adopt alternative cell fates during development. In Bacillus subtilis, the transition from planktonic growth to biofilm formation and sporulation is controlled by a complex regulatory circuit, in which the most important event is activation of Spo0A, a transcription factor and a master regulator for genes involved in both biofilm formation and sporulation. In B. cereus, the regulatory pathway controlling biofilm formation and cell differentiation is much less clear. In this study, we show that a novel gene, comER, plays a significant role in biofilm formation as well as sporulation in both B. subtilis and B. cereus. Mutations in the comER gene result in defects in biofilm formation and a delay in spore formation in the two Bacillus species. Our evidence supports the idea that comER may be part of the regulatory circuit that controls Spo0A activation. comER likely acts upstream of sda, a gene encoding a small checkpoint protein for both sporulation and biofilm formation, by blocking the phosphor-relay and thereby Spo0A activation. In summary, our studies outlined a conserved, positive role for comER, a gene whose function was previously uncharacterized, in the regulation of biofilm formation and sporulation in the two Bacillus species. PMID:27446060

Curcumin and Curcuma longa L. extract ameliorate lipid accumulation through the regulation of the endoplasmic reticulum redox and ER stress.

PubMed

Lee, Hwa-Young; Kim, Seung-Wook; Lee, Geum-Hwa; Choi, Min-Kyung; Chung, Han-Wool; Lee, Yong-Chul; Kim, Hyung-Ryong; Kwon, Ho Jeong; Chae, Han-Jung

2017-07-26

For this study, we examined the effects of curcumin against acute and chronic stress, paying specific attention to ROS. We also aimed to clarify the differences between acute and chronic stress conditions. We investigated the effects of curcumin against acute stress (once/1 day CCl 4 treatment) and chronic-stress (every other day/4week CCl 4 treatment). Compared with acute stress, in which the antioxidant system functioned properly and aspartate transaminase (AST) and ROS production increased, chronic stress increased AST, alanine aminotransferase (ALT), hepatic enzymes, and ROS more significantly, and the antioxidant system became impaired. We also found that ER-originated ROS accumulated in the chronic model, another difference between the two conditions. ER stress was induced consistently, and oxidative intra-ER protein folding status, representatively PDI, was impaired, especially in chronic stress. The PDI-associated client protein hepatic apoB accumulated with the PDI-binding status in chronic stress, and curcumin recovered the altered ER folding status, regulating ER stress and the resultant hepatic dyslipidemia. Throughout this study, curcumin and curcumin-rich Curcuma longa L. extract promoted recovery from CCl 4 -induced hepatic toxicity in both stress conditions. For both stress-associated hepatic dyslipidemia, curcumin and Curcuma longa L. extract might be recommendable to recover liver activity.

Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway.

PubMed

Namba, Takushi; Chu, Kiki; Kodama, Rika; Byun, Sanguine; Yoon, Kyoung Wan; Hiraki, Masatsugu; Mandinova, Anna; Lee, Sam W

2015-08-21

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53.

Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway

PubMed Central

Kodama, Rika; Byun, Sanguine; Yoon, Kyoung Wan; Hiraki, Masatsugu; Mandinova, Anna; Lee, Sam W.

2015-01-01

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53. PMID:26254280

Videogames for Emotion Regulation: A Systematic Review.

PubMed

Villani, Daniela; Carissoli, Claudia; Triberti, Stefano; Marchetti, Antonella; Gilli, Gabriella; Riva, Giuseppe

2018-04-01

Emotion regulation (ER) supports multiple individual functions and promotes mental health and wellbeing. Among the tools that may be used to help people in managing their affective states, videogames are reaching attention and are showing positive effects. Yet, little is known about their effectiveness. This study aims to assess the amount and quality of studies investigating the effects and modalities of the use of videogames for ER. A systematic literature search according to PRISMA guidelines was performed. Subsequently, according to expert advice other few studies have been added. Twenty-three studies met the inclusion criteria and were included in the review; they can be categorized into three groups, namely (1) cross-sectional and qualitative studies, (2) experimental studies investigating the effects of videogame experience on ER and (3) ER intervention with serious games. Discussion of the reviewed studies highlights that frequent gaming with commercial games offers more opportunities for ER improvement (related to gameplay and enjoyment of fictional properties) than limited-time experiences, such as those supported by bespoke serious games. This research area is still in its infancy and findings need to be interpreted with caution; furthermore, future reviews are encouraged to include clinical populations. Videogames offer several opportunities for ER and a challenge for educational and psychological interventions.

The Entangled ER-Mitochondrial axis as a potential therapeutic strategy in Neurodegeneration: A Tangled Duo Unchained

PubMed Central

Joshi, Amit U.; Kornfeld, Opher S.; Mochly-Rosen, Daria

2016-01-01

Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca2+ transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases. PMID:27212603

Unexpected magnetism, and transport properties in mixed lanthanide compound

NASA Astrophysics Data System (ADS)

Pathak, Arjun; Gschneidner, Karl, Jr.; Pecharsky, Vitalij; Ames Laboratory Team

For intelligent materials design it is desirable to have compounds which have multiple functionalities such as a large magnetoresistance, ferromagnetic and ferrimagnetic states, and field-induced first-order metamagnetic transitions. Here, we discuss one such example where we have combined two lanthanide elements Pr and Er in Pr0.6Er0.4Al2. This compound exhibits multiple functionalities in magnetic fields between 1 and 40 kOe. It undergoes only a trivial ferrimagnetism to paramagnetism transition in a zero magnetic field, but Pr0.6Er0.4Al2 exhibits a large positive magnetoresistance (MR) for H >=40 kOe, a small but non negligible negative MR for H <=30 kOe, and a clear Griffiths-like phase behavior at <1 kOe. The compound also exhibits an asymmetry of hysteresis loop, or exchange bias (EB) effect after field cooling from the paramagnetic state. These phenomena are attributed to the competition between single-ion anisotropies of Pr and Er ions coupled with the opposite nearest-neighbor and next-nearest-neighbor exchange interactions. This work was supported by the US Department of Energy, Office of Basic Energy Science, Division of Material Sciences and Engineering. The research was performed at the Ames Laboratory. The Ames Laboratory is operated by Iowa State University for the US D.

Estrogen receptor modulatory effects of germinated brown rice bioactives in the uterus of rats through the regulation of estrogen-induced genes

PubMed Central

Muhammad, Sani Ismaila; Maznah, Ismail; Mahmud, Rozi Bint; Saeed, Mohammed Ibrahim; Imam, Mustapha Umar; Ishaka, Aminu

2013-01-01

Purpose The expression of genes regulated by estrogen in the uterus was studied in ovariectomized (OVX) rats treated with germinated brown rice (GBR) bioactives, and compared to Remifemin or estrogen at different doses to identify the regulation of these genes in the uterus and their molecular mechanisms. Methods Rats were treated orally with GBR bioactives (phenolics), acylated steryl glucosides (ASG), γ-amino butyric acid (GABA), and γ-oryzanol (ORZ) at 100 and 200 mg/kg, Remifemin (REM) at 10 mg/kg and 20 mg/kg, or estrogen (EST) at 0.2 mg/kg. Ribonucleic acid (RNA) was extracted from the uterus, and messenger (m)RNA expression of selected genes encoding estrogen receptor-beta (ER-β), calcium-binding protein (CaBP9k), complement protein (C3), heat shock protein 70 kDa (HSP70), and interleukin (IL)-4 receptor were quantified. Similarly, serum steroid hormone concentration was monitored at 2, 4, and 8 weeks after treatments. ER-β antibody binding to the uterus sections was also studied using immunohistochemistry. Results The group treated with EST (0.2 mg/kg) upregulated ER-β, C3, and IL-4 receptor genes compared to other groups (P<0.001). GBR phenolics (200 mg/kg) treatment upregulated the ER-β gene almost to the level of the sham non-treated group. The CaBP9k gene showed upregulation in groups treated with ASG (200 mg/kg), EST (0.2 mg/kg), and ORZ (200 mg/kg) (P<0.05). Estrogen levels increased in groups treated with EST, ASG, and ORZ (200 mg/kg) compared to the OVX untreated group (P<0.05), and there was a slight non-significant decrease (P>0.05) in the progesterone levels in the OVX untreated group compared to the sham and other treated groups. There was a significant increase at 8 weeks in the level of FSH (P<0.05) in the treated groups compared to the OVX untreated group. There was no significant difference (P>0.05) in serum luteinizing hormone (LH) between the OVX untreated group and other groups. The sham and GBR phenolics treated group showed ER-β reactivity at the glandular epithelium, while the group treated with EST showed immunoreactivity at the glandular, luminal, and stromal epithelium. Conclusion GBR phenolics moderately regulate the expression of ER-β, HSP70, and IL-4 receptor genes, and gave a positive immunoreaction to ER-β antigen in the uterus. ASG regulates the expression of CaBP9k and IL-4 receptor genes, and ORZ regulates the expression of the CaBP9k gene, while GABA at 100 mg/kg regulates the expression of the HSP70 gene. GBR and its bioactives might have an effect on estrogen-regulated genes in the uterus of rats. PMID:24324328

The Endoplasmic Reticulum Exit of Glutamate Transporter Is Regulated by the Inducible Mammalian Yip6b/GTRAP3-18 Protein*Ⓢ

PubMed Central

Ruggiero, Alicia M.; Liu, Yiting; Vidensky, Svetlana; Maier, Susanne; Jung, Elizabeth; Farhan, Hesso; Robinson, Michael B.; Sitte, Harald H.; Rothstein, Jeffrey D.

2015-01-01

GTRAP3-18 interacts with and reduces the activity of the neuronal specific Na+/K+ glutamate transporter, EAAC1 both in vitro and in vivo. GTRAP3-18 and the related isoform, JM4, are distant relatives of the Rab GTPase-interacting factor PRA1, and share a topology of four transmembrane domains and cytosolic termini. GTRAP3-18 and JM4 are resident endoplasmic reticulum (ER) proteins. The physiological role of GTRAP3-18 is poorly understood. We demonstrate for the first time that GTRAP3-18 is a regulator of ER protein trafficking. Expression of GTRAP3-18 delays the ER exit of EAAC1, as well as other members of the excitatory amino acid transporter family. GTRAP3-18 uses hydrophobic domain interactions in the ER membrane to self-associate and cytoplasmic interactions at the C terminus to regulate trafficking. The features of GTRAP3-18 activity are consistent with recent phylogenic sequence analyses suggesting GTRAP3-18 and JM4 be reclassified as mammalian isoforms of the yeast protein family Yip, Yip6b, and Yip6a, respectively. PMID:18167356

Hypoxia induces cyclophilin B through the activation of transcription factor 6 in gastric adenocarcinoma cells.

PubMed

Jeong, Kwon; Kim, Kiyoon; Kim, Hunsung; Oh, Yoojung; Kim, Seong-Jin; Jo, Yunhee; Choe, Wonchae

2015-06-01

Hypoxia is an important form of physiological stress that induces cell death, due to the resulting endoplasmic reticulum (ER) stress, particularly in solid tumors. Although previous studies have indicated that cyclophilin B (CypB) plays a role in ER stress, there is currently no direct information supporting the mechanism of CypB involvement under hypoxic conditions. However, it has previously been demonstrated that ER stress positively regulates the expression of CypB. In the present study, it was demonstrated that CypB is transcriptionally regulated by hypoxia-mediated activation of transcription factor 6 (ATF6), an ER stress transcription factor. Subsequently, the effects of ATF6 on CypB promoter activity were investigated and an ATF6-responsive region in the promoter was identified. Hypoxia and ATF6 expression each increased CypB promoter activity. Collectively, these results demonstrate that ATF6 positively regulates the expression of CypB by binding to an ATF6-responsive region in the promoter, which may play an important role in the attenuation of apoptosis in the adaption to hypoxia. These results suggest that CypB may be a key molecule in the adaptation of cells to hypoxic conditions.

Hypoxia induces cyclophilin B through the activation of transcription factor 6 in gastric adenocarcinoma cells

PubMed Central

JEONG, KWON; KIM, KIYOON; KIM, HUNSUNG; OH, YOOJUNG; KIM, SEONG-JIN; JO, YUNHEE; CHOE, WONCHAE

2015-01-01

Hypoxia is an important form of physiological stress that induces cell death, due to the resulting endoplasmic reticulum (ER) stress, particularly in solid tumors. Although previous studies have indicated that cyclophilin B (CypB) plays a role in ER stress, there is currently no direct information supporting the mechanism of CypB involvement under hypoxic conditions. However, it has previously been demonstrated that ER stress positively regulates the expression of CypB. In the present study, it was demonstrated that CypB is transcriptionally regulated by hypoxia-mediated activation of transcription factor 6 (ATF6), an ER stress transcription factor. Subsequently, the effects of ATF6 on CypB promoter activity were investigated and an ATF6-responsive region in the promoter was identified. Hypoxia and ATF6 expression each increased CypB promoter activity. Collectively, these results demonstrate that ATF6 positively regulates the expression of CypB by binding to an ATF6-responsive region in the promoter, which may play an important role in the attenuation of apoptosis in the adaption to hypoxia. These results suggest that CypB may be a key molecule in the adaptation of cells to hypoxic conditions. PMID:26137159

Theory of Self- vs. Externally-Regulated LearningTM: Fundamentals, Evidence, and Applicability

PubMed Central

de la Fuente-Arias, Jesús

2017-01-01

The Theory of Self- vs. Externally-Regulated LearningTM has integrated the variables of SRL theory, the DEDEPRO model, and the 3P model. This new Theory has proposed: (a) in general, the importance of the cyclical model of individual self-regulation (SR) and of external regulation stemming from the context (ER), as two different and complementary variables, both in combination and in interaction; (b) specifically, in the teaching-learning context, the relevance of different types of combinations between levels of self-regulation (SR) and of external regulation (ER) in the prediction of self-regulated learning (SRL), and of cognitive-emotional achievement. This review analyzes the assumptions, conceptual elements, empirical evidence, benefits and limitations of SRL vs. ERL Theory. Finally, professional fields of application and future lines of research are suggested. PMID:29033872

Role of ERRF, a Novel ER-Related Nuclear Factor, in the Growth Control of ER-Positive Human Breast Cancer Cells

PubMed Central

Su, Dan; Fu, Xiaoying; Fan, Songqing; Wu, Xiao; Wang, Xin-Xin; Fu, Liya; Dong, Xue-Yuan; Ni, Jianping Jenny; Fu, Li; Zhu, Zhengmao; Dong, Jin-Tang

2012-01-01

Whereas estrogen–estrogen receptor α (ER) signaling plays an important role in breast cancer growth, it is also necessary for the differentiation of normal breast epithelial cells. How this functional conversion occurs, however, remains unknown. Based on a genome-wide sequencing study that identified mutations in several breast cancer genes, we examined some of the genes for mutations, expression levels, and functional effects on cell proliferation and tumorigenesis. We present the data for C1orf64 or ER-related factor (ERRF) from 31 cell lines and 367 primary breast cancer tumors. Whereas mutation of ERRF was infrequent (1 of 79 or 1.3%), its expression was up-regulated in breast cancer, and the up-regulation was more common in lower-stage tumors. In addition, increased ERRF expression was significantly associated with ER and/or progesterone receptor (PR) positivity, which was still valid in human epidermal growth factor receptor 2 (HER2)–negative tumors. In ER-positive tumors, ERRF expression was inversely correlated with HER2 status. Furthermore, higher ERRF protein expression was significantly associated with better disease-free survival and overall survival, particularly in ER- and/or PR-positive and HER2-negative tumors (luminal A subtype). Functionally, knockdown of ERRF in two ER-positive breast cancer cell lines, T-47D and MDA-MB-361, suppressed cell growth in vitro and tumorigenesis in xenograft models. These results suggest that ERRF plays a role in estrogen-ER–mediated growth of breast cancer cells and could, thus, be a potential therapeutic target. PMID:22341523

The Batten disease gene CLN3 confers resistance to endoplasmic reticulum stress induced by tunicamycin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Dan, E-mail: danw@bjmu.edu.cn; Liu, Jing; Wu, Baiyan

2014-04-25

Highlights: • The work reveals a protective properties of CLN3 towards TM-induced apoptosis. • CLN3 regulates expression of the GRP78 and the CHOP in response to the ER stress. • CLN3 plays a specific role in the ERS response. - Abstract: Mutations in CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early-onset neurodegenerative disorder that is characterized by the accumulation of ceroid lipofuscin within lysosomes. The function of the CLN3 protein remains unclear and is presumed to be related to Endoplasmic reticulum (ER) stress. To investigate the function of CLN3 in the ER stress signaling pathway,more » we measured proliferation and apoptosis in cells transfected with normal and mutant CLN3 after treatment with the ER stress inducer tunicamycin (TM). We found that overexpression of CLN3 was sufficient in conferring increased resistance to ER stress. Wild-type CLN3 protected cells from TM-induced apoptosis and increased cell proliferation. Overexpression of wild-type CLN3 enhanced expression of the ER chaperone protein, glucose-regulated protein 78 (GRP78), and reduced expression of the proapoptotic protein CCAAT/-enhancer-binding protein homologous protein (CHOP). In contrast, overexpression of mutant CLN3 or siRNA knockdown of CLN3 produced the opposite effect. Together, our data suggest that the lack of CLN3 function in cells leads to a failure of management in the response to ER stress and this may be the key deficit in JNCL that causes neuronal degeneration.« less

Involvement of endoplasmic reticulum stress in the necroptosis of microglia/macrophages after spinal cord injury.

PubMed

Fan, H; Tang, H-B; Kang, J; Shan, L; Song, H; Zhu, K; Wang, J; Ju, G; Wang, Y-Z

2015-12-17

Microglia/macrophages play a crucial role in inflammation after spinal cord injury (SCI). Although extensive studies have been performed on the mechanisms of microglia/macrophage activation and recruitment, how microglia/macrophages are eliminated remains unclear. In the present study, we observed a high-level expression of mixed lineage kinase domain-like protein (MLKL), a key molecule in the execution of necroptosis, in microglia/macrophages after SCI in mice. In vivo PI-labeling and Necrostatin-1 treatment confirmed the necroptosis of microglia/macrophages. Interestingly, our electronic microscopic (EM) study revealed that MLKL localized not only at the membrane but also on the endoplasmic reticulum (ER) of necroptotic microglia/macrophages. Furthermore, receptor-interacting protein 3 (RIP3), another necrosome component, was also found on the ER of necroptotic microglia/macrophages. And Glucose-regulated protein 78 (GRP78), an ER stress sensor, was up-regulated in MLKL-positive microglia/macrophages after SCI, suggesting a possible link between necroptosis and ER stress. In vitro, oxygen-glucose deprivation (OGD) stress induced ER stress and necroptosis in microglia. Inhibiting ER stress by 4-phenylbutyrate (4-PBA) significantly blocked the OGD-induced necroptosis of microglia. In the end, our data showed that, GRP78 and phosphorylated MLKL were co-expressed by the microglia/macrophages in the injured human spinal cord. Taken together, these results suggested that microglia/macrophages undergo an ER-stress involved necroptosis after SCI, implying that ER stress and necroptosis could be manipulated for modulating inflammation post-SCI. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

SR/ER-mitochondrial local communication: Calcium and ROS

PubMed Central

Csordás, György; Hajnóczky, György

2009-01-01

Mitochondria form junctions with the sarco/endoplasmic reticulum (SR/ER), which support signal transduction and biosynthetic pathways and affect organellar distribution. Recently, these junctions have received attention because of their pivotal role in mediating calcium signal propagation to the mitochondria, which is important for both ATP production and mitochondrial cell death. Many of the SR/ER-mitochondrial calcium transporters and signaling proteins are sensitive to redox regulation and are directly exposed to the reactive oxygen species (ROS) produced in the mitochondria and SR/ER. Although ROS has been emerging as a novel signaling entity, the redox signaling of the SR/ER-mitochondrial interface is yet to be elucidated. We describe here possible mechanisms of the mutual interaction between local Ca2+ and ROS signaling in the control of SR/ER-mitochondrial function. PMID:19527680

[Estrogen receptor alpha in obesity and diabetes].

PubMed

Cahua-Pablo, José Ángel; Flores-Alfaro, Eugenia; Cruz, Miguel

2016-01-01

Estradiol (E2) is an important hormone in reproductive physiology, cardiovascular, skeletal and in the central nervous system (CNS). In human and rodents, E2 and its receptors are involved in the control of energy and glucose metabolism in health and metabolic diseases. The estrogen receptor (ER) belongs to the superfamily of nuclear receptors (NR), which are transcription factors that regulate gene expression. Three ER, ER-alpha, ER-beta and the G protein-coupled ER (GPER; also called GPR30) in tissues are involved in glucose and lipid homeostasis. Also, it may have important implications for risk factors associated with metabolic syndrome (MS), insulin resistance (IR), obesity and type 2 diabetes (T2D).

The endoplasmic reticulum: structure, function and response to cellular signaling.

PubMed

Schwarz, Dianne S; Blower, Michael D

2016-01-01

The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.

Eat it right: ER-phagy and recovER-phagy.

PubMed

Loi, Marisa; Fregno, Ilaria; Guerra, Concetta; Molinari, Maurizio

2018-05-25

The endoplasmic reticulum (ER) is the site of protein, lipid, phospholipid, steroid and oligosaccharide synthesis and modification, calcium ion storage, and detoxification of endogenous and exogenous products. Its volume (and activity) must be maintained under normal growth conditions, must be expanded in a controlled manner on activation of ER stress programs and must be reduced to pre-stress size during the recovery phase that follows ER stress termination. ER-phagy is the constitutive or regulated fragmentation and delivery of ER fragments to lysosomal compartments for clearance. It gives essential contribution to the maintenance of cellular homeostasis, proteostasis, lipidostasis and oligosaccharidostasis (i.e. the capacity to produce the proteome, lipidome and oligosaccharidome in appropriate quality and quantity). ER turnover is activated on ER stress, nutrient deprivation, accumulation of misfolded polypeptides, pathogen attack and by activators of macroautophagy. The selectivity of these poorly characterized catabolic pathways is ensured by proteins displayed at the limiting membrane of the ER subdomain to be removed from cells. These proteins are defined as ER-phagy receptors and engage the cytosolic macroautophagy machinery via specific modules that associate with ubiquitin-like, cytosolic proteins of the Atg8/LC3/GABARAP family. In this review, we give an overview on selective ER turnover and on the yeast and mammalian ER-phagy receptors identified so far. © 2018 The Author(s).

Hormonal Resistance and Metastasis: ER-coregulator-Src Signaling Targeted Therapy

DTIC Science & Technology

2010-09-01

receptors and coregulators The human estrogen receptor (ER) is a key transcriptional regulator in breast cancer biology (Green and Carroll, 2007; Heldring...al, 1991) and over-expression of Cyclin D1 has been noted in over 50% of human breast tumors of all histological types (Gillett et al, 1994; Kenny et...CDK inhibitors Down regulation of p21 has been implicated with Tamoxifen resistant phenotype. Somatic deletion of p21 gene in human breast cancer

Social-cognitive, physiological, and neural mechanisms underlying emotion regulation impairments: Understanding anxiety in autism spectrum disorder

PubMed Central

White, Susan W.; Mazefsky, Carla A.; Dichter, Gabriel S.; Chiu, Pearl H.; Richey, John A.; Ollendick, Thomas H.

2014-01-01

Anxiety is one of the most common clinical problems among children, adolescents, and adults with autism spectrum disorder (ASD), yet we know little about its etiology in the context of ASD. We posit that emotion regulation (ER) impairments are a risk factor for anxiety in ASD. Specifically, we propose that one reason why anxiety disorders are so frequently comorbid with ASD is because ER impairments are ubiquitous to ASD, stemming from socio-cognitive, physiological, and neurological processes related to impaired cognitive control, regulatory processes, and arousal. In this review, we offer a developmental model of how ER impairments may arise in ASD, and when (moderating influences) and how (meditational mechanisms) they result in anxiety. PMID:24951837

Series Connected Converter for Control of Multi-Bus Spacecraft Power Utility

NASA Technical Reports Server (NTRS)

Beach, Raymond F. (Inventor); Brush, Andy (Inventor)

1997-01-01

The invention provides a power system using series connected regulators. Power from a source, such as a solar array, is processed through the regulators and provided to corresponding buses used to charge a battery and supply loads. The regulators employ a bypass loop around a DC-DC converter. The bypass loop connects a hot input of the converter to a return output, preferably though an inductor. Part of the current from the source passes through the bypass loop to the power bus. The converter bucks or boosts the voltage from the source to maintain the desired voltage at the bus. Thus, only part of the power is processed through the converter. The converter can also be used without the bypass loop to provide isolation. All of the converters can be substantially identical.

Unfolded Protein Response of the Endoplasmic Reticulum in Tumor Progression and Immunogenicity

PubMed Central

Yoo, Yoon Seon; Han, Hye Gyeong

2017-01-01

The endoplasmic reticulum (ER) is a pivotal regulator of folding, quality control, trafficking, and targeting of secreted and transmembrane proteins, and accordingly, eukaryotic cells have evolved specialized machinery to ensure that the ER enables these proteins to acquire adequate folding and maturation in the presence of intrinsic and extrinsic insults. This adaptive capacity of the ER to intrinsic and extrinsic perturbations is important for maintaining protein homeostasis, which is termed proteostasis. Failure in adaptation to these perturbations leads to accumulation of misfolded or unassembled proteins in the ER, which is termed ER stress, resulting in the activation of unfolded protein response (UPR) of the ER and the execution of ER-associated degradation (ERAD) to restore homeostasis. Furthermore, both of the two axes play key roles in the control of tumor progression, inflammation, immunity, and aging. Therefore, understanding UPR of the ER and subsequent ERAD will provide new insights into the pathogenesis of many human diseases and contribute to therapeutic intervention in these diseases. PMID:29430279

Changes in need satisfaction and motivation orientation as predictors of psychological and behavioural outcomes in exercise referral.

PubMed

Rahman, Rachel Jane; Thogersen-Ntoumani, Cecilie; Thatcher, Joanne; Doust, Jonathan

2011-11-01

Employing Self-Determination Theory (Deci & Ryan, 1985) as a theoretical framework, this study examined psychological need satisfaction and motivational regulations as predictors of psychological and behavioural outcomes in exercise referral (ER). ER patients (N = 293; mean age 54.49) completed the measures of motivational regulations, psychological need satisfaction, health-related quality of life, life satisfaction, anxiety, depression and physical activity at entry, exit and 6 months following the end of a supervised exercise programme. Change in (Δ) intrinsic motivation during the scheme significantly predicted adherence and Δ habitual physical activity. Δ psychological need satisfaction from entry to exit significantly predicted Δ habitual physical activity from exit to 6-month follow-up. Δ psychological need satisfaction significantly predicted Δ motivational regulation and Δ psychological outcomes. Contrary to expectations, Δ self-determined regulation did not significantly predict Δ psychological outcomes during the structured part of the scheme, however, it did significantly predict Δ in psychological outcomes from exit to 6-month follow-up. These findings expand on cross-sectional research to demonstrate that psychological need satisfaction during supervised ER longitudinally predicts motivational regulation and psychological outcomes up to 6 months after a structured programme.

Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation.

PubMed

Fujimori, Tsutomu; Suno, Ryoji; Iemura, Shun-Ichiro; Natsume, Tohru; Wada, Ikuo; Hosokawa, Nobuko

2017-08-01

The folding of newly synthesized proteins in the endoplasmic reticulum (ER) is assisted by ER-resident chaperone proteins. BiP (immunoglobulin heavy-chain-binding protein), a member of the HSP70 family, plays a central role in protein quality control. The chaperone function of BiP is regulated by its intrinsic ATPase activity, which is stimulated by ER-resident proteins of the HSP40/DnaJ family, including ERdj3. Here, we report that two closely related proteins, SDF2 and SDF2L1, regulate the BiP chaperone cycle. Both are ER-resident, but SDF2 is constitutively expressed, whereas SDF2L1 expression is induced by ER stress. Both luminal proteins formed a stable complex with ERdj3 and potently inhibited the aggregation of different types of misfolded ER cargo. These proteins associated with non-native proteins, thus promoting the BiP-substrate interaction cycle. A dominant-negative ERdj3 mutant that inhibits the interaction between ERdj3 and BiP prevented the dissociation of misfolded cargo from the ERdj3-SDF2L1 complex. Our findings indicate that SDF2 and SDF2L1 associate with ERdj3 and act as components in the BiP chaperone cycle to prevent the aggregation of misfolded proteins, partly explaining the broad folding capabilities of the ER under various physiological conditions. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Mammalian ECD Protein Is a Novel Negative Regulator of the PERK Arm of the Unfolded Protein Response

PubMed Central

Olou, Appolinaire A.; Sarkar, Aniruddha; Bele, Aditya; Gurumurthy, C. B.; Mir, Riyaz A.; Ammons, Shalis A.; Mirza, Sameer; Saleem, Irfana; Urano, Fumihiko; Band, Hamid

2017-01-01

ABSTRACT Mammalian Ecdysoneless (ECD) is a highly conserved ortholog of the Drosophila Ecd gene product whose mutations impair the synthesis of Ecdysone and produce cell-autonomous survival defects, but the mechanisms by which ECD functions are largely unknown. Here we present evidence that ECD regulates the endoplasmic reticulum (ER) stress response. ER stress induction led to a reduced ECD protein level, but this effect was not seen in PKR-like ER kinase knockout (PERK-KO) or phosphodeficient eukaryotic translation initiation factor 2α (eIF2α) mouse embryonic fibroblasts (MEFs); moreover, ECD mRNA levels were increased, suggesting impaired ECD translation as the mechanism for reduced protein levels. ECD colocalizes and coimmunoprecipitates with PERK and GRP78. ECD depletion increased the levels of both phospho-PERK (p-PERK) and p-eIF2α, and these effects were enhanced upon ER stress induction. Reciprocally, overexpression of ECD led to marked decreases in p-PERK, p-eIF2α, and ATF4 levels but robust increases in GRP78 protein levels. However, GRP78 mRNA levels were unchanged, suggesting a posttranscriptional event. Knockdown of GRP78 reversed the attenuating effect of ECD overexpression on PERK signaling. Significantly, overexpression of ECD provided a survival advantage to cells upon ER stress induction. Taken together, our data demonstrate that ECD promotes survival upon ER stress by increasing GRP78 protein levels to enhance the adaptive folding protein in the ER to attenuate PERK signaling. PMID:28652267

Choline kinase inhibition induces exacerbated endoplasmic reticulum stress and triggers apoptosis via CHOP in cancer cells

PubMed Central

Sanchez-Lopez, E; Zimmerman, T; Gomez del Pulgar, T; Moyer, M P; Lacal Sanjuan, J C; Cebrian, A

2013-01-01

Endoplasmic reticulum (ER) is a central organelle in eukaryotic cells that regulates protein synthesis and maturation. Perturbation of ER functions leads to ER stress, which has been previously associated with a broad variety of diseases. ER stress is generally regarded as compensatory, but prolonged ER stress has been involved in apoptosis induced by several cytotoxic agents. Choline kinase α (ChoKα), the first enzyme in the Kennedy pathway, is responsible for the generation of phosphorylcholine (PCho) that ultimately renders phosphatidylcholine. ChoKα overexpression and high PCho levels have been detected in several cancer types. Inhibition of ChoKα has demonstrated antiproliferative and antitumor properties; however, the mechanisms underlying these activities remain poorly understood. Here, we demonstrate that ChoKα inhibitors (ChoKIs), MN58b and RSM932A, induce cell death in cancer cells (T47D, MCF7, MDA-MB231, SW620 and H460), through the prolonged activation of ER stress response. Evidence of ChoKIs-induced ER stress includes enhanced production of glucose-regulated protein, 78 kDa (GRP78), protein disulfide isomerase, IRE1α, CHOP, CCAAT/enhancer-binding protein beta (C/EBPβ) and TRB3. Although partial reduction of ChoKα levels by small interfering RNA was not sufficient to increase the production of ER stress proteins, silencing of ChoKα levels also show a decrease in CHOP overproduction induced by ChoKIs, which suggests that ER stress induction is due to a change in ChoKα protein folding after binding to ChoKIs. Silencing of CHOP expression leads to a reduction in C/EBPβ, ATF3 and GRP78 protein levels and abrogates apoptosis in tumor cells after treatment with ChoKIs, suggesting that CHOP maintains ER stress responses and triggers the pro-apoptotic signal. Consistent with the differential effect of ChoKIs in cancer and primary cells previously described, ChoKIs only promoted a transient and moderated ER stress response in the non-tumorogenic cells MCF10A. In conclusion, pharmacological inhibition of ChoKα induces cancer cell death through a mechanism that involves the activation of exaggerated and persistent ER stress supported by CHOP overproduction. PMID:24287694

Acid-Sensing Ion Channel 1a Regulates Fate of Rat Nucleus Pulposus Cells in Acid Stimulus Through Endoplasmic Reticulum Stress.

PubMed

Xie, Zhi-Yang; Chen, Lu; Zhang, Cong; Liu, Lei; Wang, Feng; Cai, Feng; Wang, Xiao-Hu; Shi, Rui; Sinkemani, Arjun; Yu, Hao-Min; Hong, Xin; Wu, Xiao-Tao

2018-01-01

Acid-sensing ion channel 1a (ASIC1a) participates in human intervertebral disc degeneration (IVDD) and regulates the destiny of nucleus pulposus cells (NPCs) in acid stimulus. However, the mechanism of ASIC1a activation and its downstream pathway remain unclear. Endoplasmic reticulum (ER) stress also participates in the acid-induced apoptosis of NPCs. The main purpose of this study was to investigate whether there is any connection between ASIC1a and ER stress in an acid-induced nucleus pulposus degeneration model. The IVDs of Sprague-Dawley rats were stained by immunohistochemical staining to evaluate the expression of ASIC1a in normal and degenerated rat nucleus pulposus. ASIC1a expression was also quantified by quantitative real-time-polymerase chain reaction and Western blotting analysis. NPCs were exposed to the culture media with acidity at pH 7.2 and 6.5 for 24 h, with or without 4-phenylbutyrate (4-PBA, a blocker of the ER stress pathway). Cell apoptosis was examined by Annexin V/Propidium Iodide (PI) staining and was quantified using flow cytometry analysis. ASIC1a-mediated intracellular calcium was determined by Ca 2+ imaging using Fura-2-AM. Acidity-induced changes in ER stress markers were studied using Western blotting analysis. In vivo , ASIC1a expression was upregulated in natural degeneration. In vitro , acid stimulus increased intracellular calcium levels, but this effect was blocked by knockdown of ASIC1a, and this reversal was partly inhibited by 4-PBA. In addition, blockade of ASIC1a reduced expression of ER stress markers, especially the proapoptotic markers. ASIC1a partly regulates ER stress and promotes apoptosis of NPCs under acid stimulus and may be a novel therapeutic target in IVDD.

Endoplasmic reticulum stress is increased after spontaneous labor in human fetal membranes and myometrium where it regulates the expression of prolabor mediators.

PubMed

Liong, Stella; Lappas, Martha

2014-09-01

Increasing evidence indicates that endoplasmic reticulum (ER) stress is involved in various diseases. In nongestational tissues, several markers of the unfolded protein response (UPR) have been shown to regulate the inflammatory response. Thus, the aim of this study was to determine the effect of human labor on markers of ER stress in fetal membranes and myometrium. In addition, the effect of ER stress inhibition on the expression and secretion of proinflammatory and prolabor mediators was also assessed. The markers of ER stress, GRP78, IRE1, and spliced XBP1 (XBP1s), were significantly increased in fetal membranes and myometrium after term and preterm labor compared to nonlaboring samples. Given that inflammation is considered to be one of the leading causes of spontaneous preterm birth, here we used bacterial endotoxin lipopolysaccharide (LPS) as a model for infection-induced preterm birth. In term nonlabored fetal membranes and myometrium, LPS induced UPR activation as evidenced by a significant increase in the expression of GRP78, IRE1, and XBP1s in fetal membranes and myometrium. The use of the chemical chaperones 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) alleviated ER stress induced by LPS. 4-PBA and TUDCA also ameliorated the increase in LPS-induced prolabor mediators. Our data suggest that the UPR may regulate the inflammatory responses associated with labor or infection in fetal membranes and myometrium of pregnant term and preterm women. Thus, the use of ER stress inhibitors, in particular 4-PBA or TUDCA, may be a potential therapeutic strategy for the prevention of infection-mediated spontaneous preterm birth. © 2014 by the Society for the Study of Reproduction, Inc.

Regulation of macroautophagy in ovarian cancer cells in vitro and in vivo by controlling Glucose regulatory protein 78 and AMPK

PubMed Central

Kandala, Prabodh K.; Srivastava, Sanjay K.

2012-01-01

In this study we show that diindolylmethane (DIM) induces autophagy in ovarian cancer cells by regulating endoplasmic reticulum (ER) stress and AMPK. Treatment of SKOV-3, OVCAR-3 and TOV-21G ovarian cancer cells with varying concentrations of DIM for 24 hours resulted in a concentration dependent induction of autophagy as measured by flowcytometry. Electron microscopy confirmed the presence of autophagosomes in DIM treated cells. Western blot analysis showed that DIM treatment increased the expression of LC3B, a hall mark of autophagy as well as p62 and Atg 12 proteins that are accumulated during autophagy. Autophagy inhibitors bafilomycin or chloroquine inhibited DIM induced autophagy. Furthermore, DIM treatment significantly increased the expression of ER stress regulators such as Grp78, IRE1 and GADD153. Cycloheximide or ER stress inhibitor mithramycin not only blocked ER stress proteins that were activated by DIM but also autophagy. Silencing Grp78 or GADD 153 significantly blocked the expression of LC3B and p62 indicating that autophagy in our model is mediated by ER stress. Knocking out LC3B inhibited DIM induced autophagy. DIM treatment increased the cytosolic calcium levels which lead to the activation of AMPK in our model. Chelating cytosolic calcium with BAPT-AM abrogated not only the phosphorylation of AMPK but also prevented DIM induced autophagy. Inhibiting AMPK by a chemical inhibitor or siRNA blocked the induction of LC3B or p62, indicating that DIM mediated autophagy requires activation of AMPK. Oral administration of DIM significantly suppressed SKOV-3 tumor xenografts in nude mice. Activation of ER stress and autophagy were observed in the tumors of DIM treated mice. Taken together, these results suggest that induction of autophagy by DIM in ovarian cancer cells was associated with ER stress and AMPK activation. PMID:22564965

RCAD/BiP pathway is necessary for the proper synthesis of digestive enzymes and secretory function of the exocrine pancreas.

PubMed

Miller, Camille; Cai, Yafei; Patton, Tadd; Graves, Sarai Hacker; Li, Honglin; Sabbatini, Maria Eugenia

2017-03-01

Alcoholism causes an imbalance of endoplasmic reticulum (ER) homeostasis in pancreatic acini. In those cells, the ER is involved in the synthesis and folding of pancreatic enzymes. Ubiquitin-fold modifier 1 (Ufm1) is part of a novel ubiquitin-like modification system involved in maintaining ER homeostasis. Among the components of the Ufm1 system, Regulator of C53 and DDRGK1 (RCAD) has recently been identified as a Ufm1-specific E3 ligase that promotes ufmylation of DDRGK1, an RCAD-interacting protein. We determined the importance of RCAD in the proper synthesis and secretion of pancreatic enzymes using mice with genetically deleted RCAD. The pancreas of RCAD-deficient mice was of normal size and histology. Using quantitative PCR and Western blotting, we found that amylase was upregulated in pancreas organs from RCAD-knockout (KO) mice. Constitutive amylase secretion was much higher in isolated pancreatic acini from RCAD KO mice, whereas CCK-stimulated amylase secretion was disturbed. RCAD deficiency caused a downregulation in expression of ER chaperone BiP, which affected ER homeostasis and activated both apoptosis and trypsin. We also found that both RCAD and DDRGK1 transcript levels were upregulated in pancreatic acini from alcohol-preferring rats. Elevated expression of RCAD and DDRGK1 was associated with increased ER stress and UPR activation. Because of the lack of BiP expression, caspase 3 and trypsin activation we enhanced in RCAD-deficient pancreatic acini upon treatment with ethanol and CCK. In conclusion, the RCAD/BiP pathway is required for proper synthesis and secretion of pancreatic enzymes. In alcoholism, increased levels of components of the Ufm1 system could prevent the deleterious effects of alcohol in the pancreas by regulating BiP levels. NEW & NOTEWORTHY RCAD/BiP pathway is required for the proper synthesis and secretion of amylase from pancreatic acini, as well as for the maintenance of the ER homeostasis. In alcoholism, the exocrine pancreas could increase the levels of components of the Ufm1 system to protect itself from alcohol's deleterious effects by regulating the expression of ER chaperone BiP. Copyright © 2017 the American Physiological Society.

The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility.

PubMed

Lamontanara, Allan Joaquim; Georgeon, Sandrine; Tria, Giancarlo; Svergun, Dmitri I; Hantschel, Oliver

2014-11-17

The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.

The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility

NASA Astrophysics Data System (ADS)

Lamontanara, Allan Joaquim; Georgeon, Sandrine; Tria, Giancarlo; Svergun, Dmitri I.; Hantschel, Oliver

2014-11-01

The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2-kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr-Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker. Disruption of the SH2-kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.

Identification of a calmodulin-regulated Ca2+-ATPase in the endoplasmic reticulum

NASA Technical Reports Server (NTRS)

Hong, B.; Ichida, A.; Wang, Y.; Gens, J. S.; Pickard, B. G.; Harper, J. F.; Evans, M. L. (Principal Investigator)

1999-01-01

A unique subfamily of calmodulin-dependent Ca2+-ATPases was recently identified in plants. In contrast to the most closely related pumps in animals, plasma membrane-type Ca2+-ATPases, members of this new subfamily are distinguished by a calmodulin-regulated autoinhibitor located at the N-terminal instead of a C-terminal end. In addition, at least some isoforms appear to reside in non-plasma membrane locations. To begin delineating their functions, we investigated the subcellular localization of isoform ACA2p (Arabidopsis Ca2+-ATPase, isoform 2 protein) in Arabidopsis. Here we provide evidence that ACA2p resides in the endoplasmic reticulum (ER). In buoyant density sucrose gradients performed with and without Mg2+, ACA2p cofractionated with an ER membrane marker and a typical "ER-type" Ca2+-ATPase, ACA3p/ECA1p. To visualize its subcellular localization, ACA2p was tagged with a green fluorescence protein at its C terminus (ACA2-GFPp) and expressed in transgenic Arabidopsis. We collected fluorescence images from live root cells using confocal and computational optical-sectioning microscopy. ACA2-GFPp appeared as a fluorescent reticulum, consistent with an ER location. In addition, we observed strong fluorescence around the nuclei of mature epidermal cells, which is consistent with the hypothesis that ACA2p may also function in the nuclear envelope. An ER location makes ACA2p distinct from all other calmodulin-regulated pumps identified in plants or animals.

Oestrogen receptor negativity in breast cancer: a cause or consequence?

PubMed Central

Gajulapalli, Vijaya Narasihma Reddy; Malisetty, Vijaya Lakshmi; Chitta, Suresh Kumar; Manavathi, Bramanandam

2016-01-01

Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers. PMID:27884978

Hypothalamic ER–associated degradation regulates POMC maturation, feeding, and age-associated obesity

PubMed Central

Kim, Geun Hyang; Somlo, Diane R.M.; Haataja, Leena; Song, Soobin; Nillni, Eduardo A.

2018-01-01

Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron–specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding. PMID:29457782

Interleukin 17A exacerbates ER-stress-mediated inflammation of macrophages following ICH.

PubMed

Yang, Zhao; Liu, Qingjun; Shi, Hui; Jiang, Xuheng; Wang, Song; Lu, Yuanlan; Zhang, Ji; Huang, Xiaofei; Yu, Anyong

2018-05-30

IL-17A contributes to the initiation of inflammation following intracerebral hemorrhage (ICH). Endoplasmic reticulum (ER) stress acts on protein folding and contributes to inflammatory diseases. The role of IL-17A in the regulation of ER stress following ICH has not been well characterized. In this study, macrophages were stimulated with IL-17A, and then, ER stress and downstream pro-inflammatory factors were measured in vitro. In addition, brain edema and brain injury in ICH mice were assessed in vivo. We demonstrated that IL-17A induced ER stress in macrophages and thus promoted inflammation in vitro. Conversely, IL-17A inhibition attenuated ER stress and neuroinflammation. Furthermore, ERK 1/2 and p38 MAPK pathways mediated IL-17A-induced ER stress in macrophages. We also showed that IL-17A inhibition significantly attenuated ER stress and brain injury in ICH mice. In conclusion, our results demonstrate that IL 17A increases ER stress in macrophages and represents a novel mechanism in ICH. Copyright © 2018. Published by Elsevier Ltd.

The indirect effect of panic disorder on smoking cognitions via difficulties in emotion regulation.

PubMed

Yang, Min-Jeong; Zvolensky, Michael J; Leyro, Teresa M

2017-09-01

Panic disorder (PD) and cigarette smoking are highly comorbid and associated with worse panic and smoking outcomes. Smoking may become an overlearned automatized response to relieve panic-like withdrawal distress, leading to corresponding smoking cognitions, which contribute to its reinforcing properties and difficultly abstaining. Difficulties in emotion regulation (ER) may underlie this relation such that in the absence of adaptive emotion regulatory strategies, smokers with PD may more readily rely upon smoking to manage affective distress. In the current study, the indirect relation between PD status and smoking cognitions through ER difficulties was examined among daily smokers (N=74). We found evidence for an indirect relation between PD status and negative affect, addictive and habitual smoking motives, and anticipating smoking will result in negative reinforcement and personal harm, through self-reported difficulties with ER. Our findings are aligned with theoretical models on anxiety and smoking, and suggest that reports of greater smoking cognitions may be due to ER difficulties. Copyright © 2017. Published by Elsevier Ltd.

A pH-Regulated Quality Control Cycle for Surveillance of Secretory Protein Assembly

PubMed Central

Vavassori, Stefano; Cortini, Margherita; Masui, Shoji; Sannino, Sara; Anelli, Tiziana; Caserta, Imma R.; Fagioli, Claudio; Mossuto, Maria F.; Fornili, Arianna; van Anken, Eelco; Degano, Massimo; Inaba, Kenji; Sitia, Roberto

2013-01-01

Summary To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH-regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44’s active cysteine, simultaneously unmask the substrate binding site and −RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles. PMID:23685074

Hostility/anger as a mediator between college students' emotion regulation abilities and symptoms of depression, social anxiety, and generalized anxiety.

PubMed

Asberg, Kia

2013-01-01

Internalizing problems are common among college students and have been linked consistently to deficits in emotion regulation (ER). Also, hostility/anger (animosity toward others, phenomenological aspect of anger) is an important feature of internalizing problems, but has received limited attention as a mediator between ER and outcomes. Results (N = 160) indicated that although college students' ER abilities corresponded with all three types of internalizing symptoms, hostility/anger mediated fully the relationship for symptoms of depression and social anxiety, but not generalized anxiety (GAD). The stronger interpersonal aspect inherent in depression and social anxiety relative to GAD may in part explain findings, but findings must be viewed in lieu of limitations, which include self-report, a non-clinical sample, and a cross-sectional design. Overall, hostility/anger may be important to address in interventions and programs aimed at reducing internalizing problems, especially among those who demonstrate ER deficits and are prone to depression and social anxiety.

Cognitive Emotion Regulation and Written Exposure Therapy for Posttraumatic Stress Disorder

PubMed Central

Wisco, Blair E.; Sloan, Denise M.; Marx, Brian P.

2014-01-01

We examined the extent to which cognitive emotion-regulation (ER) strategies moderated posttraumatic stress disorder (PTSD) treatment outcome among 40 motor vehicle accident survivors. Participants were randomly assigned to either a brief written exposure therapy (WET) condition or a waitlist condition and were assessed pre- and posttreatment and at a 3-month follow-up. Positive-reappraisal and putting-into-perspective strategies at baseline interacted with condition to predict symptom change over time. Both strategies predicted greater reductions in PTSD in the waitlist group, suggesting facilitation of natural recovery. However, positive reappraisal was associated with smaller reductions in PTSD in the WET group, suggesting that this strategy may interfere with treatment. Treatment also reduced use of the maladaptive ER strategy of rumination. These results provide evidence that putting-into-perspective and positive-reappraisal strategies are beneficial in the absence of treatment and that certain types of ER strategies may reduce response to WET, highlighting the importance of future research examining ER during treatment. PMID:24482755

Emotion regulation moderates relationships between body image concerns and psychological symptomatology.

PubMed

Hughes, Elizabeth K; Gullone, Eleonora

2011-06-01

The study investigated the moderating role of emotion regulation (ER) in relationships between body image concerns and psychological symptomatology. A community sample of 533 boys and girls (11-20 years) completed measures assessing body image thoughts and feelings, domain-specific and general ER strategies, drive for thinness, and bulimic, depressive and anxiety symptoms. Results indicated that ER moderated relationships between body image concerns and both bulimic and depressive symptoms, but not relationships between body image concerns and drive for thinness or anxiety symptoms. Adolescents who reported frequent body image concerns were more likely to have higher levels of bulimic symptoms if they tended to use avoidance and internal dysfunctional ER strategies. Furthermore, adolescents who reported frequent body image concerns were more likely to have higher levels of depressive symptoms if they used positive rational acceptance and internal functional strategies infrequently. Implications of the findings for prevention and intervention are discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Estrogen Enhances Malignant Phenotypes in Human Salivary Adenoid Cystic Carcinoma Cells.

PubMed

Sumida, Tomoki; Ishikawa, Akiko; Kamata, Y U; Nakano, Hiroyuki; Yamada, Tomohiro; Mori, Yoshihide

2016-06-01

Adenoid cystic carcinoma (SGC) is a common type of salivary gland cancer (SGC). Surgery is the first treatment choice because chemoradiotherapy is usually not effective. Therefore, new treatment modalities are urgently needed. In this study, it was investigated whether the estrogen axis could be a treatment target or not. Adenoid cystic carcinoma (ACC) ACCM cells, were used. The specific cell line lacks estrogen receptor (ER). ER was introduced in ACCM cells, and the effect of 17β-estradiol (E2) was investigated on cell proliferation, cell-cycle distribution, and cell motility. E2 induced cell proliferation, and the S-phase fraction increased in a dose-dependent manner. Cell motility was also up-regulated compared to control cells. The estrogen/ER system up-regulated malignant phenotypes in ER-positive ACC, and hormone therapy may have a potential as effective treatment for this malignancy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs.

PubMed

Hayashi, Teruo

2015-01-01

Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions. Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Proteostasis: bad news and good news from the endoplasmic reticulum.

PubMed

Noack, Julia; Brambilla Pisoni, Giorgia; Molinari, Maurizio

2014-01-01

The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection aging and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis. Here we present a review of mechanisms regulating folding and quality control of proteins expressed in the ER, and we describe the protein degradation and the ER stress pathways activated by the expression of misfolded proteins in the ER lumen. Finally, we highlight select examples of proteopathies (also known as conformational disorders or protein misfolding diseases) caused by protein misfolding in the ER and/or affecting cellular proteostasis and therapeutic interventions that might alleviate or cure the disease symptoms.

Orchestrating phospholipid biosynthesis: Phosphatidic acid conducts and Opi1p performs.

PubMed

Salsaa, Michael; Case, Kendall; Greenberg, Miriam L

2017-11-10

Phosphatidic acid (PA) and the conserved integral ER membrane protein Scs2p regulate localization of the transcriptional repressor Opi1p, which controls expression of phospholipid biosynthesis genes, but the mechanisms conducting Opi1p localization are not fully understood. A new study suggests the existence of a distinct pool of PA in the ER that is required for regulation of Opi1p localization and thus phospholipid metabolism in yeast. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Dealing with feeling: a meta-analysis of the effectiveness of strategies derived from the process model of emotion regulation.

PubMed

Webb, Thomas L; Miles, Eleanor; Sheeran, Paschal

2012-07-01

The present meta-analysis investigated the effectiveness of strategies derived from the process model of emotion regulation in modifying emotional outcomes as indexed by experiential, behavioral, and physiological measures. A systematic search of the literature identified 306 experimental comparisons of different emotion regulation (ER) strategies. ER instructions were coded according to a new taxonomy, and meta-analysis was used to evaluate the effectiveness of each strategy across studies. The findings revealed differences in effectiveness between ER processes: Attentional deployment had no effect on emotional outcomes (d(+) = 0.00), response modulation had a small effect (d(+) = 0.16), and cognitive change had a small-to-medium effect (d(+) = 0.36). There were also important within-process differences. We identified 7 types of attentional deployment, 4 types of cognitive change, and 4 types of response modulation, and these distinctions had a substantial influence on effectiveness. Whereas distraction was an effective way to regulate emotions (d(+) = 0.27), concentration was not (d(+) = -0.26). Similarly, suppressing the expression of emotion proved effective (d(+) = 0.32), but suppressing the experience of emotion or suppressing thoughts of the emotion-eliciting event did not (d(+) = -0.04 and -0.12, respectively). Finally, reappraising the emotional response proved less effective (d(+) = 0.23) than reappraising the emotional stimulus (d(+) = 0.36) or using perspective taking (d(+) = 0.45). The review also identified several moderators of strategy effectiveness including factors related to the (a) to-be-regulated emotion, (b) frequency of use and intended purpose of the ER strategy, (c) study design, and (d) study characteristics.

Higher-order looping and nuclear organization of antigen receptor loci facilitate targeted RAG cleavage and regulated rearrangement in recombination centers

PubMed Central

Chaumeil, Julie; Micsinai, Mariann; Ntziachristos, Panagiotis; Deriano, Ludovic; Wang, Joy M-H; Ji, Yanhong; Nora, Elphege P.; Rodesch, Matthew J.; Jeddeloh, Jeffrey A.; Aifantis, Iannis; Kluger, Yuval; Schatz, David G.; Skok, Jane A.

2013-01-01

SUMMARY V(D)J recombination is essential for generating a diverse array of B and T cell receptors that can recognize and combat foreign antigen. As with any recombination event, tight control is essential to prevent the occurrence of genetic anomalies that drive cellular transformation. One important aspect of regulation is directed targeting of the RAG recombinase. Indeed, RAG accumulates at the 3’ end of individual antigen receptor loci poised for rearrangement, however, it is not known whether focal binding is involved in regulating cleavage, and what mechanisms lead to enrichment of RAG in this region. Here we show that mono-allelic looping out of the 3’ end of Tcra, coupled with transcription and increased chromatin/nuclear accessibility, are linked to focal RAG binding and ATM-mediated regulated mono-allelic cleavage on looped out 3’ regions. Our data identify higher order loop formation as a key determinant of directed RAG targeting and the maintenance of genome stability. PMID:23416051

SNAREs support atlastin-mediated homotypic ER fusion in Saccharomyces cerevisiae

PubMed Central

Lee, Miriam; Ko, Young-Joon; Moon, Yeojin; Han, Minsoo; Kim, Hyung-Wook; Lee, Sung Haeng; Kang, KyeongJin

2015-01-01

Dynamin-like GTPases of the atlastin family are thought to mediate homotypic endoplasmic reticulum (ER) membrane fusion; however, the underlying mechanism remains largely unclear. Here, we developed a simple and quantitative in vitro assay using isolated yeast microsomes for measuring yeast atlastin Sey1p-dependent ER fusion. Using this assay, we found that the ER SNAREs Sec22p and Sec20p were required for Sey1p-mediated ER fusion. Consistently, ER fusion was significantly reduced by inhibition of Sec18p and Sec17p, which regulate SNARE-mediated membrane fusion. The involvement of SNAREs in Sey1p-dependent ER fusion was further supported by the physical interaction of Sey1p with Sec22p and Ufe1p, another ER SNARE. Furthermore, our estimation of the concentration of Sey1p on isolated microsomes, together with the lack of fusion between Sey1p proteoliposomes even with a 25-fold excess of the physiological concentration of Sey1p, suggests that Sey1p requires additional factors to support ER fusion in vivo. Collectively, our data strongly suggest that SNARE-mediated membrane fusion is involved in atlastin-initiated homotypic ER fusion. PMID:26216899

Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX-2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes.

PubMed

Yu, Seon-Mi; Kim, Song-Ja

2010-11-30

Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation, inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress, via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein, as determined by a Western blot analysis. In addition, induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DG- modified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also, treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression, N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2 assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway.

Different Roles of GRP78 on Cell Proliferation and Apoptosis in Cartilage Development.

PubMed

Xiong, Zhangyuan; Jiang, Rong; Li, Xiangzhu; Liu, Yanna; Guo, Fengjin

2015-09-07

Eukaryotic cells possess several mechanisms to adapt to endoplasmic reticulum (ER) stress and thereby survive. ER stress activates a set of signaling pathways collectively termed as the unfolded protein response (UPR). We previously reported that Bone morphogenetic protein 2 (BMP2) mediates mild ER stress and activates UPR signal molecules in chondrogenesis. The mammalian UPR protects the cell against the stress of misfolded proteins in the endoplasmic reticulum. Failure to adapt to ER stress causes the UPR to trigger apoptosis. Glucose regulated protein 78 (GRP78), as an important molecular chaperone in UPR signaling pathways, is responsible for binding to misfolded or unfolded protein during ER stress. However the influence on GRP78 in BMP2-induced chondrocyte differentiation has not yet been elucidated and the molecular mechanism underlyng these processes remain unexplored. Herein we demonstrate that overexpression of GRP78 enhanced cell proliferation in chondrocyte development with G1 phase advance, S phase increasing and G2-M phase transition. Furthermore, overexpression of GRP78 inhibited ER stress-mediated apoptosis and then reduced apoptosis in chondrogenesis induced by BMP2, as assayed by cleaved caspase3, caspase12, C/EBP homologous protein (CHOP/DDIT3/GADD153), p-JNK (phosphorylated c-Jun N-terminal kinase) expression during the course of chondrocyte differentiation by Western blot. In addition, flow cytometry (FCM) assay, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay and immune-histochemistry analysis also proved this result in vitro and in vivo. It was demonstrated that GRP78 knockdown via siRNA activated the ER stress-specific caspase cascade in developing chondrocyte tissue. Collectively, these findings reveal a novel critical role of GRP78 in regulating ER stress-mediated apoptosis in cartilage development and the molecular mechanisms involved.

Hydrogen Sulfide Inhibits Formaldehyde-Induced Endoplasmic Reticulum Stress in PC12 Cells by Upregulation of SIRT-1

PubMed Central

Zhang, Ping; Chen, Li-Xun; Wang, Li; Xie, Ming; Wang, Chun-Yan; Tang, Xiao-Qing

2014-01-01

Background Formaldehyde (FA), a well-known environmental pollutant, has been classified as a neurotoxic molecule. Our recent data demonstrate that hydrogen sulfide (H2S), the third gaseous transmitter, has a protective effect on the neurotoxicity of FA. However, the exact mechanisms underlying this protection remain largely unknown. Endoplasmic reticulum (ER) stress has been implicated in the neurotoxicity of FA. Silent mating type information regulator 2 homolog 1 (SIRT-1), a histone deacetylases, has various biological activities, including the extension of lifespan, the modulation of ER stress, and the neuroprotective action. Objective We hypothesize that the protection of H2S against FA-induced neurotoxicity involves in inhibiting ER stress by upregulation of SIRT-1. The present study attempted to investigate the protective effect of H2S on FA-induced ER stress in PC12 cells and the contribution of SIRT-1 to the protection of H2S against FA-induced injuries, including ER stress, cytotoxicity and apoptosis. Principal Findings We found that exogenous application of sodium hydrosulfide (NaHS; an H2S donor) significantly attenuated FA-induced ER stress responses, including the upregulated levels of glucose-regulated protein 78, C/EBP homologous protein, and cleaved caspase-12 expression. We showed that NaHS upregulates the expression of SIRT-1 in PC12 cells. Moreover, the protective effects of H2S on FA-elicited ER stress, cytotoxicity and apoptosis were reversed by Sirtinol, a specific inhibitor of SIRT-1. Conclusion/Significance These data indicate that H2S exerts its protection against the neurotoxicity of FA through overcoming ER stress via upregulation of SIRT-1. Our findings provide novel insights into the protective mechanisms of H2S against FA-induced neurotoxicity. PMID:24587076

Folding of thyroglobulin in the calnexin/calreticulin pathway and its alteration by loss of Ca2+ from the endoplasmic reticulum.

PubMed Central

Di Jeso, Bruno; Ulianich, Luca; Pacifico, Francesco; Leonardi, Antonio; Vito, Pasquale; Consiglio, Eduardo; Formisano, Silvestro; Arvan, Peter

2003-01-01

During its initial folding in the endoplasmic reticulum (ER), newly synthesized thyroglobulin (Tg) is known to interact with calnexin and other ER molecular chaperones, but its interaction with calreticulin has not been examined previously. In the present study, we have investigated the interactions of endogenous Tg with calreticulin and with several other ER chaperones. We find that, in FRTL-5 and PC-Cl3 cells, calnexin and calreticulin interact with newly synthesized Tg in a carbohydrate-dependent manner, with largely overlapping kinetics that are concomitant with the maturation of Tg intrachain disulphide bonds, preceding Tg dimerization and exit from the ER. Calreticulin co-precipitates more newly synthesized Tg than does calnexin; however, using two different experimental approaches, calnexin and calreticulin were found in ternary complexes with Tg, making this the first endogenous protein reported in ternary complexes with calnexin and calreticulin in the ER of live cells. Depletion of Ca(2+) from the ER elicited by thapsigargin (a specific inhibitor of ER Ca(2+)-ATPases) results in retention of Tg in this organelle. Interestingly, thapsigargin treatment induces the premature exit of Tg from the calnexin/calreticulin cycle, while stabilizing and prolonging interactions of Tg with BiP (immunoglobulin heavy chain binding protein) and GRP94 (glucose-regulated protein 94), two chaperones whose binding is not carbohydrate-dependent. Our results suggest that calnexin and calreticulin, acting in ternary complexes with a large glycoprotein substrate such as Tg, might be engaged in the folding of distinct domains, and indicate that lumenal Ca(2+) strongly influences the folding of exportable glycoproteins, in part by regulating the balance of substrate binding to different molecular chaperone systems within the ER. PMID:12401114

Valsartan protects HK-2 cells from contrast media-induced apoptosis by inhibiting endoplasmic reticulum stress.

PubMed

Peng, Ping-An; Wang, Le; Ma, Qian; Xin, Yi; Zhang, Ou; Han, Hong-Ya; Liu, Xiao-Li; Ji, Qing-Wei; Zhou, Yu-Jie; Zhao, Ying-Xin

2015-12-01

Contrast-induced acute kidney injury (CI-AKI) is associated with increasing in-hospital and long-term adverse clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI). Contrast media (CM)-induced renal tubular cell apoptosis is reported to participate in this process by activating endoplasmic reticulum (ER) stress. An angiotensin II type 1 receptor (AT1R) antagonist can alleviate ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic mice and can reduce CM-induced renal apoptosis by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction of bcl-2 mRNA, but the effect of the AT1R blocker on ER stress in the pathogenesis of CI-AKI is still unknown. In this study, we explored the effect of valsartan on meglumine diatrizoate-induced human renal tubular cell apoptosis by measuring changes in ER stress-related biomarkers. The results showed that meglumine diatrizoate caused significant cell apoptosis by up-regulating the expression of ER stress markers, including glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein-homologous protein (CHOP) and caspase 12, in a time- and dose-dependent manner, which could be alleviated by preincubation with valsartan. In conclusion, valsartan had a potential nephroprotective effect on meglumine diatrizoate-induced renal cell apoptosis by inhibiting ER stress. © 2015 International Federation for Cell Biology.

Stability of multiloop LQ regulators with nonlinearities. I - Regions of attraction. II - Regions of ultimate boundedness

NASA Technical Reports Server (NTRS)

Joshi, S. M.

1986-01-01

An investigation is conducted for the closed loop stability of linear time-invariant systems controlled by linear quadratic (LQ) regulators, in cases where nonlinearities exist in the control channels lying outside the stability sector in regions away from the origin. The estimate of the region of attraction thus obtained furnishes methods for the selection of performance function weights for more robust LQ designs. Attention is then given to the closed loop stability of linear time-invariant systems controlled by the LQ regulators when the nonlinearities in the loops escape the stability sector in a bounded region containing the origin.

A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality

NASA Astrophysics Data System (ADS)

Noël, Emily S.; Verhoeven, Manon; Lagendijk, Anne Karine; Tessadori, Federico; Smith, Kelly; Choorapoikayil, Suma; den Hertog, Jeroen; Bakkers, Jeroen

2013-11-01

Breaking left-right symmetry in bilateria is a major event during embryo development that is required for asymmetric organ position, directional organ looping and lateralized organ function in the adult. Asymmetric expression of Nodal-related genes is hypothesized to be the driving force behind regulation of organ laterality. Here we identify a Nodal-independent mechanism that drives asymmetric heart looping in zebrafish embryos. In a unique mutant defective for the Nodal-related southpaw gene, preferential dextral looping in the heart is maintained, whereas gut and brain asymmetries are randomized. As genetic and pharmacological inhibition of Nodal signalling does not abolish heart asymmetry, a yet undiscovered mechanism controls heart chirality. This mechanism is tissue intrinsic, as explanted hearts maintain ex vivo retain chiral looping behaviour and require actin polymerization and myosin II activity. We find that Nodal signalling regulates actin gene expression, supporting a model in which Nodal signalling amplifies this tissue-intrinsic mechanism of heart looping.

Loop equations and bootstrap methods in the lattice

DOE PAGES

Anderson, Peter D.; Kruczenski, Martin

2017-06-17

Pure gauge theories can be formulated in terms of Wilson Loops by means of the loop equation. In the large-N limit this equation closes in the expectation value of single loops. In particular, using the lattice as a regulator, it becomes a well defined equation for a discrete set of loops. In this paper we study different numerical approaches to solving this equation.

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

PubMed

Ghoussaini, Maya; Edwards, Stacey L; Michailidou, Kyriaki; Nord, Silje; Cowper-Sal Lari, Richard; Desai, Kinjal; Kar, Siddhartha; Hillman, Kristine M; Kaufmann, Susanne; Glubb, Dylan M; Beesley, Jonathan; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Guo, Qi; Schmidt, Marjanka K; Shah, Mitul; Luben, Robert; Brown, Judith; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Lambrechts, Diether; Thienpont, Bernard; Neven, Patrick; Wildiers, Hans; Broeks, Annegien; Van't Veer, Laura J; Th Rutgers, Emiel J; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; Dos-Santos-Silva, Isabel; Gibson, Lorna; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Qiuyin; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Lee, Daphne S C; Wong, Tien Y; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; van Deurzen, Carolien H M; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Kapuscinski, Miroslav K; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Chen, Shou-Tung; Alnæs, Grethe Grenaker; Borresen-Dale, Anne-Lise; Giles, Graham G; Milne, Roger L; McLean, Catriona; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Buhari, Shaik Ahmad Bin Syed; Teo, Yik Ying; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Brauch, Hiltrud; Brüning, Thomas; Koto, Yon-Dschun; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Dörk, Thilo; Bogdanova, Natalia V; Helbig, Sonja; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Hamann, Ute; Torres, Diana; Zheng, Wei; Long, Jirong; Anton-Culver, Hoda; Neuhausen, Susan L; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Alvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; de Santiago, Ines; Carroll, Jason; Caldas, Carlos; Brown, Melissa A; Lupien, Mathieu; Kristensen, Vessela N; Pharoah, Paul D P; Chenevix-Trench, Georgia; French, Juliet D; Easton, Douglas F; Dunning, Alison M

2014-09-23

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

Low-dose radiation suppresses Pokemon expression under hypoxic conditions.

PubMed

Kim, Seung-Whan; Yu, Kweon; Shin, Kee-Sun; Kwon, Kisang; Hwang, Tae-Sik; Kwon, O-Yu

2014-01-01

Our previous data demonstrated that CoCl2-induced hypoxia controls endoplasmic reticulum (ER) stress-associated and other intracellular factors. One of them, the transcription factor Pokemon, was differentially regulated by low-dose radiation (LDR). There are limited data regarding how this transcription factor is involved in expression of the unfolded protein response (UPR) under hypoxic conditions. The purpose of this study was to obtain clues on how Pokemon is involved in the UPR. Pokemon was selected as a differentially expressed gene under hypoxic conditions; however, its regulation was clearly repressed by LDR. It was also demonstrated that both expression of ER chaperones and ER stress sensors were affected by hypoxic conditions, and the same results were obtained when cells in which Pokemon was up- or down-regulated were used. The current state of UPR and LDR research associated with the Pokemon pathway offers an important opportunity to understand the oncogenesis, senescence, and differentiation of cells, as well as to facilitate introduction of new therapeutic radiopharmaceuticals.

VCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation

PubMed Central

Shih, Yu-Tzu; Hsueh, Yi-Ping

2016-01-01

Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders. Here, using expression of mutant proteins, a knockdown approach and disease mutation knockin mice, we show that VCP (valosin-containing protein), together with its cofactor P47 and the endoplasmic reticulum (ER) morphology regulator ATL1 (Atlastin-1), regulates tubular ER formation and influences the efficiency of protein synthesis to control dendritic spine formation in neurons. Strengthening the significance of protein synthesis in dendritic spinogenesis, the translation blocker cyclohexamide and the mTOR inhibitor rapamycin reduce dendritic spine density, while a leucine supplement that increases protein synthesis ameliorates the dendritic spine defects caused by Vcp and Atl1 deficiencies. Because VCP and ATL1 are the causative genes of several neurodegenerative and neurodevelopmental disorders, we suggest that impaired ER formation and inefficient protein synthesis are significant in the pathogenesis of multiple neurological disorders. PMID:26984393

VCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation.

PubMed

Shih, Yu-Tzu; Hsueh, Yi-Ping

2016-03-17

Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders. Here, using expression of mutant proteins, a knockdown approach and disease mutation knockin mice, we show that VCP (valosin-containing protein), together with its cofactor P47 and the endoplasmic reticulum (ER) morphology regulator ATL1 (Atlastin-1), regulates tubular ER formation and influences the efficiency of protein synthesis to control dendritic spine formation in neurons. Strengthening the significance of protein synthesis in dendritic spinogenesis, the translation blocker cyclohexamide and the mTOR inhibitor rapamycin reduce dendritic spine density, while a leucine supplement that increases protein synthesis ameliorates the dendritic spine defects caused by Vcp and Atl1 deficiencies. Because VCP and ATL1 are the causative genes of several neurodegenerative and neurodevelopmental disorders, we suggest that impaired ER formation and inefficient protein synthesis are significant in the pathogenesis of multiple neurological disorders.

Endoplasmic Reticulum Stress in Arterial Smooth Muscle Cells: A Novel Regulator of Vascular Disease

PubMed Central

Furmanik, Malgorzata; Shanahan, Catherine M.

2017-01-01

Cardiovascular disease continues to be the leading cause of death in industrialised societies. The idea that the arterial smooth muscle cell (ASMC) plays a key role in regulating many vascular pathologies has been gaining importance, as has the realisation that not enough is known about the pathological cellular mechanisms regulating ASMC function in vascular remodelling. In the past decade endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been recognised as a stress response underlying many physiological and pathological processes in various vascular cell types. Here we summarise what is known about how ER stress signalling regulates phenotypic switching, trans/dedifferentiation and apoptosis of ASMCs and contributes to atherosclerosis, hypertension, aneurysms and vascular calcification.

Suppression Benefits Boys in Taiwan: The Relation between Gender, Emotional Regulation Strategy, and Mental Health

PubMed Central

Yeh, Kuang-Hui; Bedford, Olwen; Wu, Chih-Wen; Wang, Shu-Yi; Yen, Nai-Shing

2017-01-01

Emotion regulation (ER) strategies have a clear impact on mental health outcomes. In 2 studies (N = 695, N = 433) we investigated gender differences in the use of 2 ER strategies (reappraisal and suppression) to handle parent-child conflict in Taiwanese adolescents. We also identified the implications of these differences for some negative emotions (self-blame and resentment) and internalizing problems (psychosomatic symptoms and social withdrawal). Results of the correlation analyses in both studies indicated that reappraisal and suppression ER strategies are positively correlated only in male Taiwanese adolescents. Hierarchical regression analyses in the second study confirmed that reappraisal buffers male but not female adolescents against the negative effects of suppression on the arousal of negative affect and internalizing problems. PMID:28220099

Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1

PubMed Central

Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava; Saez, Borja; Graubert, Timothy A.; Zou, Lee

2017-01-01

R loop, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA (ssDNA), has emerged as a major source of genomic instability. RNaseH1, which cleaves the RNA in RNA:DNA hybrids, plays an important role in R loop suppression. Here, we show that replication protein A (RPA), a ssDNA-binding protein, interacts with RNaseH1 and colocalizes with both RNaseH1 and R loops in cells. In vitro, purified RPA directly enhances the association of RNaseH1 with RNA:DNA hybrids and stimulates the activity of RNaseH1 on R loops. An RPA binding-defective RNaseH1 mutant is not efficiently stimulated by RPA in vitro, fails to accumulate at R loops in cells, and loses the ability to suppress R loops and associated genomic instability. Thus, in addition to sensing DNA damage and replication stress, RPA is a sensor of R loops and a regulator of RNaseH1, extending the versatile role of RPA in suppression of genomic instability. PMID:28257700

ApoER2 and Reelin are expressed in regenerating peripheral nerve and regulate Schwann cell migration by activating the Rac1 GEF protein, Tiam1.

PubMed

Pasten, Consuelo; Cerda, Joaquín; Jausoro, Ignacio; Court, Felipe A; Cáceres, Alfredo; Marzolo, Maria-Paz

2015-11-01

ApoER2 and its ligand Reelin participate in neuronal migration during development. Upon receptor binding, Reelin induces the proteolytic processing of ApoER2 as well as the activation of signaling pathway, including small Rho GTPases. Besides its presence in the central nervous system (CNS), Reelin is also secreted by Schwann cells (SCs), the glial cells of the peripheral nervous system (PNS). Reelin deficient mice (reeler) show decreased axonal regeneration in the PNS; however neither the presence of ApoER2 nor the role of the Reelin signaling pathway in the PNS have been evaluated. Interestingly SC migration occurs during PNS development and during injury-induced regeneration and involves activation of small Rho GTPases. Thus, Reelin-ApoER2 might regulate SC migration during axon regeneration in the PNS. Here we demonstrate the presence of ApoER2 in PNS. After sciatic nerve injury Reelin was induced and its receptor ApoER2 was proteolytically processed. In vitro, SCs express both Reelin and ApoER2 and Reelin induces SC migration. To elucidate the molecular mechanism underlying Reelin-dependent SC migration, we examined the involvement of Rac1, a conspicuous small GTPase family member. FRET experiments revealed that Reelin activates Rac1 at the leading edge of SCs. In addition, Tiam1, a major Rac1-specific GEF was required for Reelin-induced SC migration. Moreover, Reelin-induced SC migration was decreased after suppression of the polarity protein PAR3, consistent with its association to Tiam1. Even more interesting, we demonstrated that PAR3 binds preferentially to the full-length cytoplasmic tail of ApoER2 corresponding to the splice-variant containing the exon 19 that encodes a proline-rich insert and that ApoER2 was required for SC migration. Our study reveals a novel function for Reelin/ApoER2 in PNS, inducing cell migration of SCs, a process relevant for PNS development and regeneration. Copyright © 2015 Elsevier Inc. All rights reserved.

Immunohistochemical status of p53, MDM2, bcl2, bax, and ER in invasive ductal breast carcinoma in Tunisian patients.

PubMed

Baccouche, Sami; Daoud, Jamel; Frikha, Mounir; Mokdad-Gargouri, Raja; Gargouri, Ali; Jlidi, Rachid

2003-12-01

TP53 gene alterations have been associated with sporadic breast cancer. To assess the role of p53 in invasive ductal carcinoma (IDC) of the breast among Tunisian patients, p53 protein status was studied by immuno-histochemical analysis. The p53 protein was expressed in 41 of 70 (58%) tumors. Study of the status of its target gene expression showed that MDM2 was overexpressed in 43 tumors (61%), bcl2 in 29 (41%), and bax in only 9 (12%). Estrogen receptor (ER) was detected in 38 tumor tissues (54%). The accumulated p53 was significantly associated with MDM2-positive, bcl2-negative, and ER-negative tumors (P = 0.024, P = 0.000027, and P = 0.000008, respectively), whereas with bax the correlaton was not significant. Bcl2 immunostaining displayed a positive correlation with ER (P = 0.001). A significantly higher fraction of p53-positive cells was observed in ER-negative SBRII-SBRIII tumors than in ER-positive SBRI-SBRII tumors (P = 0.000066). bcl2-positive tumors were significantly correlated with ER-positive/SBRI-SBRII tumors (P = 0.007), but negatively correlated with p53/bax (P = 0000004). MDM2 immunostaining displayed the same phenotype as p53 in the correlation with bcl2 and ER (P = 0.003), strengthened by significant associations between MDM2-positive/p53-positive and bcl2-negative or ER-negative, respectively (P = 0.00005 and P = 0.000001, respectively). MDM2-positive cells were significantly correlated with the p53-positive/bax-negative phenotype (P = 0.04). These results suggest that p53 accumulated in these tumor tissues is associated with bad prognostic markers (ER-negative, SBRIII) of IDC. MDM2 overexpression might be responsible for the accumulated p53 value in IDC. Regulation of the apoptotic process is involved in IDC; bcl2 is associated with a good prognostic marker (ER-positive and SBRI-II), whereas the regulation of bax is complex and does not necessarily correlate with the overexpression of p53.

Dealing with feeling: Specific emotion regulation skills predict responses to stress in psychosis.

PubMed

Lincoln, Tania M; Hartmann, Maike; Köther, Ulf; Moritz, Steffen

2015-08-15

Elevated negative affect is an established link between minor stressors and psychotic symptoms. Less clear is why people with psychosis fail to regulate distressing emotions effectively. This study tests whether subjective, psychophysiological and symptomatic responses to stress can be predicted by specific emotion regulation (ER) difficulties. Participants with psychotic disorders (n=35) and healthy controls (n=28) were assessed for ER-skills at baseline. They were then exposed to a noise versus no stressor on different days, during which self-reported stress responses, state paranoia and skin conductance levels (SCL) were assessed. Participants with psychosis showed a stronger increase in self-reported stress and SCL in response to the stressor than healthy controls. Stronger increases in self-reported stress were predicted by a reduced ability to be aware of and tolerate distressing emotions, whereas increases in SCL were predicted by a reduced ability to be aware of, tolerate, accept and modify them. Although paranoid symptoms were not significantly affected by the stressors, individual variation in paranoid responses was also predicted by a reduced ability to be aware of and tolerate emotions. Differences in stress responses in the samples were no longer significant after controlling for ER skills. Thus, interventions that improve ER-skills could reduce stress-sensitivity in psychosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Time course of emotion-related responding during distraction and reappraisal

PubMed Central

Schönfelder, Sandra; Kanske, Philipp; Heissler, Janine

2014-01-01

Theoretical accounts of emotion regulation (ER) discriminate various cognitive strategies to voluntarily modify emotional states. Amongst these, attentional deployment (i.e. distraction) and cognitive change (i.e. reappraisal), have been shown to successfully down-regulate emotions. Neuroimaging studies found that both strategies differentially engage neural structures associated with selective attention, working memory and cognitive control. The aim of this study was to further delineate similarities and differences between the ER strategies reappraisal and distraction by investigating their temporal brain dynamics using event-related potentials (ERPs) and their patterns of facial expressive behavior. Twenty-one participants completed an ER experiment in which they had to either passively view positive, neutral and negative pictures, reinterpret them to down-regulate affective responses (reappraisal), or solve a concurrently presented mathematical equation (distraction). Results demonstrate the efficacy of both strategies in the subjective control of emotion, accompanied by reductions of facial expressive activity (Corrugator supercilii and Zygomaticus major). ERP results indicated that distraction, compared with reappraisal, yielded a stronger and earlier attenuation of the late positive potential (LPP) magnitude for negative pictures. For positive pictures, only distraction but not reappraisal had significant effect on LPP attenuation. The results support the process model of ER, separating subtypes of cognitive strategies based on their specific time course. PMID:23988760

Skin Barrier and Calcium.

PubMed

Lee, Sang Eun; Lee, Seung Hun

2018-06-01

Epidermal barrier formation and the maintenance of barrier homeostasis are essential to protect us from the external environments and organisms. Moreover, impaired keratinocytes differentiation and dysfunctional skin barrier can be the primary causes or aggravating factors for many inflammatory skin diseases including atopic dermatitis and psoriasis. Therefore, understanding the regulation mechanisms of keratinocytes differentiation and skin barrier homeostasis is important to understand many skin diseases and establish an effective treatment strategy. Calcium ions (Ca 2+ ) and their concentration gradient in the epidermis are essential in regulating many skin functions, including keratinocyte differentiation, skin barrier formation, and permeability barrier homeostasis. Recent studies have suggested that the intracellular Ca 2+ stores such as the endoplasmic reticulum (ER) are the major components that form the epidermal calcium gradient and the ER calcium homeostasis is crucial for regulating keratinocytes differentiation, intercellular junction formation, antimicrobial barrier, and permeability barrier homeostasis. Thus, both Ca 2+ release from intracellular stores, such as the ER and Ca 2+ influx mechanisms are important in skin barrier. In addition, growing evidences identified the functional existence and the role of many types of calcium channels which mediate calcium flux in keratinocytes. In this review, the origin of epidermal calcium gradient and their role in the formation and regulation of skin barrier are focused. We also focus on the role of ER calcium homeostasis in skin barrier. Furthermore, the distribution and role of epidermal calcium channels, including transient receptor potential channels, store-operated calcium entry channel Orai1, and voltage-gated calcium channels in skin barrier are discussed.

Learn about the Cross-Media Electronic Reporting Rule

EPA Pesticide Factsheets

The Cross-Media Electronic Reporting Regulation (CROMERR) provides the legal framework for electronic reporting (ER) under all of the Environmental Protection Agency's (EPA) environmental regulations.

A training rule which guarantees finite-region stability for a class of closed-loop neural-network control systems.

PubMed

Kuntanapreeda, S; Fullmer, R R

1996-01-01

A training method for a class of neural network controllers is presented which guarantees closed-loop system stability. The controllers are assumed to be nonlinear, feedforward, sampled-data, full-state regulators implemented as single hidden-layer neural networks. The controlled systems must be locally hermitian and observable. Stability of the closed-loop system is demonstrated by determining a Lyapunov function, which can be used to identify a finite stability region about the regulator point.

Resolving Turbine Degradation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Matthew; Kruizenga, Alan Michael; Withey, Elizabeth Ann

2017-08-01

The supercritical carbon dioxide (S-CO2) Brayton Cycle has gained significant attention in the last decade as an advanced power cycle capable of achieving high efficiency power conversion. Sandia National Laboratories, with support from the U.S. Department of Energy Office of Nuclear Energy (US DOE-NE), has been conducting research and development in order to deliver a technology that is ready for commercialization. Root cause analysis has been performed on the Recompression Loop at Sandia National Laboratories. It was found that particles throughout the loop are stainless steel, likely alloy 316 based upon the elemental composition. Deployment of a filter scheme ismore » underway to both protect the turbomachinery and also for purposes of determining the specific cause for the particulate. Shake down tests of electric resistance (ER) as a potential in-situ monitoring scheme shows promise in high temperature systems. A modified instrument was purchased and held at 650°C for more than 1.5 months to date without issue. Quantitative measurements of this instrument will be benchmarked against witness samples in the future, but all qualitative trends to date are as to be expected. ER is a robust method for corrosion monitoring, but very slow at responding and can take several weeks under conditions to see obvious changes in behavior. Electrochemical noise was identified as an advanced technique that should be pursued for the ability to identify transients that would lead to poor material performance.« less

7 CFR 3701.7 - Requests for published data and information.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Section 3701.7 Agriculture Regulations of the Department of Agriculture (Continued) ECONOMIC RESEARCH....usda.gov. Searching on the website is available by topic, by title, or by date. The titles displayed in the search include ERS's separately published research reports as well as articles in ERS-produced...

7 CFR 3701.7 - Requests for published data and information.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Section 3701.7 Agriculture Regulations of the Department of Agriculture (Continued) ECONOMIC RESEARCH....usda.gov. Searching on the website is available by topic, by title, or by date. The titles displayed in the search include ERS's separately published research reports as well as articles in ERS-produced...

7 CFR 3701.7 - Requests for published data and information.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Section 3701.7 Agriculture Regulations of the Department of Agriculture (Continued) ECONOMIC RESEARCH....usda.gov. Searching on the website is available by topic, by title, or by date. The titles displayed in the search include ERS's separately published research reports as well as articles in ERS-produced...

7 CFR 3701.7 - Requests for published data and information.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Section 3701.7 Agriculture Regulations of the Department of Agriculture (Continued) ECONOMIC RESEARCH....usda.gov. Searching on the website is available by topic, by title, or by date. The titles displayed in the search include ERS's separately published research reports as well as articles in ERS-produced...

Mammalian ECD Protein Is a Novel Negative Regulator of the PERK Arm of the Unfolded Protein Response.

PubMed

Olou, Appolinaire A; Sarkar, Aniruddha; Bele, Aditya; Gurumurthy, C B; Mir, Riyaz A; Ammons, Shalis A; Mirza, Sameer; Saleem, Irfana; Urano, Fumihiko; Band, Hamid; Band, Vimla

2017-09-15

Mammalian Ecdysoneless (ECD) is a highly conserved ortholog of the Drosophila Ecd gene product whose mutations impair the synthesis of Ecdysone and produce cell-autonomous survival defects, but the mechanisms by which ECD functions are largely unknown. Here we present evidence that ECD regulates the endoplasmic reticulum (ER) stress response. ER stress induction led to a reduced ECD protein level, but this effect was not seen in PKR-like ER kinase knockout (PERK-KO) or phosphodeficient eukaryotic translation initiation factor 2α (eIF2α) mouse embryonic fibroblasts (MEFs); moreover, ECD mRNA levels were increased, suggesting impaired ECD translation as the mechanism for reduced protein levels. ECD colocalizes and coimmunoprecipitates with PERK and GRP78. ECD depletion increased the levels of both phospho-PERK (p-PERK) and p-eIF2α, and these effects were enhanced upon ER stress induction. Reciprocally, overexpression of ECD led to marked decreases in p-PERK, p-eIF2α, and ATF4 levels but robust increases in GRP78 protein levels. However, GRP78 mRNA levels were unchanged, suggesting a posttranscriptional event. Knockdown of GRP78 reversed the attenuating effect of ECD overexpression on PERK signaling. Significantly, overexpression of ECD provided a survival advantage to cells upon ER stress induction. Taken together, our data demonstrate that ECD promotes survival upon ER stress by increasing GRP78 protein levels to enhance the adaptive folding protein in the ER to attenuate PERK signaling. Copyright © 2017 Olou et al.

Taurine and its neuroprotective role.

PubMed

Kumari, Neeta; Prentice, Howard; Wu, Jang-Yen

2013-01-01

Taurine plays multiple roles in the CNS including acting as a -neuro-modulator, an osmoregulator, a regulator of cytoplasmic calcium levels, a trophic factor in development, and a neuroprotectant. In neurons taurine has been shown to prevent mitochondrial dysfunction and to protect against endoplasmic reticulum (ER) stress associated with neurological disorders. In cortical neurons in culture taurine protects against excitotoxicity through reversing an increase in levels of key ER signaling components including eIF-2-alpha and cleaved ATF6. The role of communication between the ER and mitochondrion is also important and examples are presented of protection by taurine against ER stress together with prevention of subsequent mitochondrial initiated apoptosis.

DNA Topoisomerase 1 Prevents R-loop Accumulation to Modulate Auxin-Regulated Root Development in Rice.

PubMed

Shafiq, Sarfraz; Chen, Chunli; Yang, Jing; Cheng, Lingling; Ma, Fei; Widemann, Emilie; Sun, Qianwen

2017-06-05

R-loop structures (RNA:DNA hybrids) have important functions in many biological processes, including transcriptional regulation and genome instability among diverse organisms. DNA topoisomerase 1 (TOP1), an essential manipulator of DNA topology during RNA transcription and DNA replication processes, can prevent R-loop accumulation by removing the positive and negative DNA supercoiling that is made by RNA polymerases during transcription. TOP1 is required for plant development, but little is known about its function in preventing co-transcriptional R-loop accumulation in various biological processes in plants. Here we show that knockdown of OsTOP1 strongly affects rice development, causing defects in root architecture and gravitropism, which are the consequences of misregulation of auxin signaling and transporter genes. We found that R-loops are naturally formed at rice auxin-related gene loci, and overaccumulate when OsTOP1 is knocked down or OsTOP1 protein activity is inhibited. OsTOP1 therefore sets the accurate expression levels of auxin-related genes by preventing the overaccumulation of inherent R-loops. Our data reveal R-loops as important factors in polar auxin transport and plant root development, and highlight that OsTOP1 functions as a key to link transcriptional R-loops with plant hormone signaling, provide new insights into transcriptional regulation of hormone signaling in plants. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

ER-driven membrane contact sites: Evolutionary conserved machineries for stress response and autophagy regulation?

PubMed Central

Molino, Diana; Nascimbeni, Anna Chiara; Giordano, Francesca; Codogno, Patrice

2017-01-01

ABSTRACT Endoplasmic Reticulum (ER), spreading in the whole cell cytoplasm, is a central player in eukaryotic cell homeostasis, from plants to mammals. Beside crucial functions, such as membrane lipids and proteins synthesis and outward transport, the ER is able to connect to virtually every endomembrane compartment by specific tethering molecular machineries, which enables the establishment of membrane-membrane contact sites. ER-mitochondria contact sites have been shown to be involved in autophagosome biogenesis, the main organelle of the autophagy degradation pathway. More recently we demonstrated that also ER-plasma membrane contact sites are sites for autophagosomes assembly, suggesting that more generally ER-organelles contacts are involved in autophagy and organelle biogenesis. Here we aim to discuss the functioning of ER-driven contact sites in mammals and plants and more in particular emphasize on their recently highlighted function in autophagy to finally conclude on some key questions that may be useful for further research in the field. PMID:29259731

Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity.

PubMed

Henis-Korenblit, Sivan; Zhang, Peichuan; Hansen, Malene; McCormick, Mark; Lee, Seung-Jae; Cary, Michael; Kenyon, Cynthia

2010-05-25

When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.

A Large and Intact Viral Particle Penetrates the Endoplasmic Reticulum Membrane to Reach the Cytosol

PubMed Central

Inoue, Takamasa; Tsai, Billy

2011-01-01

Non-enveloped viruses penetrate host membranes to infect cells. A cell-based assay was used to probe the endoplasmic reticulum (ER)-to-cytosol membrane transport of the non-enveloped SV40. We found that, upon ER arrival, SV40 is released into the lumen and undergoes sequential disulfide bond disruptions to reach the cytosol. However, despite these ER-dependent conformational changes, SV40 crosses the ER membrane as a large and intact particle consisting of the VP1 coat, the internal components VP2, VP3, and the genome. This large particle subsequently disassembles in the cytosol. Mutant virus and inhibitor studies demonstrate VP3 and likely the viral genome, as well as cellular proteasome, control ER-to-cytosol transport. Our results identify the sequence of events, as well as virus and host components, that regulate ER membrane penetration. They also suggest that the ER membrane supports passage of a large particle, potentially through either a sizeable protein-conducting channel or the lipid bilayer. PMID:21589906

Endoplasmic reticulum stress in obesity and obesity-related disorders: An expanded view.

PubMed

Pagliassotti, Michael J; Kim, Paul Y; Estrada, Andrea L; Stewart, Claire M; Gentile, Christopher L

2016-09-01

The endoplasmic reticulum (ER) is most notable for its central roles in calcium ion storage, lipid biosynthesis, and protein sorting and processing. By virtue of its extensive membrane contact sites that connect the ER to most other organelles and to the plasma membrane, the ER can also regulate diverse cellular processes including inflammatory and insulin signaling, nutrient metabolism, and cell proliferation and death via a signaling pathway called the unfolded protein response (UPR). Chronic UPR activation has been observed in liver and/or adipose tissue of dietary and genetic murine models of obesity, and in human obesity and non-alcoholic fatty liver disease (NAFLD). Activation of the UPR in obesity and obesity-related disorders likely has two origins. One linked to classic ER stress involving the ER lumen and one linked to alterations to the ER membrane environment. This review discusses both of these origins and also considers the role of post-translational protein modifications, such as acetylation and palmitoylation, and ER-mitochondrial interactions to obesity-mediated impairments in the ER and activation of the UPR. Copyright © 2016 Elsevier Inc. All rights reserved.

Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

PubMed Central

Plate, Lars; Cooley, Christina B; Chen, John J; Paxman, Ryan J; Gallagher, Ciara M; Madoux, Franck; Genereux, Joseph C; Dobbs, Wesley; Garza, Dan; Spicer, Timothy P; Scampavia, Louis; Brown, Steven J; Rosen, Hugh; Powers, Evan T; Walter, Peter; Hodder, Peter; Wiseman, R Luke; Kelly, Jeffery W

2016-01-01

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases. DOI: http://dx.doi.org/10.7554/eLife.15550.001 PMID:27435961

Receptor-mediated Drp1 oligomerization on endoplasmic reticulum

PubMed Central

Ji, Wei-Ke; Fan, Xintao; Strack, Stefan

2017-01-01

Drp1 is a dynamin guanosine triphosphatase important for mitochondrial and peroxisomal division. Drp1 oligomerization and mitochondrial recruitment are regulated by multiple factors, including interaction with mitochondrial receptors such as Mff, MiD49, MiD51, and Fis. In addition, both endoplasmic reticulum (ER) and actin filaments play positive roles in mitochondrial division, but mechanisms for their roles are poorly defined. Here, we find that a population of Drp1 oligomers is associated with ER in mammalian cells and is distinct from mitochondrial or peroxisomal Drp1 populations. Subpopulations of Mff and Fis1, which are tail-anchored proteins, also localize to ER. Drp1 oligomers assemble on ER, from which they can transfer to mitochondria. Suppression of Mff or inhibition of actin polymerization through the formin INF2 significantly reduces all Drp1 oligomer populations (mitochondrial, peroxisomal, and ER bound) and mitochondrial division, whereas Mff targeting to ER has a stimulatory effect on division. Our results suggest that ER can function as a platform for Drp1 oligomerization, and that ER-associated Drp1 contributes to mitochondrial division. PMID:29158231

Regulation of inflorescence architecture by intertissue layer ligand-receptor communication between endodermis and phloem.

PubMed

Uchida, Naoyuki; Lee, Jin Suk; Horst, Robin J; Lai, Hung-Hsueh; Kajita, Ryoko; Kakimoto, Tatsuo; Tasaka, Masao; Torii, Keiko U

2012-04-17

Multicellular organisms achieve final body shape and size by coordinating cell proliferation, expansion, and differentiation. Loss of function in the Arabidopsis ERECTA (ER) receptor-kinase gene confers characteristic compact inflorescence architecture, but its underlying signaling pathways remain unknown. Here we report that the expression of ER in the phloem is sufficient to rescue compact er inflorescences. We further identified two Epidermal Patterning Factor-like (EPFL) secreted peptide genes, EPFL4 and EPFL6/CHALLAH (CHAL), as redundant, upstream components of ER-mediated inflorescence growth. The expression of EPFL4 or EPFL6 in the endodermis, a layer adjacent to phloem, is sufficient to rescue the er-like inflorescence of epfl4 epfl6 plants. EPFL4 and EPFL6 physically associate with ER in planta. Finally, transcriptome analysis of er and epfl4 epfl6 revealed a potential downstream component as well as a role for plant hormones in EPFL4/6- and ER-mediated inflorescence growth. Our results suggest that intercell layer communication between the endodermis and phloem mediated by peptide ligands and a receptor kinase coordinates proper inflorescence architecture in Arabidopsis.

Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy

PubMed Central

McLelland, Gian-Luca; Goiran, Thomas; Yi, Wei; Dorval, Geneviève; Chen, Carol X; Lauinger, Nadine D; Krahn, Andrea I; Valimehr, Sepideh; Rakovic, Aleksandar; Rouiller, Isabelle; Durcan, Thomas M; Trempe, Jean-François

2018-01-01

Despite their importance as signaling hubs, the function of mitochondria-ER contact sites in mitochondrial quality control pathways remains unexplored. Here we describe a mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin. Mitochondria-ER appositions are destroyed during mitophagy, and reducing mitochondria-ER contacts increases the rate of mitochondrial degradation. Mechanistically, parkin/PINK1 catalyze a rapid burst of Mfn2 phosphoubiquitination to trigger p97-dependent disassembly of Mfn2 complexes from the outer mitochondrial membrane, dissociating mitochondria from the ER. We additionally demonstrate that a major portion of the facilitatory effect of p97 on mitophagy is epistatic to Mfn2 and promotes the availability of other parkin substrates such as VDAC1. Finally, we reconstitute the action of these factors on Mfn2 and VDAC1 ubiquitination in a cell-free assay. We show that mitochondria-ER tethering suppresses mitophagy and describe a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondria-ER contact sites. PMID:29676259

Endoplasmic Reticulum Stress in Obesity and Obesity-Related Disorders: An Expanded View

PubMed Central

Pagliassotti, M.J.; Kim, P. Y.; Estrada, A.L.; Stewart, C.M.; Gentile, C.L.

2016-01-01

The Endoplasmic Reticulum (ER) is most notable for its central roles in calcium ion storage, lipid biosynthesis, and protein sorting and processing. By virtue of its extensive membrane contact sites that connect the ER to most other organelles and to the plasma membrane, the ER can also regulate diverse cellular processes including inflammatory and insulin signaling, nutrient metabolism, and cell proliferation and death via a signaling pathway called the unfolded protein response (UPR). Chronic UPR activation has been observed in liver and/or adipose tissue of dietary and genetic murine models of obesity, and in human obesity and non-alcoholic fatty liver disease (NAFLD). Activation of the UPR in obesity and obesity-related disorders likely has two origins. One linked to classic ER stress involving the ER lumen and one linked to alterations to the ER membrane environment. This review discusses both of these origins and also considers the role of post-translational protein modifications, such as acetylation and palmitoylation, and ER-mitochondrial interactions to obesity-mediated impairments in the ER and activation of the UPR. PMID:27506731

Successful Application of Adaptive Emotion Regulation Skills Predicts the Subsequent Reduction of Depressive Symptom Severity but neither the Reduction of Anxiety nor the Reduction of General Distress during the Treatment of Major Depressive Disorder

PubMed Central

Wirtz, Carolin M.; Radkovsky, Anna; Ebert, David D.; Berking, Matthias

2014-01-01

Objective Deficits in general emotion regulation (ER) skills have been linked to symptoms of depression and are thus considered a promising target in the treatment of Major depressive disorder (MDD). However, at this point, the extent to which such skills are relevant for coping with depression and whether they should instead be considered a transdiagnostic factor remain unclear. Therefore, the present study aimed to investigate whether successful ER skills application is associated with changes in depressive symptom severity (DSS), anxiety symptom severity (ASS), and general distress severity (GDS) over the course of treatment for MDD. Methods Successful ER skills application, DSS, ASS, and GDS were assessed four times during the first three weeks of treatment in 175 inpatients who met the criteria for MDD. We computed Pearson correlations to test whether successful ER skills application and the three indicators of psychopathology are cross-sectionally associated. We then performed latent growth curve modelling to test whether changes in successful ER skills application are negatively associated with a reduction of DSS, ASS, or GDS. Finally, we utilized latent change score models to examine whether successful ER skills application predicts subsequent reduction of DSS, ASS, or GDS. Results Successful ER skills application was cross-sectionally associated with lower levels of DSS, ASS, and GDS at all points of assessment. An increase in successful skills application during treatment was associated with a decrease in DSS and GDS but not ASS. Finally, successful ER skills application predicted changes in subsequent DSS but neither changes in ASS nor changes in GDS. Conclusions Although general ER skills might be relevant for a broad range of psychopathological symptoms, they might be particularly important for the maintenance and treatment of depressive symptoms. PMID:25330159

Alteration of the proteostasis network of plant cells promotes the post-endoplasmic reticulum trafficking of recombinant mutant (L444P) human β-glucocerebrosidase

PubMed Central

Babajani, Gholamreza; Kermode, Allison R

2014-01-01

Gaucher disease is a prevalent lysosomal storage disease characterized by a deficiency in the activity of lysosomal acid β-glucosidase (glucocerebrosidase, GCase, EC 3.2.1.45). One of the most prevalent disease-causing mutations in humans is a L444P missense mutation in the GCase protein, which results in its disrupted folding in the endoplasmic reticulum (ER) and impaired post-ER trafficking. To determine whether the post-ER trafficking of this severely malfolded protein can be restored, we expressed the mutant L444P GCase as a recombinant protein in transgenic tobacco (Nicotiana tabacum L. cv Bright Yellow 2 [BY2]) cells, in which the GCase variant was equipped with a plant signal peptide to allow for secretion upon rescued trafficking out of the ER. The recombinant L444P mutant GCase was retained in the plant endoplasmic reticulum (ER). Kifunensine and Eeyarestatin I, both inhibitors of ER-associated degradation (ERAD), and the proteostasis regulators, celastrol and MG-132, increased the steady-state levels of the mutant protein inside the plant cells and further promoted the post-ER trafficking of L444P GCase, as indicated by endoglycosidase-H sensitivity- and secretion- analyses. Transcript profiling of genes encoding ER-molecular chaperones, ER stress responsive proteins, and cytoplasmic heat shock response proteins, revealed insignificant or only very modest changes in response to the ERAD inhibitors and proteostasis regulators. An exception was the marked response to celastrol which reduced the steady-state levels of cytoplasmic HSP90 transcripts and protein. As HSP90 participates in the targeting of misfolded proteins to the proteasome pathway, its down-modulation in response to celastrol may partly account for the mechanism of improved homeostasis of L444P GCase mediated by this triterpene. PMID:24713615

Progesterone induces progesterone receptor gene (PGR) expression via rapid activation of protein kinase pathways required for cooperative estrogen receptor alpha (ER) and progesterone receptor (PR) genomic action at ER/PR target genes.

PubMed

Diep, Caroline H; Ahrendt, Hannah; Lange, Carol A

2016-10-01

Progesterone Receptors (PRs) are critical effectors of estrogen receptor (ER) signaling required for mammary gland development and reproductive proficiency. In breast and reproductive tract malignancies, PR expression is a clinical prognostic marker of ER action. While estrogens primarily regulate PR expression, other factors likely contribute to a dynamic range of receptor expression across diverse tissues. In this study, we identified estrogen-independent but progestin (R5020)-dependent regulation of ER target genes including PGR in ER+/PR+ cancer cell lines. R5020 (10nM-10μM range) induced dose-dependent PR mRNA and protein expression in the absence of estrogen but required both PR and ERα. Antagonists of either PR (RU486, onapristone) or ERα (ICI 182,780) attenuated R5020 induction of TFF1, CTSD, and PGR. Chromatin immunoprecipitation (ChIP) assays performed on ER+/PR+ cells demonstrated that both ERα and PR were recruited to the same ERE/Sp1 site-containing region of the PGR proximal promoter in response to high dose progestin (10μM). Recruitment of ERα and PR to chromatin and subsequent PR mRNA induction were dependent upon rapid activation of MAPK/ERK and AKT; inhibition of these kinase pathways via U0126 or LY294002 blocked these events. Overall, we have identified a novel mechanism of ERα activation initiated by rapid PR-dependent kinase pathway activation and associated with phosphorylation of ERα Ser118 for estrogen-independent but progestin-dependent ER/PR cross talk. These studies may provide insight into mechanisms of persistent ER-target gene expression during periods of hormone (i.e. estrogen) ablation and suggest caution following prolonged treatment with aromatase or CYP17 inhibitors (i.e. contexts when progesterone levels may be abnormally elevated). Copyright © 2016 Elsevier Inc. All rights reserved.

Cytolethal distending toxins require components of the ER-associated degradation pathway for host cell entry.

PubMed

Eshraghi, Aria; Dixon, Shandee D; Tamilselvam, Batcha; Kim, Emily Jin-Kyung; Gargi, Amandeep; Kulik, Julia C; Damoiseaux, Robert; Blanke, Steven R; Bradley, Kenneth A

2014-07-01

Intracellular acting protein exotoxins produced by bacteria and plants are important molecular determinants that drive numerous human diseases. A subset of these toxins, the cytolethal distending toxins (CDTs), are encoded by several Gram-negative pathogens and have been proposed to enhance virulence by allowing evasion of the immune system. CDTs are trafficked in a retrograde manner from the cell surface through the Golgi apparatus and into the endoplasmic reticulum (ER) before ultimately reaching the host cell nucleus. However, the mechanism by which CDTs exit the ER is not known. Here we show that three central components of the host ER associated degradation (ERAD) machinery, Derlin-2 (Derl2), the E3 ubiquitin-protein ligase Hrd1, and the AAA ATPase p97, are required for intoxication by some CDTs. Complementation of Derl2-deficient cells with Derl2:Derl1 chimeras identified two previously uncharacterized functional domains in Derl2, the N-terminal 88 amino acids and the second ER-luminal loop, as required for intoxication by the CDT encoded by Haemophilus ducreyi (Hd-CDT). In contrast, two motifs required for Derlin-dependent retrotranslocation of ERAD substrates, a conserved WR motif and an SHP box that mediates interaction with the AAA ATPase p97, were found to be dispensable for Hd-CDT intoxication. Interestingly, this previously undescribed mechanism is shared with the plant toxin ricin. These data reveal a requirement for multiple components of the ERAD pathway for CDT intoxication and provide insight into a Derl2-dependent pathway exploited by retrograde trafficking toxins.

Cytolethal Distending Toxins Require Components of the ER-Associated Degradation Pathway for Host Cell Entry

PubMed Central

Eshraghi, Aria; Dixon, Shandee D.; Tamilselvam, Batcha; Kim, Emily Jin-Kyung; Gargi, Amandeep; Kulik, Julia C.; Damoiseaux, Robert; Blanke, Steven R.; Bradley, Kenneth A.

2014-01-01

Intracellular acting protein exotoxins produced by bacteria and plants are important molecular determinants that drive numerous human diseases. A subset of these toxins, the cytolethal distending toxins (CDTs), are encoded by several Gram-negative pathogens and have been proposed to enhance virulence by allowing evasion of the immune system. CDTs are trafficked in a retrograde manner from the cell surface through the Golgi apparatus and into the endoplasmic reticulum (ER) before ultimately reaching the host cell nucleus. However, the mechanism by which CDTs exit the ER is not known. Here we show that three central components of the host ER associated degradation (ERAD) machinery, Derlin-2 (Derl2), the E3 ubiquitin-protein ligase Hrd1, and the AAA ATPase p97, are required for intoxication by some CDTs. Complementation of Derl2-deficient cells with Derl2:Derl1 chimeras identified two previously uncharacterized functional domains in Derl2, the N-terminal 88 amino acids and the second ER-luminal loop, as required for intoxication by the CDT encoded by Haemophilus ducreyi (Hd-CDT). In contrast, two motifs required for Derlin-dependent retrotranslocation of ERAD substrates, a conserved WR motif and an SHP box that mediates interaction with the AAA ATPase p97, were found to be dispensable for Hd-CDT intoxication. Interestingly, this previously undescribed mechanism is shared with the plant toxin ricin. These data reveal a requirement for multiple components of the ERAD pathway for CDT intoxication and provide insight into a Derl2-dependent pathway exploited by retrograde trafficking toxins. PMID:25078082

Estrogen receptor alpha and nuclear factor Y coordinately regulate the transcription of the SUMO-conjugating UBC9 gene in MCF-7 breast cancer cells.

PubMed

Ying, Shibo; Dünnebier, Thomas; Si, Jing; Hamann, Ute

2013-01-01

UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO) to target proteins thereby changing their functions. Recently, it was noted that UBC9 expression and activity play a role in breast tumorigenesis and response to anticancer drugs. However, the underlying mechanism is poorly understood. To investigate the transcriptional regulation of the UBC9 gene, we identified and characterized its promoter and cis-elements. Promoter activity was tested using luciferase reporter assays. The binding of transcription factors to the promoter was detected by chromatin immunoprecipitation (ChIP), and their functional role was confirmed by siRNA knockdown. UBC9 mRNA and protein levels were measured by quantitative reverse transcription PCR and Western blot analysis, respectively. An increased expression of UBC9 mRNA and protein was found in MCF-7 breast cancer cells treated with 17β-estradiol (E2). Analysis of various deletion mutants revealed a 137 bp fragment upstream of the transcription initiation site to be sufficient for reporter gene transcription. Mutations of putative estrogen receptor α (ER-α) (one imperfect estrogen response element, ERE) and/or nuclear factor Y (NF-Y) binding sites (two CCAAT boxes) markedly reduced promoter activity. Similar results were obtained in ER-negative MDA-MB-231 cells except that the ERE mutation did not affect promoter activity. Additionally, promoter activity was stimulated upon E2 treatment and overexpression of ER-α or NF-YA in MCF-7 cells. ChIP confirmed direct binding of both transcription factors to the UBC9 promoter in vivo. Furthermore, UBC9 expression was diminished by ER-α and NF-Y siRNAs on the mRNA and protein levels. In conclusion, we identified the proximal UBC9 promoter and provided evidence that ER-α and NF-Y regulate UBC9 expression on the transcriptional level in response to E2 in MCF-7 cells. These findings may contribute to a better understanding of the regulation of UBC9 in ER-positive breast cancer and be useful for the development of cancer therapies targeting UBC9.

NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of homocysteine-induced endoplasmic reticulum protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maeda, Tomoji, E-mail: t-maeda@nichiyaku.ac.jp; Tanabe-Fujimura, Chiaki; Fujita, Yu

2016-05-13

Homocysteine-induced endoplasmic reticulum (ER) protein (Herp) is an ER stress-inducible key regulatory component of ER-associated degradation (ERAD) that has been implicated in insulin hypersecretion in diabetic mouse models. Herp expression is tightly regulated. Additionally, Herp is a highly labile protein and interacts with various proteins, which are characteristic features of ubiquitinated protein. Previously, we reported that ubiquitination is not required for Herp degradation. In addition, we found that the lysine residues of Herp (which are ubiquitinated by E3 ubiquitin ligase) are not sufficient for regulation of Herp degradation. In this study, we found that NAD(P)H quinone oxidoreductase 1 (NQO1)-mediated targetingmore » of Herp to the proteasome was involved in Herp degradation. In addition, we found that Herp protein levels were markedly elevated in synoviolin-null cells. The E3 ubiquitin ligase synoviolin is a central component of ERAD and is involved in the degradation of nuclear factor E2-related factor-2 (Nrf2), which regulates cellular reactive oxygen species. Additionally, NQO1 is a target of Nrf2. Thus, our findings indicated that NQO1 could stabilize Herp protein expression via indirect regulation of synoviolin. -- Highlights: •Herp interacts with NQO1. •NQO1 regulates Herp degradation.« less

Characterization of WDR20: A new regulator of the ERAD machinery.

PubMed

Ju, Lin-Gao; Lin, Xiang; Yan, Dong; Li, Qing-Lan; Wu, Min; Li, Lian-Yun

2018-07-01

ERAD is an important process of protein quality control that eliminates misfolded or unassembled proteins from ER. Before undergoing proteasome degradation, the misfolded proteins are dislocated from ER membrane into cytosol, which requires the AAA ATPase p97/VCP and its cofactor, the NPL4-UFD1 dimer. Here, we performed a CRISPR-based screen and identify many candidates for ERAD regulation. We further confirmed four proteins, FBOX2, TRIM6, UFL1 and WDR20, are novel regulators for ERAD. Then the molecular mechanism for WDR20 in ERAD is further characterized. Depletion of WDR20 inhibits the degradation of TCRα, a typical ERAD substrate, while WDR20 overexpression reduces TCRα protein level. WDR20 associates with TCRα and central regulators of the ERAD system, p97, GP78 and HRD1. A portion of WDR20 localizes to the ER-containing microsomal membrane. WDR20 expression increases TCRα ubiquitination, and HRD1 E3 ligase is essential for the process. WDR20 seems to serve as an adaptor protein to mediate the interaction between p97 and TCRα. Our study provides novel candidates and reveals an unexpected role of WDR20 in ERAD regulation. Copyright © 2018 Elsevier B.V. All rights reserved.

Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis.

PubMed

Lombardi, Angela; Inabnet, William Barlow; Owen, Randall; Farenholtz, Kaitlyn Ellen; Tomer, Yaron

2015-01-01

Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available; however, its use is limited by a serious side effect profile, including thyroiditis. The mechanisms underlying AMIO thyroid toxicity have been elusive; thus, identification of novel approaches in order to prevent thyroiditis is essential in patients treated with AMIO. Our aim was to evaluate whether AMIO treatment could induce endoplasmic reticulum (ER) stress in human thyroid cells and the possible implications of this effect in AMIO-induced destructive thyroiditis. Here we report that AMIO, but not iodine, significantly induced the expression of ER stress markers including Ig heavy chain-binding protein (BiP), phosphoeukaryotic translation initiation factor 2α (eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO down-regulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced down-regulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1 cells and human primary thyrocytes with the chemical chaperone 4-phenylbutyric acid completely prevented the effect of AMIO on both ER stress induction and Tg down-regulation. We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation, providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.

Keratinocyte secretion of cyclophilin B via the constitutive pathway is regulated through its cyclosporin-binding site.

PubMed

Fearon, Paula; Lonsdale-Eccles, Ann A; Ross, O Kehinde; Todd, Carole; Sinha, Aparna; Allain, Fabrice; Reynolds, Nick J

2011-05-01

Cyclophilin B (CypB) is an endoplasmic reticulum (ER)-resident member of the cyclophilin family of proteins that bind cyclosporin A (CsA). We report that as in other cell types, CypB trafficked from the ER and was secreted by keratinocytes into the media in response to CsA. Concentrations as low as 1 pM of CsA induced secretion of CypB. Using brefeldin A, we showed that CypB is secreted from keratinocytes via the constitutive secretory pathway. We defined that substitution of tryptophan residue 128 in the CsA-binding site of CypB with alanine resulted in dissociation of CypB(W128A)-green fluorescent protein (GFP) from the ER. Photobleaching studies revealed a significant reduction in the diffusible mobility of CypB(W128A)-GFP compared with CypB(WT)-GFP, consistent with redistribution of CypB(W128A)-GFP into secretory vesicles disconnected from the ER/Golgi network. Furthermore, CsA significantly decreased the mobility of CypB(WT)-GFP but not CypB(W128A)-GFP. These studies demonstrate that therapeutically relevant concentrations of CsA regulate secretion of CypB by keratinocytes, and that a key residue within the CsA-binding site of CypB controls retention of CypB within the ER and regulates entry into the secretory pathway. As keratinocytes express CypB receptors (CD147) and CypB exhibits chemotactic properties, these data have implications for the therapeutic effects of CsA in inflammatory skin disease.

Keratinocyte Secretion of Cyclophilin B via the Constitutive Pathway Is Regulated through Its Cyclosporin-Binding Site

PubMed Central

Fearon, Paula; Lonsdale-Eccles, Ann A; Ross, O Kehinde; Todd, Carole; Sinha, Aparna; Allain, Fabrice; Reynolds, Nick J

2011-01-01

Cyclophilin B (CypB) is an endoplasmic reticulum (ER)-resident member of the cyclophilin family of proteins that bind cyclosporin A (CsA). We report that as in other cell types, CypB trafficked from the ER and was secreted by keratinocytes into the media in response to CsA. Concentrations as low as 1 p of CsA induced secretion of CypB. Using brefeldin A, we showed that CypB is secreted from keratinocytes via the constitutive secretory pathway. We defined that substitution of tryptophan residue 128 in the CsA-binding site of CypB with alanine resulted in dissociation of CypBW128A-green fluorescent protein (GFP) from the ER. Photobleaching studies revealed a significant reduction in the diffusible mobility of CypBW128A-GFP compared with CypBWT-GFP, consistent with redistribution of CypBW128A-GFP into secretory vesicles disconnected from the ER/Golgi network. Furthermore, CsA significantly decreased the mobility of CypBWT-GFP but not CypBW128A-GFP. These studies demonstrate that therapeutically relevant concentrations of CsA regulate secretion of CypB by keratinocytes, and that a key residue within the CsA-binding site of CypB controls retention of CypB within the ER and regulates entry into the secretory pathway. As keratinocytes express CypB receptors (CD147) and CypB exhibits chemotactic properties, these data have implications for the therapeutic effects of CsA in inflammatory skin disease. PMID:21270823

Apoptosis-linked Gene-2 (ALG-2)/Sec31 Interactions Regulate Endoplasmic Reticulum (ER)-to-Golgi Transport

PubMed Central

Helm, Jared R.; Bentley, Marvin; Thorsen, Kevin D.; Wang, Ting; Foltz, Lauren; Oorschot, Viola; Klumperman, Judith; Hay, Jesse C.

2014-01-01

Luminal calcium released from secretory organelles has been suggested to play a regulatory role in vesicle transport at several steps in the secretory pathway; however, its functional roles and effector pathways have not been elucidated. Here we demonstrate for the first time that specific luminal calcium depletion leads to a significant decrease in endoplasmic reticulum (ER)-to-Golgi transport rates in intact cells. Ultrastructural analysis revealed that luminal calcium depletion is accompanied by increased accumulation of intermediate compartment proteins in COPII buds and clusters of unfused COPII vesicles at ER exit sites. Furthermore, we present several lines of evidence suggesting that luminal calcium affected transport at least in part through calcium-dependent interactions between apoptosis-linked gene-2 (ALG-2) and the Sec31A proline-rich region: 1) targeted disruption of ALG-2/Sec31A interactions caused severe defects in ER-to-Golgi transport in intact cells; 2) effects of luminal calcium and ALG-2/Sec31A interactions on transport mutually required each other; and 3) Sec31A function in transport required luminal calcium. Morphological phenotypes of disrupted ALG-2/Sec31A interactions were characterized. We found that ALG-2/Sec31A interactions were not required for the localization of Sec31A to ER exit sites per se but appeared to acutely regulate the stability and trafficking of the cargo receptor p24 and the distribution of the vesicle tether protein p115. These results represent the first outline of a mechanism that connects luminal calcium to specific protein interactions regulating vesicle trafficking machinery. PMID:25006245

Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells.

PubMed

Sharan, Shruti; Nikhil, Kumar; Roy, Partha

2013-06-01

Endocrine disrupting chemicals are the natural/synthetic compounds which mimic or inhibit the actions of endogenous hormones. Organotin compounds, such as tributyltin (TBT) are typical environmental contaminants and suspected endocrine-disrupting chemical. The present study evaluates the estrogenic potential of this compound in vitro in ER (+) breast adenocarcinoma, MCF-7 cell line. Our data showed that tributyltin chloride (TBTCl) had agonistic activities for estrogen receptor-α (ER-α). Its estrogenic potential was checked using cell proliferation assay, aromatase assay, transactivation assay, and protein expression analysis. Low dose treatment of TBTCl had a proliferative effect on MCF-7 cells and resulted in up-regulation of aromatase enzyme activity and enhanced estradiol production in MCF-7 cells. Immunofluorescence staining showed translocation of ER-α from cytoplasm to nucleus and increased expression of ER-α, 3β-HSD and aromatase on treatment with increasing doses of TBTCl. Further, to decipher the probable signaling pathways involved in its action, the MCF-7 cells were transfected with different pathway dependent luciferase reporter plasmids (CRE, SRE, NF-κB and AP1). A significant increase in CRE and SRE and decrease in NF-κB regulated pathway were observed (p<0.05). Our results thus showed that the activation of SRE by TBTCl may be due to ligand dependent ER-α activation of the MAPK pathway and increased phosphorylation of ERK. In summary, the present data suggests that low dose of tributyltin genomically and non-genomically augmented estrogen dependent signaling by targeting various pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) interacts with estrogen receptor and predicted poor survival in breast cancer.

PubMed

Huang, Nai-Si; Chi, Ya-Yun; Xue, Jing-Yan; Liu, Meng-Ying; Huang, Sheng; Mo, Miao; Zhou, Shu-Ling; Wu, Jiong

2016-06-21

Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1), a lncRNA that was first recognized as a prognostic parameter for patient survival of stage I lung cancer, is up-regulated in multiple human malignancies, including breast cancer. However, the mechanism of its function remained elusive. In the current study, by examining MALAT1 expression on mRNA level, we demonstrated that compared with MCF10A, MALAT1 expression was up-regulated in the majority of breast cancer cell lines (9/12). In 26 pairs of estrogen receptor (ER)-positive breast cancer samples, MALAT1 expression was significantly up-regulated compared with adjacent normal tissues (P = 0.012). Furthermore, of 204 breast cancer patients, high MALAT1 expression was associated with positive ER (P = 0.023) and progesterone receptor (PR) (P = 0.024) status. Further analysis using TCGA database revealed that ER and its target genes PGR and CCND1, were overexpressed in MALAT1 altered group compared with unaltered group, both on the mRNA and protein level. Lastly, we verified MALAT1's prognostic value in breast cancer. At the cut-off value of 75%, MALAT1 was the only independent prognostic factor of recurrence-free survival (RFS) in ER-negative patients in a multivariate Cox regression model (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.02-7.83). MALAT1 overexpression was also associated with poor RFS in tamoxifen treated ER-positive breast cancer patients, which might serve as a potential biomarker to predict endocrine treatment sensitivity.

NELL2 function in the protection of cells against endoplasmic reticulum stress.

PubMed

Kim, Dong Yeol; Kim, Han Rae; Kim, Kwang Kon; Park, Jeong Woo; Lee, Byung Ju

2015-01-01

Continuous intra- and extracellular stresses induce disorder of Ca(2+) homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress-induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This anti-apoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti- and pro-apoptotic proteins and on the protection from ER stress-induced cell death.

Up-regulation of mRNA ventricular PRNP prion protein gene expression in air pollution highly exposed young urbanites: endoplasmic reticulum stress, glucose regulated protein 78, and nanosized particles.

PubMed

Villarreal-Calderon, Rodolfo; Franco-Lira, Maricela; González-Maciel, Angélica; Reynoso-Robles, Rafael; Harritt, Lou; Pérez-Guillé, Beatriz; Ferreira-Azevedo, Lara; Drecktrah, Dan; Zhu, Hongtu; Sun, Qiang; Torres-Jardón, Ricardo; Aragón-Flores, Mariana; Calderón-Garcidueñas, Ana; Diaz, Philippe; Calderón-Garcidueñas, Lilian

2013-11-28

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role.

Up-Regulation of mRNA Ventricular PRNP Prion Protein Gene Expression in Air Pollution Highly Exposed Young Urbanites: Endoplasmic Reticulum Stress, Glucose Regulated Protein 78, and Nanosized Particles

PubMed Central

Villarreal-Calderon, Rodolfo; Franco-Lira, Maricela; González-Maciel, Angélica; Reynoso-Robles, Rafael; Harritt, Lou; Pérez-Guillé, Beatriz; Ferreira-Azevedo, Lara; Drecktrah, Dan; Zhu, Hongtu; Sun, Qiang; Torres-Jardón, Ricardo; Aragón-Flores, Mariana; Calderón-Garcidueñas, Ana; Diaz, Philippe; Calderón-Garcidueñas, Lilian

2013-01-01

Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role. PMID:24287918

NFκB- and AP-1-mediated DNA looping regulates matrix metalloproteinase-9 transcription in TNF-α-treated human leukemia U937 cells.

PubMed

Chen, Ying-Jung; Chang, Long-Sen

2015-10-01

The aim of this study is to explore the spatial association of critical genomic elements in the effect of TNF-α on matrix metalloproteinase-9 (MMP-9) expression in human leukemia U937 cells. TNF-α up-regulated MMP-9 protein expression and mRNA level in U937 cells, and Akt-mediated-NFκB/p65 activation and JNK-mediated c-Jun activation were proven to be involved in TNF-α-induced MMP-9 up-regulation. Promoter luciferase activity assay revealed that NFκB (nt-600) and AP-1 (nt-79) binding sites were crucial for TNF-α-induced transcription of MMP-9 gene. The results of a chromatin immunoprecipitation assay indicated that TNF-α reduced histone deacetylase-1 (HDAC-1) recruitment but increased p300 (a histone acetyltransferase) recruitment to MMP-9 promoter regions surrounding NFκB and AP-1 binding sites. Consistently, TNF-α increased enrichment of the acetylated histone H3 mark on MMP-9 promoter regions. DNA affinity purification assay revealed that p300 and HDAC1 could bind oligonucleotides containing AP-1/c-Jun and NFκB/p65 binding sites. Chromosome conformation capture assay showed that TNF-α stimulated chromosomal loops in the MMP-9 promoter via NFκB/p65 and AP-1/c-Jun. The p300-associated acetyltransferase activity was crucial for p65/c-Jun-mediated DNA looping, and inhibition of HDAC activity increased the level of DNA looping. Reduction in the level of DNA looping eliminated all TNF-α-stimulated MMP-9 up-regulation. Taken together, our data suggest that p65/c-Jun-mediated DNA looping is involved in TNF-α-induced MMP-9 up-regulation and that the recruitment of p300 or HDAC1 to NFκB and AP-1 binding sites modifies the level of DNA looping. Copyright © 2015 Elsevier B.V. All rights reserved.

Emotion regulation choice in female patients with borderline personality disorder: Findings from self-reports and experimental measures.

PubMed

Sauer, Christina; Sheppes, Gal; Lackner, Helmut Karl; Arens, Elisabeth A; Tarrasch, Ricardo; Barnow, Sven

2016-08-30

Emotion dysregulation is a core feature of borderline personality disorder (BPD). So far, many studies have tested the consequences of the implementation of certain emotion regulation (ER) strategies, but there have been no investigations about ER choices in BPD. Thus, the aim of this study was to investigate habitual ER choices by self-report questionnaires and experimentally by testing the preference to select between distraction and reappraisal when facing different emotional intensities (high vs. low) and contents (borderline-specific vs. unspecific negative) in patients with BPD (n=24) compared with clinical controls (patients with major depression, n=19) and a healthy control group (n=32). Additionally, heart rate (HR) responses were continuously assessed. Main results revealed that both patient groups showed maladaptive self-reported ER choice profiles compared with HC. We found, however, no differences between the groups in the choice of distraction and reappraisal on the behavioral level and in HR responses. In BPD, within-group analyses revealed a positive correlation between symptom severity and the preference for distraction under high-intensity borderline-specific stimuli. Our findings provide preliminary evidence of ER choices in BPD and show the robustness of the choice effect in patients with affective disorders. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Wogonin prevents rat dorsal root ganglion neurons death via inhibiting tunicamycin-induced ER stress in vitro.

PubMed

Xu, Shujuan; Zhao, Xin; Zhao, Quanlai; Zheng, Quan; Fang, Zhen; Yang, Xiaoming; Wang, Hong; Liu, Ping; Xu, Hongguang

2015-04-01

Wogonin is a natural flavonoid isolated from the root of Scutellaria baicalensis Georgi, which has been widely used in various research areas for its anti-oxidant, anti-inflammatory, and anti-cancer activities. It also presents a neuroprotective effect in the brain while encounters stress conditions, but the mechanisms controlling the neuroprotective effect of wogonin are not clear. In this study, we investigated the biomechanism underlying the neuroprotective effect of wogonin on rat dorsal root ganglion (DRG) neurons. Wogonin pre-treatment at 75 μM significantly increased the cell viability of DRG neurons and decreased the number of the propidium iodide-positive DRG neurons before the endoplasmic reticulum (ER) stress is being induced by tunicamycin (TUN) (0.75 μg/mL). In addition, Wogonin also inhibited the release of LDH and up-regulated the level of GSH. Furthermore, wogonin decreased the activation of ER stress-related molecules, including glucose-regulated protein 78 (GRP78), GRP94, C/EBP-homologous protein, active caspase12 and active caspase3, phosphorylation of pancreatic ER stress kinase, and eukaryotic initiation factor 2 alpha (eIF2α). In summary, our results indicated that wogonin could protect DRG neurons against TUN-induced ER stress.

Selective export of autotaxin from the endoplasmic reticulum.

PubMed

Lyu, Lin; Wang, Baolu; Xiong, Chaoyang; Zhang, Xiaotian; Zhang, Xiaoyan; Zhang, Junjie

2017-04-28

Autotaxin (ATX) or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid generation. The mechanism of ATX protein trafficking is largely unknown. Here, we demonstrated that p23, a member of the p24 protein family, was the protein-sorting receptor required for endoplasmic reticulum (ER) export of ATX. A di-phenylalanine (Phe-838/Phe-839) motif in the human ATX C-terminal region was identified as a transport signal essential for the ATX-p23 interaction. Knockdown of individual Sec24 isoforms by siRNA revealed that ER export of ATX was impaired only if Sec24C was down-regulated. These results suggest that ATX is selectively exported from the ER through a p23, Sec24C-dependent pathway. In addition, it was found that AKT signaling played a role in ATX secretion regulation to facilitate ATX ER export by enhancing the nuclear factor of activated T cell-mediated p23 expression. Furthermore, the di-hydrophobic amino acid motifs (FY) also existed in the C-terminal regions of human ENPP1 and ENPP3. Such a p23, Sec24C-dependent selective ER export mechanism is conserved among these ENPP family members. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Input filter compensation for switching regulators

NASA Technical Reports Server (NTRS)

Kelkar, S. S.; Lee, F. C.

1983-01-01

A novel input filter compensation scheme for a buck regulator that eliminates the interaction between the input filter output impedance and the regulator control loop is presented. The scheme is implemented using a feedforward loop that senses the input filter state variables and uses this information to modulate the duty cycle signal. The feedforward design process presented is seen to be straightforward and the feedforward easy to implement. Extensive experimental data supported by analytical results show that significant performance improvement is achieved with the use of feedforward in the following performance categories: loop stability, audiosusceptibility, output impedance and transient response. The use of feedforward results in isolating the switching regulator from its power source thus eliminating all interaction between the regulator and equipment upstream. In addition the use of feedforward removes some of the input filter design constraints and makes the input filter design process simpler thus making it possible to optimize the input filter. The concept of feedforward compensation can also be extended to other types of switching regulators.

A close connection between the PERK and IRE arms of the UPR and the transcriptional regulation of autophagy.

PubMed

Deegan, Shane; Koryga, Izabela; Glynn, Sharon A; Gupta, Sanjeev; Gorman, Adrienne M; Samali, Afshin

2015-01-02

Endoplasmic reticulum (ER) stress is known to lead to activation of both the unfolded protein response (UPR) and autophagy. Although regulatory connections have been identified between the UPR and autophagy, it is still unclear to what extent the UPR regulates the genes involved at the different stages of the autophagy pathway. Here, we carried out a microarray analysis of HCT116 cells subjected to ER stress and observed the transcriptional upregulation of a large cohort of autophagy-related genes. Of particular interest, we identified the transcriptional upregulation of the autophagy receptor genes SQSTM1/p62, NBR1 and BNIP3L/NIX in response to ER stress and show that the inhibition of the UPR transmembrane receptors, PERK and IRE1, abrogates this upregulation. Copyright © 2014 Elsevier Inc. All rights reserved.

Why might poor sleep quality lead to depression? A role for emotion regulation.

PubMed

O'Leary, Kimberly; Bylsma, Lauren M; Rottenberg, Jonathan

2017-12-01

Disordered sleep is strongly linked to future depression, but the reasons for this link are not well understood. This study tested one possibility - that poorer sleep impairs emotion regulation (ER), which over time leads to increased depressive symptoms. Our sample contained individuals with a wide range of depression symptoms (current depression, N = 54, remitted depression, N = 36, and healthy control, N = 53), who were followed clinically over six months and reassessed for changes in depressive symptom levels. As predicted, maladaptive ER mediated both cross-sectional and prospective relationships between poor sleep quality and depression symptoms. In contrast, an alternative mediator, physical activity levels, did not mediate the link between sleep quality and depression symptoms. Maladaptive ER may help explain why sleep difficulties contribute to depression symptoms; implications for interventions are discussed.

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.

PubMed

Ribas, Ricardo; Pancholi, Sunil; Rani, Aradhana; Schuster, Eugene; Guest, Stephanie K; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Thornhill, Allan; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

2018-06-08

Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER.

Closed-Loop Control Better than Open-Loop Control of Profofol TCI Guided by BIS: A Randomized, Controlled, Multicenter Clinical Trial to Evaluate the CONCERT-CL Closed-Loop System

PubMed Central

Zhang, Xuena; Wu, Anshi; Yao, Shanglong; Xue, Zhanggang; Yue, Yun

2015-01-01

Background The CONCERT-CL closed-loop infusion system designed by VERYARK Technology Co., Ltd. (Guangxi, China) is an innovation using TCI combined with closed-loop controlled intravenous anesthesia under the guide of BIS. In this study we performed a randomized, controlled, multicenter study to compare closed-loop control and open-loop control of propofol by using the CONCERT-CL closed-loop infusion system. Methods 180 surgical patients from three medical centers undergone TCI intravenous anesthesia with propofol and remifentanil were randomly assigned to propofol closed-loop group and propofol opened-loop groups. Primary outcome was global score (GS, GS = (MDAPE+Wobble)/% of time of bispectral index (BIS) 40-60). Secondary outcomes were doses of the anesthetics and emergence time from anesthesia, such as, time to tracheal extubation. Results There were 89 and 86 patients in the closed-loop and opened-loop groups, respectively. GS in the closed-loop groups (22.21±8.50) were lower than that in the opened-loop group (27.19±15.26) (p=0.009). The higher proportion of time of BIS between 40 and 60 was also observed in the closed-loop group (84.11±9.50%), while that was 79.92±13.17% in the opened-loop group, (p=0.016). No significant differences in propofol dose and time of tracheal extubation were observed. The frequency of propofol regulation in the closed-loop group (31.55±9.46 times/hr) was obverse higher than that in the opened-loop group (6.84±6.21 times/hr) (p=0.000). Conclusion The CONCERT-CL closed-loop infusion system can automatically regulate the TCI of propofol, maintain the BIS value in an adequate range and reduce the workload of anesthesiologists better than open-loop system. Trial Registration ChiCTR ChiCTR-OOR-14005551 PMID:25886041

Measurement techniques for the characterization in the frequency domain of regulated energy-storage DC-to-DC converters. M.S. Thesis

NASA Technical Reports Server (NTRS)

Bahler, D. D.

1978-01-01

Procedures are presented for obtaining valid frequency-domain transfer functions of regulated reactor energy-storage dc-to-dc converters. These procedures are for measuring loop gain, closed loop gain, output impedance, and audio susceptibility. The applications of these measurements are discussed.

Regulation of SOBIR1 accumulation and activation of defense responses in bir1-1 by specific components of ER quality control.

PubMed

Sun, Tongjun; Zhang, Qian; Gao, Minghui; Zhang, Yuelin

2014-03-01

Receptor-like kinases play diverse roles in plant biology. Arabidopsis BAK1-INTERACTING RECEPTOR-LIKE KINASE 1 (BIR1) functions as a negative regulator of plant immunity. bir1-1 mutant plants display spontaneous cell death and constitutive defense responses that are dependent on SUPPRESSOR OF BIR1,1 (SOBIR1) and PHYTOALEXIN DEFICIENT4 (PAD4). Here we report that mutations in three components of ER quality control, CALRETICULIN3 (CRT3), ER-LOCALIZED DnaJ-LIKE PROTEIN 3b (ERdj3b) and STROMAL-DERIVED FACTOR-2 (SDF2), also suppress the spontaneous cell death and constitutive defense responses in bir1-1. Further analysis revealed that accumulation of the SOBIR1 protein is reduced in crt3-1 and erdj3b-1 mutant plants. These data suggest that ER quality control plays important roles in the biogenesis of SOBIR1, and is required for cell death and defense responses in bir1-1. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Diet-induced obesity induces endoplasmic reticulum stress and insulin resistance in the amygdala of rats☆

PubMed Central

Castro, Gisele; C. Areias, Maria Fernanda; Weissmann, Lais; Quaresma, Paula G.F.; Katashima, Carlos K.; Saad, Mario J.A.; Prada, Patricia O.

2013-01-01

Insulin acts in the hypothalamus, decreasing food intake (FI) by the IR/PI3K/Akt pathway. This pathway is impaired in obese animals and endoplasmic reticulum (ER) stress and low-grade inflammation are possible mechanisms involved in this impairment. Here, we highlighted the amygdala as an important brain region for FI regulation in response to insulin. This regulation was dependent on PI3K/AKT pathway similar to the hypothalamus. Insulin was able to decrease neuropeptide Y (NPY) and increase oxytocin mRNA levels in the amygdala via PI3K, which may contribute to hypophagia. Additionally, obese rats did not reduce FI in response to insulin and AKT phosphorylation was decreased in the amygdala, suggesting insulin resistance. Insulin resistance was associated with ER stress and low-grade inflammation in this brain region. The inhibition of ER stress with PBA reverses insulin action/signaling, decreases NPY and increases oxytocin mRNA levels in the amygdala from obese rats, suggesting that ER stress is probably one of the mechanisms that induce insulin resistance in the amygdala. PMID:24251109

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

PubMed Central

Fessart, Delphine; Domblides, Charlotte; Avril, Tony; Eriksson, Leif A; Begueret, Hugues; Pineau, Raphael; Malrieux, Camille; Dugot-Senant, Nathalie; Lucchesi, Carlo; Chevet, Eric; Delom, Frederic

2016-01-01

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. DOI: http://dx.doi.org/10.7554/eLife.13887.001 PMID:27240165

G Protein-Coupled Estrogen Receptor in Energy Homeostasis and Obesity Pathogenesis

PubMed Central

Shi, Haifei; Dharshan Senthil Kumar, Shiva Priya; Liu, Xian

2013-01-01

Obesity and its related metabolic diseases have reached a pandemic level worldwide. There are sex differences in the prevalence of obesity and its related metabolic diseases, with men being more vulnerable than women; however, the prevalence of these disorders increases dramatically in women after menopause, suggesting that sex steroid hormone estrogens play key protective roles against development of obesity and metabolic diseases. Estrogens are important regulators of several aspects of metabolism, including body weight and body fat, caloric intake and energy expenditure, and glucose and lipid metabolism in both males and females. Estrogens act in complex ways on their nuclear estrogen receptors (ERs) ERα and ERβ and transmembrane ERs such as G protein-coupled estrogen receptor. Genetic tools, such as different lines of knockout mouse models, and pharmacological agents, such as selective agonists and antagonists, are available to study function and signaling mechanisms of ERs. We provide an overview of the evidence for the physiological and cellular actions of ERs in estrogen-dependent processes in the context of energy homeostasis and body fat regulation and discuss its pathology that leads to obesity and related metabolic states. PMID:23317786

GABAB receptor cell surface export is controlled by an endoplasmic reticulum gatekeeper

PubMed Central

Doly, Stéphane; Shirvani, Hamasseh; Gäta, Gabriel; Meye, Frank; Emerit, Michel-Boris; Enslen, Hervé; Achour, Lamia; Pardo-Lopez, Liliana; Kwon, Yang Seung; Armand, Vincent; Gardette, Robert; Giros, Bruno; Gassmann, Martin; Bettler, Bernhard; Mameli, Manuel; Darmon, Michèle; Marullo, Stefano

2016-01-01

Summary Endoplasmic reticulum (ER) release and cell surface export of many G protein-coupled receptors (GPCRs), are tightly regulated. For GABAB receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gate-keepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function. PMID:26033241

Binding to membrane proteins within the endoplasmic reticulum cannot explain the retention of the glucose-regulated protein GRP78 in Xenopus oocytes.

PubMed

Ceriotti, A; Colman, A

1988-03-01

We have studied the compartmentation and movement of the rat 78-kd glucose-regulated protein (GRP78) and other secretory and membrane proteins in Xenopus oocytes. Full length GRP78, normally found in the lumen of rat endoplasmic reticulum (ER), is localized to a membraneous compartment in oocytes and is not secreted. A truncated GRP78 lacking the C-terminal (KDEL) ER retention signal is secreted, although at a slow rate. When the synthesis of radioactive GRP78 is confined to a polar (animal or vegetal) region of the oocyte and the subsequent movement across the oocyte monitored, we find that both full-length and truncated GRP78 move at similar rates and only slightly slower than a secretory protein, chick ovalbumin. In contrast, a plasma membrane protein (influenza haemagglutinin) and two ER membrane proteins (rotavirus VP10 and a mutant haemagglutinin) remained confined to their site of synthesis. We conclude that the retention of GRP78 in the ER is not due to its tight binding to a membrane-bound receptor.

Proteomic Analysis of Calcium Effects on Soybean Root Tip under Flooding and Drought Stresses.

PubMed

Wang, Xin; Komatsu, Setsuko

2017-08-01

Flooding and drought are disadvantageous environmental conditions that induce cytosolic calcium in soybean. To explore the effects of flooding- and drought-induced increases in calcium, a gel-free/label-free proteomic analysis was performed. Cytosolic calcium was decreased by blocking calcium channels in the endoplasmic reticulum (ER) and plasma membrane under both stresses. Calnexin, protein disulfide isomerase, heat shock proteins and thioredoxin were predominantly affected as the ER proteins in response to calcium, and ER-associated degradation-related proteins of HCP-like superfamily protein were up-regulated under stress exposure and then down-regulated. Glycolysis, fermentation, the tricarboxylic acid cycle and amino acid metabolism were mainly induced as the types of cellular metabolism in response to calcium under both stresses. Pyruvate decarboxylase was increased and decreased under flooding and drought, respectively, and was further decreased by the reduction of cytosolic calcium; however, it was recovered by exogenous calcium under both stresses. Furthermore, pyruvate decarboxylase activity was increased under flooding, but decreased under drought. These results suggest that calcium is involved in protein folding in the ER, and ER-associated degradation might alleviate ER stress during the early stage of both stresses. Furthermore, calcium appears to modify energy metabolism, and pyruvate decarboxylase may be a key enzyme in this process under flooding and drought. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B.

PubMed

Lennemann, Nicholas J; Coyne, Carolyn B

2017-02-01

The endoplasmic reticulum (ER) is exploited by several diverse viruses during their infectious life cycles. Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), utilize the ER as a source of membranes to establish their replication organelles and to facilitate their assembly and eventual maturation along the secretory pathway. To maintain normal homeostasis, host cells have evolved highly efficient processes to dynamically regulate the ER, such as through reticulophagy, a selective form of autophagy that leads to ER degradation. Here, we identify the ER-localized reticulophagy receptor FAM134B as a host cell restriction factor for both DENV and ZIKV. We show that RNAi-mediated depletion of FAM134B significantly enhances both DENV and ZIKV replication at an early stage of the viral life cycle. Consistent with its role as an antiviral host factor, we found that several flaviviruses including DENV, ZIKV, and West Nile virus (WNV), utilize their NS3 virally-encoded proteases to directly cleave FAM134B at a single site within its reticulon homology domain (RHD). Mechanistically, we show that NS3-mediated cleavage of FAM134B blocks the formation of ER and viral protein-enriched autophagosomes, suggesting that the cleavage of FAM134B serves to specifically suppress the reticulophagy pathway. These findings thus point to an important role for FAM134B and reticulophagy in the regulation of flavivirus infection and suggest that these viruses specifically target these pathways to promote viral replication.

Endoplasmic Reticulum Stress and Nox-Mediated Reactive Oxygen Species Signaling in the Peripheral Vasculature: Potential Role in Hypertension

PubMed Central

Nabeebaccus, Adam A.; Shah, Ajay M.; Camargo, Livia L.; Filho, Sidney V.; Lopes, Lucia R.

2014-01-01

Abstract Significance: Reactive oxygen species (ROS) are produced during normal endoplasmic reticulum (ER) metabolism. There is accumulating evidence showing that under stress conditions such as ER stress, ROS production is increased via enzymes of the NADPH oxidase (Nox) family, especially via the Nox2 and Nox4 isoforms, which are involved in the regulation of blood pressure. Hypertension is a major contributor to cardiovascular and renal disease, and it has a complex pathophysiology involving the heart, kidney, brain, vessels, and immune system. ER stress activates the unfolded protein response (UPR) signaling pathway that has prosurvival and proapoptotic components. Recent Advances: Here, we summarize the evidence regarding the association of Nox enzymes and ER stress, and its potential contribution in the setting of hypertension, including the role of other conditions that can lead to hypertension (e.g., insulin resistance and diabetes). Critical Issues: A better understanding of this association is currently of great interest, as it will provide further insights into the cellular mechanisms that can drive the ER stress-induced adaptive versus maladaptive pathways linked to hypertension and other cardiovascular conditions. More needs to be learnt about the precise signaling regulation of Nox(es) and ER stress in the cardiovascular system. Future Directions: The development of specific approaches that target individual Nox isoforms and the UPR signaling pathway may be important for the achievement of therapeutic efficacy in hypertension. Antioxid. Redox Signal. 20, 121–134. PMID:23472786

cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice*

PubMed Central

Ma, Hongwei; Butler, Michael R.; Thapa, Arjun; Belcher, Josh; Yang, Fan; Baehr, Wolfgang; Biel, Martin; Michalakis, Stylianos; Ding, Xi-Qin

2015-01-01

Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca2+ channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3−/−/Nrl−/− mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Müller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca2+ channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency. PMID:26124274

Compact all-fiber figure-9 dissipative soliton resonance mode-locked double-clad Er:Yb laser.

PubMed

Krzempek, Karol; Sotor, Jaroslaw; Abramski, Krzysztof

2016-11-01

The first demonstration of a compact all-fiber figure-9 double-clad erbium-ytterbium laser working in the dissipative soliton resonance (DSR) regime is presented. Mode-locking was achieved using a nonlinear amplifying loop (NALM) resonator configuration. The laser was assembled with an additional 475 m long spool of SMF28 fiber in the NALM loop in order to obtain large net-anomalous cavity dispersion (-10.4  ps²), and therefore ensure that DSR would be the dominant mode-locking mechanism. At maximum pump power (4.78 W) the laser generated rectangular-shaped pulses with 455 ns duration and an average power of 950 mW, which at a repetition frequency of 412 kHz corresponds to a record energy of 2.3 μJ per pulse.

Interactions of endoplasmic reticulum and mitochondria Ca2+ stores with capacitative calcium entry

PubMed Central

Huang, Hsueh-Meei; Chen, Huan-Lian; Gibson, Gary E.

2014-01-01

Thiamine dependent enzymes are diminished in Alzheimer’s disease (AD). Thiamine deficiency in vitro and in rodents is a useful model of this reduction. Thiamine interacts with cellular calcium stores. To directly test the relevance of the thiamine dependent changes to dynamic processes in AD, the interactions must be studied in cells from patients with AD. These studies employed fibroblasts. Mitochondrial dysfunction including reductions in thiamine dependent enzymes and abnormalities in calcium homeostasis and oxidative processes occur in fibroblasts from Alzheimer’s Disease (AD) patients. Bombesin-releasable calcium stores (BRCS) from the endoplasmic reticulum (ER) are exaggerated in fibroblasts from patients with AD bearing a presenilin-1 (PS-1) mutation and in control fibroblasts treated with oxidants. ER calcium regulates calcium entry into the cell through capacitative calcium entry (CCE), which is reduced in fibroblasts and neurons from mice bearing PS-1 mutations. Under physiological conditions, mitochondria and ER play important and interactive roles in the regulation of Ca2+ homeostasis. Thus, the interactions of mitochondria and oxidants with CCE were tested. Inhibition of ER Ca2+-ATPase by cyclopiazonic acid (CPA) stimulates CCE. CPA-induced CCE was diminished by inhibition of mitochondrial Ca2+ export (−60%) or import (−40%). Different aspects of mitochondrial Ca2+ coupled to CPA-induced-CCE were sensitive to select oxidants. The effects were very different when CCE was examined in the presence of InsP3, a physiological regulator of ER calcium release, and subsequent CCE. CCE under these conditions was only mildly reduced (20–25%) by inhibition of mitochondrial Ca2+ export, and inhibition of mitochondrial Ca2+ uptake exaggerated CCE (+53%). However, t-BHP reversed both abnormalities. The results suggest that in the presence of InsP3, mitochondria buffer the local Ca2+ released from ER following rapid activation of InsP3R and serve as a negative feedback to the CCE. The results suggest that mitochondrial Ca2+ modifies the depletion and refilling mechanism of ER Ca2+ stores. PMID:24748364

Role of silent information regulator 1 in the protective effect of hydrogen sulfide on homocysteine-induced cognitive dysfunction: Involving reduction of hippocampal ER stress.

PubMed

Tang, Yi-Yun; Wang, Ai-Ping; Wei, Hai-Jun; Li, Man-Hong; Zou, Wei; Li, Xiang; Wang, Chun-Yan; Zhang, Ping; Tang, Xiao-Qing

2018-04-16

Homocysteine (Hcy) causes cognitive deficits and hippocampal endoplasmic reticulum (ER) stress. Our previous study has confirmed that Hydrogen sulfide (H 2 S) attenuates Hcy-induced cognitive dysfunction and hippocampal ER stress. Silent information regulator 1 (Sirt-1) is indispensable in the formation of learning and memory. Therefore, the aim of this study was to explore the role of Sirt-1 in the protective effect of H 2 S against Hcy-induced cognitive dysfunction. We found that NaHS (a donor of H 2 S) markedly up-regulated the expression of Sirt-1 in the hippocampus of Hcy-exposed rats. Sirtinol, a specific inhibitor of Sirt-1, reversed the improving role of NaHS in the cognitive function of Hcy-exposed rats, as evidenced by that sirtinol increased the escape latency and the swim distance in the acquisition trial of morris water maze (MWM) test, decreased the times crossed through and the time spent in the target quadrant in the probe trail of MWM test, and reduced the discrimination index in the novel object recognition test (NORT) in the rats cotreated with NaHS and Hcy. We also found that sirtinol reversed the protection of NaHS against Hcy-induced hippocampal ER-stress, as evidenced by up-regulating the expressions of GRP78, CHOP, and cleaved caspase-12 in the hippocampus of rats cotreated with NaHS and Hcy. These results suggested the contribution of upregulation of hippocampal Sirt-1 to the improving role of H 2 S in the cognitive function of Hcy-exposed rats, which involves suppression of hippocampal ER stress. Our finding provides a new insight into the mechanism underlying the inhibitory role of H 2 S in Hcy-induced cognitive dysfunction. Copyright © 2018 Elsevier B.V. All rights reserved.

Endoplasmic Reticulum Stress in Mice Increases Hepatic Expression of Genes Carrying a Premature Termination Codon via a Nutritional Status-Independent GRP78-Dependent Mechanism.

PubMed

Harada, Nagakatsu; Okuyama, Maiko; Yoshikatsu, Aya; Yamamoto, Hironori; Ishiwata, Saori; Hamada, Chikako; Hirose, Tomoyo; Shono, Masayuki; Kuroda, Masashi; Tsutsumi, Rie; Takeo, Jiro; Taketani, Yutaka; Nakaya, Yutaka; Sakaue, Hiroshi

2017-11-01

Nonsense-mediated mRNA decay (NMD) degrades mRNAs carrying a premature termination codon (PTC) in eukaryotes. Cellular stresses, including endoplasmic reticulum (ER) stress, inhibit NMD, and up-regulate PTC-containing mRNA (PTC-mRNA) levels in several cell lines. However, whether similar effects exist under in vivo conditions that involve systemic nutritional status is unclear. Here, we compared the effects of pharmacological induction of ER stress with those of nutritional interventions on hepatic PTC-mRNA levels in mice. In mouse livers, the ER stress inducer tunicamycin increased PTC-mRNA levels of endogenous marker genes. Tunicamycin decreased body weight and perturbed nutrient metabolism in mice. Food restriction or deprivation mimicked the effect of tunicamycin on weight loss and metabolism, but did not increase PTC-mRNA levels. Hyperphagia-induced obesity also had little effect on hepatic PTC-mRNA levels. Meanwhile, in mouse liver phosphorylation of eIF2α, a factor that regulates NMD, was increased by both tunicamycin and nutritional interventions. Hepatic expression of GRP78, a central chaperone in ER stress responses, was increased by tunicamycin but not by the nutritional interventions. In cultured liver cells (Hepa), exogenous overexpression of a phosphomimetic eIF2α failed to increase PTC-mRNA levels. However, GRP78 overexpression in Hepa cells increased PTC-mRNA and PTC-mRNA-derived protein levels. ER stress promoted localization of GRP78 to mitochondria, and exogenous expression of a GRP78 fusion protein targeted to mitochondria mimicked the effect of wild type GRP78. These results indicate that GRP78, but not nutritional status, is a potent up-regulator of hepatic PTC-mRNA levels during induction of ER stress in vivo. J. Cell. Biochem. 118: 3810-3824, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Interpersonal emotion regulation in Asperger's syndrome and borderline personality disorder.

PubMed

López-Pérez, Belén; Ambrona, Tamara; Gummerum, Michaela

2017-03-01

Interpersonal emotion regulation (ER) plays a significant role in how individuals meet others' emotional needs and shape social interactions, as it is key to initiating and maintaining high-quality social relationships. Given that individuals with borderline personality disorder (BPD) or Asperger's syndrome (AS) exhibit problems in social interactions, the aim of this study was to examine their use of different interpersonal ER strategies compared to normative control participants. Thirty individuals with AS, 30 with BPD, and 60 age-, gender-, and education-matched control participants completed a battery of measures to assess interpersonal ER, which assessed to what extent participants tended to engage in interpersonal affect improvement and worsening and to what extent they used different strategies. Before completing those measures, all groups were screened for disorders of Axis I and Axis II with the Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders. Compared to controls, individuals with AS and with BPD engaged less in affect improvement. No differences were found for affect worsening. Individuals with AS reported to use less adaptive (attention deployment, cognitive change) and more maladaptive (expressive suppression) interpersonal ER strategies, compared to individuals with BPD and control participants who did not differ from each other. The obtained results suggest the need to develop tailored ER interventions for each of the clinical groups studied. Furthermore, they highlight the need to study further potential differences in intrapersonal and interpersonal ER in clinical populations. Individuals with Asperger's syndrome (AS) and borderline personality disorder (BPD) engaged significantly less than healthy controls in interpersonal affect improvement. Individuals with BPD did not differ from healthy controls in the use of interpersonal strategies. Individuals with AS reported to use more maladaptive and less adaptive strategies than BPD individuals and healthy controls. Understanding differences in interpersonal emotion regulation in individuals with AS and with BPD and normative controls might help practitioners develop better interventions. © 2016 The British Psychological Society.

Regulation of AKT Phosphorylation at Ser473 and Thr308 by Endoplasmic Reticulum Stress Modulates Substrate Specificity in a Severity Dependent Manner

PubMed Central

Yung, Hong Wa

2011-01-01

Endoplasmic reticulum (ER) stress is a common factor in the pathophysiology of diverse human diseases that are characterised by contrasting cellular behaviours, from proliferation in cancer to apoptosis in neurodegenerative disorders. Coincidently, dysregulation of AKT/PKB activity, which is the central regulator of cell growth, proliferation and survival, is often associated with the same diseases. Here, we demonstrate that ER stress modulates AKT substrate specificity in a severity-dependent manner, as shown by phospho-specific antibodies against known AKT targets. ER stress also reduces both total and phosphorylated AKT in a severity-dependent manner, without affecting activity of the upstream kinase PDK1. Normalisation to total AKT revealed that under ER stress phosphorylation of Thr308 is suppressed while that of Ser473 is increased. ER stress induces GRP78, and siRNA-mediated knock-down of GRP78 enhances phosphorylation at Ser473 by 3.6 fold, but not at Thr308. Substrate specificity is again altered. An in-situ proximity ligation assay revealed a physical interaction between GRP78 and AKT at the plasma membrane of cells following induction of ER stress. Staining was weak in cells with normal nuclear morphology but stronger in those displaying rounded, condensed nuclei. Co-immunoprecipitation of GRP78 and P-AKT(Ser473) confirmed the immuno-complex consists of non-phosphorylated AKT (Ser473 and Thr308). The interaction is likely specific as AKT did not bind to all molecular chaperones, and GRP78 did not bind to p70 S6 kinase. These findings provide one mechanistic explanation for how ER stress contributes to human pathologies demonstrating contrasting cell fates via modulation of AKT signalling. PMID:21445305

Autophagy pathways activated in response to PDT contribute to cell resistance against ROS damage

PubMed Central

Dewaele, Michael; Martinet, Wim; Rubio, Noemí; Verfaillie, Tom; de Witte, Peter A; Piette, Jacques; Agostinis, Patrizia

2011-01-01

Abstract Reactive oxygen species (ROS) concurrently instigate apoptosis and autophagy pathways, but the link between these processes remains unclear. Because cytotoxic ROS formation is exploited in anticancer therapy, such as in photodynamic therapy (PDT), a better understanding of the complex interplay between autophagy and apoptosis is urgently required. Previously, we reported that ROS generated by PDT with an endoplasmic reticulum (ER)-associated sensitizer leads to loss of ER-Ca2+ homeostasis, ER stress and apoptosis. Here we show that PDT prompted Akt-mTOR (mammalian target of rapamycin) pathway down-regulation and stimulated macroautophagy (MA) in cancer and normal cells. Overexpression of the antioxidant enzyme glutathione peroxidase-4 reversed mTOR down-regulation and blocked MA progression and apoptosis. Attenuating MA using Atg5 knockdown or 3-methyladenine, reduced clearance of oxidatively damaged proteins and increased apoptosis, thus revealing a cytoprotective role of MA in PDT. Paradoxically, genetic loss of MA improved clearance of oxidized proteins and reduced photokilling. We found that up-regulation of chaperone-mediated autophagy (CMA) in unstressed Atg5−/− cells compensated for MA loss and increased cellular resistance to PDT. CMA-deficient cells were significantly sensitized to photokilling but were protected against the ER stressor thapsigargin. These results disclose a stress-specific recruitment of autophagy pathways with cytoprotective function and unravel CMA as the dominant defence mechanism against PDT. PMID:20626525

Participation of Water in the Binding of Estrogen Receptor with Estrogen Responsive Element in vitro.

PubMed

Zhu, Guo-Zhang; Tang, Guo-Qing; Ruan, Kang-Cheng; Gong, Yue-Ting; Zhang, Yong-Lian

1998-01-01

Many reports have showed that bound water was involved in the interaction between/among the macromolecules. However, it has not been reported whether bound water is also involved in the binding of trans-factors and cis-elements in the regulation of the eukaryotic gene trans-cription or not. Preliminary studies have been made on the effect of bound water on the binding of estrogen receptor with estrogen responsive element in vitro. In the gel retardation assay using the cytosol extract of rat uterus as the supplier of estrogen receptor and 32 bp oligonucleotide containing a concensus vitellogenin A(2) ERE as the probe, various cosolvents, such as glycerol, sucrose, N-dimethylformamide and dimethylsulfoxide, were added respectively to the reaction mixture in varying concentrations to regulate the osmotic pressure. The results indicated that the binding of ER-ERE was enhanced with the increase in the final concentration of these individual cosolvents. On the other hand, when the reaction was carried out under an increasing hydrostatic pressure, the ER-ERE binding was decreased sharply. After decompression the binding of ER-ERE was gradually restored to the normal level with the lapse of time. These results suggested that bound water was directly involved in the binding of ER-ERE and may play an important role in the regulation of the eukaryotic gene transcription.

Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum.

PubMed

Verchot, Jeanmarie

2016-11-19

The endoplasmic reticulum (ER) is central to plant virus replication, translation, maturation, and egress. Ubiquitin modification of ER associated cellular and viral proteins, alongside the actions of the 26S proteasome, are vital for the regulation of infection. Viruses can arrogate ER associated ubiquitination as well as cytosolic ubiquitin ligases with the purpose of directing the ubiquitin proteasome system (UPS) to new targets. Such targets include necessary modification of viral proteins which may stabilize certain complexes, or modification of Argonaute to suppress gene silencing. The UPS machinery also contributes to the regulation of effector triggered immunity pattern recognition receptor immunity. Combining the results of unrelated studies, many positive strand RNA plant viruses appear to interact with cytosolic Ub-ligases to provide novel avenues for controlling the deleterious consequences of disease. Viral interactions with the UPS serve to regulate virus infection in a manner that promotes replication and movement, but also modulates the levels of RNA accumulation to ensure successful biotrophic interactions. In other instances, the UPS plays a central role in cellular immunity. These opposing roles are made evident by contrasting studies where knockout mutations in the UPS can either hamper viruses or lead to more aggressive diseases. Understanding how viruses manipulate ER associated post-translational machineries to better manage virus-host interactions will provide new targets for crop improvement.

Hope, emotion regulation, and psychosocial well-being in patients newly diagnosed with cancer.

PubMed

Peh, Chao Xu; Kua, Ee Heok; Mahendran, Rathi

2016-05-01

Patients newly diagnosed with cancer are often confronted with feelings of uncertainty and life threat. A significant proportion may report impairments in psychosocial well-being. Previous studies examining protective psychological factors such as hope and emotion regulation (ER) have yet to investigate these processes concurrently within a common self-regulation framework and/or focus on newly diagnosed patients. The present study aimed to examine how hope and ER may relate to psychosocial outcomes of patients newly diagnosed with cancer. The present study used a cross-sectional design with self-report questionnaires. Participants were newly diagnosed patients (N = 101) recruited from three cancer therapy clinics in a hospital. Patients completed measures of hope, ER (cognitive reappraisal and expressive suppression), and psychosocial well-being (life satisfaction and negative affectivity). Findings showed that (1) hope and reappraisal, but not suppression, were associated with well-being and (2) the interaction between hope and reappraisal was associated with well-being; reappraisal was not associated with well-being in high hope patients, while high reappraisal was associated with better well-being in low hope patients. Individual differences in hope and reappraisal appeared to be associated with psychosocial outcomes in newly diagnosed cancer patients. Hopeful thinking appeared to benefit patients' psychosocial well-being. In addition, an interaction effect between hope and reappraisal suggested that reappraisal as an ER strategy may be particularly adaptive for patients with low hope.

Time course of emotion-related responding during distraction and reappraisal.

PubMed

Schönfelder, Sandra; Kanske, Philipp; Heissler, Janine; Wessa, Michèle

2014-09-01

Theoretical accounts of emotion regulation (ER) discriminate various cognitive strategies to voluntarily modify emotional states. Amongst these, attentional deployment (i.e. distraction) and cognitive change (i.e. reappraisal), have been shown to successfully down-regulate emotions. Neuroimaging studies found that both strategies differentially engage neural structures associated with selective attention, working memory and cognitive control. The aim of this study was to further delineate similarities and differences between the ER strategies reappraisal and distraction by investigating their temporal brain dynamics using event-related potentials (ERPs) and their patterns of facial expressive behavior. Twenty-one participants completed an ER experiment in which they had to either passively view positive, neutral and negative pictures, reinterpret them to down-regulate affective responses (reappraisal), or solve a concurrently presented mathematical equation (distraction). Results demonstrate the efficacy of both strategies in the subjective control of emotion, accompanied by reductions of facial expressive activity (Corrugator supercilii and Zygomaticus major). ERP results indicated that distraction, compared with reappraisal, yielded a stronger and earlier attenuation of the late positive potential (LPP) magnitude for negative pictures. For positive pictures, only distraction but not reappraisal had significant effect on LPP attenuation. The results support the process model of ER, separating subtypes of cognitive strategies based on their specific time course. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

PubMed

Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

2017-05-02

Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

Phosphorylation of ETS Transcription Factor ER81 in a Complex with Its Coactivators CREB-Binding Protein and p300

PubMed Central

Papoutsopoulou, Stamatia; Janknecht, Ralf

2000-01-01

The ETS protein ER81 is a DNA-binding factor capable of enhancing gene transcription and is implicated in cellular transformation, but presently the mechanisms of its actions are unclear. In this report, ER81 is shown to coimmunoprecipitate with the transcriptional coactivator CREB-binding protein (CBP) and the related p300 protein (together referred to as CBP/p300). Moreover, confocal laser microscopic studies demonstrated that ER81 and p300 colocalized to nuclear speckles. In vitro and in vivo interaction studies revealed that ER81 amino acids 249 to 429, which encompass the ETS DNA-binding domain, are responsible for binding to CBP/p300. However, mutation of a putative protein-protein interaction motif, LXXLL, in the ETS domain of ER81 did not affect interaction with CBP/p300, whereas DNA binding of ER81 was abolished. Furthermore, two regions within CBP, amino acids 451 to 721 and 1891 to 2175, are capable of binding to ER81. Consistent with the physical interaction between ER81 and the coactivators CBP and p300, ER81 transcriptional activity was potentiated by CBP/p300 overexpression. Moreover, an ER81-associated protein kinase activity was enhanced upon p300 overexpression. This protein kinase phosphorylates ER81 on serines 191 and 216, and mutation of these phosphorylation sites increased ER81 transcriptional activity in Mv1Lu cells but not in HeLa cells. Altogether, our data elucidate the mechanism of how ER81 regulates gene transcription, through interaction with the coactivators CBP and p300 and an associated kinase that may cell type specifically modulate the ability of ER81 to activate gene transcription. PMID:10982847

Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling.

PubMed

Kang, Lianguo; Zhang, Xintian; Xie, Yan; Tu, Yaping; Wang, Dong; Liu, Zhenming; Wang, Zhao-Yi

2010-04-01

Accumulating evidence suggested that an orphan G protein-coupled receptor (GPR)30, mediates nongenomic responses to estrogen. The present study was performed to investigate the molecular mechanisms underlying GPR30 function. We found that knockdown of GPR30 expression in breast cancer SK-BR-3 cells down-regulated the expression levels of estrogen receptor (ER)-alpha36, a variant of ER-alpha. Introduction of a GPR30 expression vector into GPR30 nonexpressing cells induced endogenous ER-alpha36 expression, and cotransfection assay demonstrated that GPR30 activated the promoter activity of ER-alpha36 via an activator protein 1 binding site. Both 17beta-estradiol (E2) and G1, a compound reported to be a selective GPR30 agonist, increased the phosphorylation levels of the MAPK/ERK1/2 in SK-BR-3 cells, which could be blocked by an anti-ER-alpha36-specific antibody against its ligand-binding domain. G1 induced activities mediated by ER-alpha36, such as transcription activation activity of a VP16-ER-alpha36 fusion protein and activation of the MAPK/ERK1/2 in ER-alpha36-expressing cells. ER-alpha36-expressing cells, but not the nonexpressing cells, displayed high-affinity, specific E2 and G1 binding, and E2- and G1-induced intracellular Ca(2+) mobilization only in ER-alpha36 expressing cells. Taken together, our results demonstrated that previously reported activities of GPR30 in response to estrogen were through its ability to induce ER-alpha36 expression. The selective G protein-coupled receptor (GPR)30 agonist G1 actually interacts with ER-alpha36. Thus, the ER-alpha variant ER-alpha36, not GPR30, is involved in nongenomic estrogen signaling.

The interaction between ER and NFκB in resistance to endocrine therapy

PubMed Central

2012-01-01

Endocrine therapy is a commonly used treatment for estrogen receptor (ER)-positive breast cancer. Although endocrine therapy has a favorable outcome in many patients, development of resistance is common. Recent studies have shown that NFκB, a transcription factor regulating a wide variety of cellular processes, might play a role in the development of endocrine resistance. The precise interaction between ER and NFκB and how this contributes to the attenuated responsiveness of ER-positive breast cancer cells to hormonal treatment remains unclear. This review provides an overview of the mechanisms of action for both transcription factors and focuses on the current knowledge explaining how ER and NFκB affect each other's activity and how this cross-talk might contribute to the development of an endocrine resistance phenotype in breast cancer cells. PMID:22963717

Early Detection of Ovarian Cancer by Molecular Targeted Ultrasound Imaging Together with Serum Markers of Tumor-Associated Nuclear Change and Angiogenesis

DTIC Science & Technology

2013-10-01

in a still format as well as in real-time clips (15 minutes for each hen). The effects of targeted microbubbles were visually evaluated online during...Determination of time between the serum prevalence of anti-NMP antibodies as well as increased serum IL-16 levels and the formation of solid tumor...endoplasmic reticular (ER) and mitochondrial stress. Glucose-regulated protein of 78kDa (GRP78) is a marker of ER stress. Tumor-associated ER stress

ICI 182,780-regulated gene expression in DU145 prostate cancer cells is mediated by estrogen receptor-beta/NFkappaB crosstalk.

PubMed

Leung, Yuet-Kin; Gao, Ying; Lau, Kin-Mang; Zhang, Xiang; Ho, Shuk-Mei

2006-04-01

Estrogen receptor (ER)-beta is the predominant ER subtype in prostate cancer (PCa). We previously demonstrated that ICI 182,780 (ICI), but not estrogens, exerted dose-dependent growth inhibition on DU145 PCa cells by an ER-beta-mediated pathway. Transcriptional profiling detected a greater than three-fold upregulation of seven genes after a 12-hour exposure to 1 microM ICI. Semiquantitative reverse transcriptase polymerase chain reaction confirmed the upregulation of four genes by ICI: interleukin-12alpha chain, interleukin-8, embryonic growth/differentiation factor, and RYK tyrosine kinase. Treatment with an ER-beta antisense oligonucleotide reduced cellular ER-beta mRNA and induced loss of expression of these genes. Sequence analysis revealed the presence of consensus NFkappaB sites, but not estrogen-responsive elements, in promoters of all four genes. Reporter assay and chromatin immunoprecipitation experiments demonstrated that ICI-induced gene expression could be mediated by crosstalk between ER-beta and the NFkappaB signaling pathway, denoting a novel mechanism of ER-beta-mediated ICI action. Therefore, combined therapies targeting ER-beta and NFkappaB signaling may be synergistic as treatment for PCa.

ICI 182,780-Regulated Gene Expression in DU145 Prostate Cancer Cells Is Mediated by Estrogen Receptor-β/NFκB Crosstalk1

PubMed Central

Leung, Yuet-Kin; Gao, Ying; Lau, Kin-Mang; Zhang, Xiang; Ho, Shuk-Mei

2006-01-01

Abstract Estrogen receptor (ER)-β is the predominant ER subtype in prostate cancer (PCa). We previously demonstrated that ICI 182,780 (ICI), but not estrogens, exerted dose-dependent growth inhibition on DU145 PCa cells by an ER-β-mediated pathway. Transcriptional profiling detected a greater than three-fold upregulation of seven genes after a 12-hour exposure to 1 µM ICI. Semi-quantitative reverse transcriptase polymerase chain reaction confirmed the upregulation of four genes by ICI: interleukin-12α chain, interleukin-8, embryonic growth/differentiation factor, and RYK tyrosine kinase. Treatment with an ER-β antisense oligonucleotide reduced cellular ER-β mRNA and induced loss of expression of these genes. Sequence analysis revealed the presence of consensus NFκB sites, but not estrogen-responsive elements, in promoters of all four genes. Reporter assay and chromatin immunoprecipitation experiments demonstrated that ICI-induced gene expression could be mediated by crosstalk between ER-α and the NFκB signaling pathway, denoting a novel mechanism of ER-β-mediated ICI action. Therefore, combined therapies targeting ER-β and NFκB signaling may be synergistic as treatment for PCa. PMID:16756716

Unfolded protein response activation compensates endoplasmic reticulum-associated degradation deficiency in Arabidopsis.

PubMed

Li, Qingliang; Wei, Hai; Liu, Lijing; Yang, Xiaoyuan; Zhang, Xiansheng; Xie, Qi

2017-07-01

Abiotic stresses often disrupt protein folding and induce endoplasmic reticulum (ER) stress. There is a sophisticated ER quality control (ERQC) system to mitigate the effects of malfunctioning proteins and maintain ER homeostasis. The accumulation of misfolded proteins in the ER activates the unfolded protein response (UPR) to enhance ER protein folding and the degradation of misfolded proteins mediate by ER-associated degradation (ERAD). That ERQC reduces abiotic stress damage has been well studied in mammals and yeast. However, in plants, both ERAD and UPR have been studied separately and found to be critical for plant abiotic stress tolerance. In this study, we discovered that UPR-associated transcription factors AtbZIP17, AtbZIP28 and AtbZIP60 responded to tunicamycin (TM) and NaCl induced ER stress and subsequently enhanced Arabidopsis thaliana abiotic stress tolerance. They regulated the expression level of ER chaperones and the HRD1-complex components. Moreover, overexpression of AtbZIP17, AtbZIP28 and AtbZIP60 could restore stress tolerance via ERAD in the HRD1-complex mutant hrd3a-2, which suggested that UPR and ERAD have an interactive mechanism in Arabidopsis. © 2017 Institute of Botany, Chinese Academy of Sciences.

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

PubMed Central

Kim, Min-Hyun; Aydemir, Tolunay B.; Kim, Jinhee; Cousins, Robert J.

2017-01-01

Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet–induced ER stress using Zip14−/− (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders. PMID:28673968

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress.

PubMed

Kim, Min-Hyun; Aydemir, Tolunay B; Kim, Jinhee; Cousins, Robert J

2017-07-18

Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14 -/- (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.

78 FR 19155 - Special Local Regulations; Marine Events, Wrightsville Channel; Wrightsville Beach, NC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-29

... establish a Special Local Regulation for the ``Swim the Loop/Motts Channel Sprint'' swim event, to be held..., mile 283.1, at Wrightsville Beach, North Carolina, during the swim event. DATES: Comments and related...:45 a.m., Without Limits Coaching will sponsor ``Swim the Loop'' and the ``Motts Channel Sprint'' on...

Gibberellin-regulated gene in the basal region of rice leaf sheath encodes basic helix-loop-helix transcription factor.

PubMed

Komatsu, Setsuko; Takasaki, Hironori

2009-07-01

Genes regulated by gibberellin (GA) during leaf sheath elongation in rice seedlings were identified using the transcriptome approach. mRNA from the basal regions of leaf sheaths treated with GA3 was analyzed by high-coverage gene expression profiling. 33,004 peaks were detected, and 30 transcripts showed significant changes in the presence of GA3. Among these, basic helix-loop-helix transcription factor (AK073385) was significantly upregulated. Quantitative PCR analysis confirmed that expression of AK073385 was controlled by GA3 in a time- and dose-dependent manner. Basic helix-loop-helix transcription factor (AK073385) is therefore involved in the regulation of gene expression by GA3.

Generation of signaling specificity in Arabidopsis by spatially restricted buffering of ligand-receptor interactions.

PubMed

Abrash, Emily B; Davies, Kelli A; Bergmann, Dominique C

2011-08-01

Core signaling pathways function in multiple programs during multicellular development. The mechanisms that compartmentalize pathway function or confer process specificity, however, remain largely unknown. In Arabidopsis thaliana, ERECTA (ER) family receptors have major roles in many growth and cell fate decisions. The ER family acts with receptor TOO MANY MOUTHS (TMM) and several ligands of the EPIDERMAL PATTERNING FACTOR LIKE (EPFL) family, which play distinct yet overlapping roles in patterning of epidermal stomata. Here, our examination of EPFL genes EPFL6/CHALLAH (CHAL), EPFL5/CHALLAH-LIKE1, and EPFL4/CHALLAH-LIKE2 (CLL2) reveals that this family may mediate additional ER-dependent processes. chal cll2 mutants display growth phenotypes characteristic of er mutants, and genetic interactions are consistent with CHAL family molecules acting as ER family ligands. We propose that different classes of EPFL genes regulate different aspects of ER family function and introduce a TMM-based discriminatory mechanism that permits simultaneous, yet compartmentalized and distinct, function of the ER family receptors in growth and epidermal patterning.

Input filter compensation for switching regulators

NASA Technical Reports Server (NTRS)

Lee, F. C.; Kelkar, S. S.

1982-01-01

The problems caused by the interaction between the input filter, output filter, and the control loop are discussed. The input filter design is made more complicated because of the need to avoid performance degradation and also stay within the weight and loss limitations. Conventional input filter design techniques are then dicussed. The concept of pole zero cancellation is reviewed; this concept is the basis for an approach to control the peaking of the output impedance of the input filter and thus mitigate some of the problems caused by the input filter. The proposed approach for control of the peaking of the output impedance of the input filter is to use a feedforward loop working in conjunction with feedback loops, thus forming a total state control scheme. The design of the feedforward loop for a buck regulator is described. A possible implementation of the feedforward loop design is suggested.

Theory-guided Therapeutic Function of Music to facilitate emotion regulation development in preschool-aged children.

PubMed

Sena Moore, Kimberly; Hanson-Abromeit, Deanna

2015-01-01

Emotion regulation (ER) is an umbrella term to describe interactive, goal-dependent explicit, and implicit processes that are intended to help an individual manage and shift an emotional experience. The primary window for appropriate ER development occurs during the infant, toddler, and preschool years. Atypical ER development is considered a risk factor for mental health problems and has been implicated as a primary mechanism underlying childhood pathologies. Current treatments are predominantly verbal- and behavioral-based and lack the opportunity to practice in-the-moment management of emotionally charged situations. There is also an absence of caregiver-child interaction in these treatment strategies. Based on behavioral and neural support for music as a therapeutic mechanism, the incorporation of intentional music experiences, facilitated by a music therapist, may be one way to address these limitations. Musical Contour Regulation Facilitation (MCRF) is an interactive therapist-child music-based intervention for ER development practice in preschoolers. The MCRF intervention uses the deliberate contour and temporal structure of a music therapy session to mirror the changing flow of the caregiver-child interaction through the alternation of high arousal and low arousal music experiences. The purpose of this paper is to describe the Therapeutic Function of Music (TFM), a theory-based description of the structural characteristics for a music-based stimulus to musically facilitate developmentally appropriate high arousal and low arousal in-the-moment ER experiences. The TFM analysis is based on a review of the music theory, music neuroscience, and music development literature and provides a preliminary model of the structural characteristics of the music as a core component of the MCRF intervention.

Theory-guided Therapeutic Function of Music to facilitate emotion regulation development in preschool-aged children

PubMed Central

Sena Moore, Kimberly; Hanson-Abromeit, Deanna

2015-01-01

Emotion regulation (ER) is an umbrella term to describe interactive, goal-dependent explicit, and implicit processes that are intended to help an individual manage and shift an emotional experience. The primary window for appropriate ER development occurs during the infant, toddler, and preschool years. Atypical ER development is considered a risk factor for mental health problems and has been implicated as a primary mechanism underlying childhood pathologies. Current treatments are predominantly verbal- and behavioral-based and lack the opportunity to practice in-the-moment management of emotionally charged situations. There is also an absence of caregiver–child interaction in these treatment strategies. Based on behavioral and neural support for music as a therapeutic mechanism, the incorporation of intentional music experiences, facilitated by a music therapist, may be one way to address these limitations. Musical Contour Regulation Facilitation (MCRF) is an interactive therapist-child music-based intervention for ER development practice in preschoolers. The MCRF intervention uses the deliberate contour and temporal structure of a music therapy session to mirror the changing flow of the caregiver–child interaction through the alternation of high arousal and low arousal music experiences. The purpose of this paper is to describe the Therapeutic Function of Music (TFM), a theory-based description of the structural characteristics for a music-based stimulus to musically facilitate developmentally appropriate high arousal and low arousal in-the-moment ER experiences. The TFM analysis is based on a review of the music theory, music neuroscience, and music development literature and provides a preliminary model of the structural characteristics of the music as a core component of the MCRF intervention. PMID:26528171

Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells.

PubMed

Song, Junna; Li, Jia; Hou, Fangjie; Wang, Xiaona; Liu, Baolin

2015-03-01

Endothelial dysfunction is tightly associated with cardiovascular complications in diabetic patients. This study aims to investigate the effects of mangiferin on the regulation of endothelial homeostasis under endoplasmic reticulum stress (ER stress) conditions. High glucose (25 mmol/L) exposure induced ER stress and promoted ROS production in endothelial cells. Mangiferin effectively inhibited ER stress-associated oxidative stress by attenuating IRE1α phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1β secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1β and IL-6 production, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation. NLRP3 inflammasome activation is responsible for mitochondrial cell death. Mangiferin restored the loss of the mitochondrial membrane potential (Δψm) and inhibited caspase-3 activity, and thereby protected cells from high glucose-induced apoptosis. Moreover, mangiferin inhibited ET-1 secretion and restored the loss of NO production when cells were exposed to high glucose. Mangiferin enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects, indicating the potential role of AMPK in its action. Our work showed the beneficial effects of mangiferin on the improvement of endothelial homeostasis and elucidated the molecular pathway through which mangiferin ameliorated endothelial dysfunction by inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells. These findings demonstrated the beneficial effects of mangiferin on the regulation of endothelial homeostasis and indicated its potential application in the management of diabetic cardiovascular complications. Copyright © 2015 Elsevier Inc. All rights reserved.

Simvastatin inhibits ox-LDL-induced inflammatory adipokines secretion via amelioration of ER stress in 3T3-L1 adipocyte.

PubMed

Wu, Zhi-hong; Chen, Ya-qin; Zhao, Shui-ping

2013-03-08

Adipocytes behave as a rich source of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Endoplasmic reticulum (ER) stress in adipocytes can alter adipokines secretion and induce inflammation. The aim of this study is to evaluate the effect of simvastatin on the ox-LDL-induced ER stress and expression and secretion of TNF-α and MCP-1 in 3T3-L1 adipocytes. Differentiated adipocytes were treated with various concentrations of ox-LDL (0-100 μg/ml) for 24h with or without simvastatin pre-treatment. The protein expressions of ER stress markers, glucose-regulated protein 78 (GRP78) and C/EBP homology protein (CHOP), were determined by Western blot analysis. The mRNA expressions of TNF-α and MCP-1 were measured by real-time PCR. The protein release of TNF-α and MCP-1 in culture medium were evaluated by ELISA. Ox-LDL treatment led to significant up-regulation of GRP78 and CHOP in dose-dependent manner. The expressions of TNF-α and MCP-1 were dose-dependently increased at mRNA and protein levels after ox-LDL intervention. The effects of ox-LDL on adipocytes were abolished by pre-treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone known to ameliorate ER stress. Simvastatin could inhibit ox-LDL-induced ER stress and reduce the expression of TNF-α and MCP-1 at mRNA and protien level in dose dependent manner. In conclusion, ox-LDL can stimulate the expression and secretion of TNF-α and MCP-1 through its activation of ER stress in adipocytes. Simvastatin might exert direct anti-inflammatory effects in adipocytes through amelioration of ER stress. Copyright © 2013 Elsevier Inc. All rights reserved.

Withaferin A Suppresses Estrogen Receptor-α Expression in Human Breast Cancer Cells

PubMed Central

Hahm, Eun-Ryeong; Lee, Joomin; Huang, Yi; Singh, Shivendra V.

2011-01-01

We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of MCF-7 and MDA-MB-231 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo by causing apoptosis. However, the mechanism of WA-induced apoptosis is not fully understood. The present study was designed to systematically determine the role of tumor suppressor p53 and estrogen receptor-α (ER-α) in proapoptotic response to WA using MCF-7, T47D, and ER-α overexpressing MDA-MB-231 cells as a model. WA treatment resulted in induction as well as increased Ser15 phosphorylation of p53 in MCF-7 cells, but RNA interference of this tumor suppressor gene conferred modest protection at best against WA-induced apoptosis. WA-mediated growth inhibition and apoptosis induction in MCF-7 cells were significantly attenuated in the presence of 17β-estradiol (E2). Exposure of MCF-7 cells to WA resulted in a marked decrease in protein levels of ER-α (but not ER-β) and ER-α regulated gene product pS2, and this effect was markedly attenuated in the presence of E2. WA-mediated down-regulation of ER-α protein expression correlated with a decrease in its nuclear level, suppression of its mRNA level, and inhibition of E2-dependent activation of ERE2e1b-luciferase reporter gene. Ectopic expression of ER-α in the MDA-MB-231 cell line conferred partial but statistically significant protection against WA-mediated apoptosis, but not G2/M phase cell cycle arrest. Collectively, these results indicate that WA functions as an anti-estrogen, and the proapoptotic effect of this promising natural product is partially attenuated by p53 knockdown and E2-ER-α. PMID:21432907

The Androgen Metabolite, 5α-Androstane-3β,17β-Diol (3β-Diol), Activates the Oxytocin Promoter Through an Estrogen Receptor-β Pathway

PubMed Central

Hiroi, Ryoko; Lacagnina, Anthony F.; Hinds, Laura R.; Carbone, David G.; Uht, Rosalie M.

2013-01-01

Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamic-pituitary-adrenal axis; however, the mechanisms underlying this response remain unclear. The hypothalamic-pituitary-adrenal axis is regulated by a neuroendocrine subpopulation of medial parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN). These neurons are devoid of androgen receptors (ARs). Therefore, a possibility is that the PVN target neurons respond to a metabolite in the testosterone catabolic pathway via an AR-independent mechanism. The dihydrotestosterone metabolite, 5α-androstane-3β,17β-diol (3β-diol), binds and activates estrogen receptor-β (ER-β), the predominant ER in the PVN. In the PVN, ER-β is coexpressed with oxytocin (OT). Therefore, we tested the hypothesis that 3β-diol regulates OT expression through ER-β activation. Treatment of ovariectomized rats with estradiol benzoate or 3β-diol for 4 days increased OT mRNA selectively in the midcaudal, but not rostral PVN compared with vehicle-treated controls. 3β-Diol treatment also increased OT mRNA in the hypothalamic N38 cell line in vitro. The functional interactions between 3β-diol and ER-β with the human OT promoter were examined using an OT promoter-luciferase reporter construct (OT-luc). In a dose-dependent manner, 3β-diol treatment increased OT-luc activity when cells were cotransfected with ER-β, but not ER-α. The 3β-diol–induced OT-luc activity was reduced by deletion of the promoter region containing the composite hormone response element (cHRE). Point mutations of the cHRE also prevented OT-luc activation by 3β-diol. These results indicate that 3β-diol induces OT promoter activity via ER-β–cHRE interactions. PMID:23515287

Particle-induced SIRT1 downregulation promotes osteoclastogenesis and osteolysis through ER stress regulation.

PubMed

Zhang, Liang; Bao, Dongmei; Li, Peng; Lu, Zhidong; Pang, Long; Chen, Zhirong; Guo, Haohui; Gao, Zhihui; Jin, Qunhua

2018-08-01

Sirtuin 1 (SIRT1) downregulation has been found to be induced by wear particles in aseptic prosthesis loosening (APL). Osteoclastogenesis and osteoclast activation are the main pathological factors associated with APL. However, whether SIRT1 downregulation contributes to the formation and activation of osteoclasts through the induction of endoplasmic reticulum (ER) stress is unclear. To address this, an osteolysis mouse model was used in which animals were treated with the SIRT1 activator, resveratrol (RES), or an ER stress inhibitor, 4-PBA, for two weeks. Osteolysis, osteoclastogenesis, and morphologic alteration of calvariae were observed by toluidine blue, TRAP, and H&E staining. SIRT1 expression and ER stress were evaluated by western blot analysis. In vitro, mouse macrophage RAW 264.7 cells were treated with polyethylene (PE) particles alone or combined with either RES or 4-PBA, and SIRT1 expression and ER stress were measured using western blot assays. Osteoclast differentiation was determined through TRAP staining. Osteoclast activation was evaluated by culturing osteoclast cells on bone slices followed by toluidine blue staining. Mechanistically, osteoclastogenesis-related MAPK activation, NFATc1 and c-Fos expression, and NF-κB translocation were determined. Both in vivo and in vitro experimental results indicated that PE particles induced SIRT1 downregulation and enhanced ER stress. SIRT1 activator RES and ER stress inhibitor 4-PBA significantly suppressed PE particle-induced osteoclast differentiation and osteolysis. In vitro experimental results showed that 4-PBA suppressed PE particle-induced ERK1/2, p38, and JNK activation, NFATc1 and c-Fos upregulation, as well as NF-κB p65 nucleus translocation. PE particle-induced downregulation of SIRT1 enhances ER stress and promotes osteoclast proliferation and bone resorption through regulation of c-Fos, NFATc1, and the MAPK and NF-κB signaling pathways. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

ERp29 Regulates ΔF508 and Wild-type Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Trafficking to the Plasma Membrane in Cystic Fibrosis (CF) and Non-CF Epithelial Cells*

PubMed Central

Suaud, Laurence; Miller, Katelyn; Alvey, Lora; Yan, Wusheng; Robay, Amal; Kebler, Catherine; Kreindler, James L.; Guttentag, Susan; Hubbard, Michael J.; Rubenstein, Ronald C.

2011-01-01

Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of ΔF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate ΔF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences ΔF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (∼1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and ΔF508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o− WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, ΔF508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased ΔF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote ΔF508-CFTR trafficking in CF epithelial cells. PMID:21525008

ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells.

PubMed

Suaud, Laurence; Miller, Katelyn; Alvey, Lora; Yan, Wusheng; Robay, Amal; Kebler, Catherine; Kreindler, James L; Guttentag, Susan; Hubbard, Michael J; Rubenstein, Ronald C

2011-06-17

Sodium 4-phenylbutyrate (4PBA) improves the intracellular trafficking of ΔF508-CFTR in cystic fibrosis (CF) epithelial cells. The underlying mechanism is uncertain, but 4PBA modulates the expression of some cytosolic molecular chaperones. To identify other 4PBA-regulated proteins that might regulate ΔF508-CFTR trafficking, we performed a differential display RT-PCR screen on IB3-1 CF bronchiolar epithelial cells exposed to 4PBA. One transcript up-regulated by 4PBA encoded ERp29, a luminal resident of the endoplasmic reticulum (ER) thought to be a novel molecular chaperone. We tested the hypothesis that ERp29 is a 4PBA-regulated ER chaperone that influences ΔF508-CFTR trafficking. ERp29 mRNA and protein expression was significantly increased (∼1.5-fold) in 4PBA-treated IB3-1 cells. In Xenopus oocytes, ERp29 overexpression increased the functional expression of both wild-type and ΔF508-CFTR over 3-fold and increased wild-type cystic fibrosis transmembrane conductance regulator (CFTR) plasma membrane expression. In CFBE41o- WT-CFTR cells, expression of and short circuit currents mediated by CFTR decreased upon depletion of ERp29 as did maturation of newly synthesized CFTR. In IB3-1 cells, ΔF508-CFTR co-immunoprecipitated with endogenous ERp29, and overexpression of ERp29 led to increased ΔF508-CFTR expression at the plasma membrane. These data suggest that ERp29 is a 4PBA-regulated ER chaperone that regulates WT-CFTR biogenesis and can promote ΔF508-CFTR trafficking in CF epithelial cells.

Modeling Tight Junction Dynamics and Oscillations

PubMed Central

Kassab, Fuad; Marques, Ricardo Paulino; Lacaz-Vieira, Francisco

2002-01-01

Tight junction (TJ) permeability responds to changes of extracellular Ca2+ concentration. This can be gauged through changes of the transepithelial electrical conductance (G) determined in the absence of apical Na+. The early events of TJ dynamics were evaluated by the fast Ca2+ switch assay (FCSA) (Lacaz-Vieira, 2000), which consists of opening the TJs by removing basal calcium (Ca2+ bl) and closing by returning Ca2+ bl to normal values. Oscillations of TJ permeability were observed when Ca2+ bl is removed in the presence of apical calcium (Ca2+ ap) and were interpreted as resulting from oscillations of a feedback control loop which involves: (a) a sensor (the Ca2+ binding sites of zonula adhaerens), (b) a control unit (the cell signaling machinery), and (c) an effector (the TJs). A mathematical model to explain the dynamical behavior of the TJs and oscillations was developed. The extracellular route (ER), which comprises the paracellular space in series with the submucosal interstitial fluid, was modeled as a continuous aqueous medium having the TJ as a controlled barrier located at its apical end. The ER was approximated as a linear array of cells. The most apical cell is separated from the apical solution by the TJ and this cell bears the Ca2+ binding sites of zonula adhaerens that control the TJs. According to the model, the control unit receives information from the Ca2+ binding sites and delivers a signal that regulates the TJ barrier. Ca2+ moves along the ER according to one-dimensional diffusion following Fick's second law. Across the TJ, Ca2+ diffusion follows Fick's first law. Our first approach was to simulate the experimental results in a semiquantitative way. The model tested against experiment results performed in the frog urinary bladder adequately predicts the responses obtained in different experimental conditions, such as: (a) TJ opening and closing in a FCSA, (b) opening by the presence of apical Ca2+ and attainment of a new steady-state, (c) the escape phase which follows the halt of TJ opening induced by apical Ca2+, (d) the oscillations of TJ permeability, and (e) the effect of Ca2+ ap concentration on the frequency of oscillations. PMID:12149284

Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

PubMed

Glubb, Dylan M; Maranian, Mel J; Michailidou, Kyriaki; Pooley, Karen A; Meyer, Kerstin B; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A; Hillman, Kristine M; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; van der Schoot, C Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A; Ruebner, Matthias; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D P; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; Collée, J Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Brown, Melissa A; Ponder, Bruce A J; Chenevix-Trench, Georgia; Thompson, Deborah J; Edwards, Stacey L; Easton, Douglas F; Dunning, Alison M; French, Juliet D

2015-01-08

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

36 CFR 1200.7 - What are NARA logos and how are they used?

Code of Federal Regulations, 2011 CFR

2011-07-01

... business cards; (2) On all NARA web and social media sites (intranet and internet), whether hosted...) Regulations.gov and FedReg.gov Web sites. ER11MY04.008 (iii) Federal Register paper edition. ER11MY04.009 (iv...) NARA Web sites (Intranet and Internet); (4) Officially approved internal and external publications; and...

Antiestrogenic activity of flavnoid phytochemicals mediated via c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha

USDA-ARS?s Scientific Manuscript database

Flavonoid phytochemicals act as both agonists and antagonists of the human estrogen receptors (ERs). While a number of these compounds act by directly binding to the ER, certain phytochemicals, such as the flavonoid compounds chalcone and flavone, elicit antagonistic effects on estrogen signaling in...

43 CFR Appendix A to Part 418 - Calculation of Efficiency Equation

Code of Federal Regulations, 2011 CFR

2011-10-01

... 43 Public Lands: Interior 1 2011-10-01 2011-10-01 false Calculation of Efficiency Equation A Appendix A to Part 418 Public Lands: Interior Regulations Relating to Public Lands BUREAU OF RECLAMATION.... 418, App. A Appendix A to Part 418—Calculation of Efficiency Equation ER18DE97.008 ER18DE97.009 ...

43 CFR Appendix A to Part 418 - Calculation of Efficiency Equation

Code of Federal Regulations, 2010 CFR

2010-10-01

... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Calculation of Efficiency Equation A Appendix A to Part 418 Public Lands: Interior Regulations Relating to Public Lands BUREAU OF RECLAMATION.... 418, App. A Appendix A to Part 418—Calculation of Efficiency Equation ER18DE97.008 ER18DE97.009 ...

TEMPERATURE-SENSITIVE, POST-TRANSLATIONAL REGULATION OF PLANT OMEGA-3 FATTY ACID DESATURASES IS MEDIATED BY THE ER-ASSOCIATED DEGRADATION PATHWAY

USDA-ARS?s Scientific Manuscript database

In plants, the endoplasmic reticulum (ER)-localized omega-3 fatty acid desaturases (Fad3s) increase the production of polyunsaturated fatty acids at cooler temperatures, but the FAD3 genes themselves are typically not upregulated during this adaptive response. Here, we expressed two closely related ...

The Sequence-specific Peptide-binding Activity of the Protein Sulfide Isomerase AGR2 Directs Its Stable Binding to the Oncogenic Receptor EpCAM.

PubMed

Mohtar, M Aiman; Hernychova, Lenka; O'Neill, J Robert; Lawrence, Melanie L; Murray, Euan; Vojtesek, Borek; Hupp, Ted R

2018-04-01

AGR2 is an oncogenic endoplasmic reticulum (ER)-resident protein disulfide isomerase. AGR2 protein has a relatively unique property for a chaperone in that it can bind sequence-specifically to a specific peptide motif (TTIYY). A synthetic TTIYY-containing peptide column was used to affinity-purify AGR2 from crude lysates highlighting peptide selectivity in complex mixtures. Hydrogen-deuterium exchange mass spectrometry localized the dominant region in AGR2 that interacts with the TTIYY peptide to within a structural loop from amino acids 131-135 (VDPSL). A peptide binding site consensus of Tx[IL][YF][YF] was developed for AGR2 by measuring its activity against a mutant peptide library. Screening the human proteome for proteins harboring this motif revealed an enrichment in transmembrane proteins and we focused on validating EpCAM as a potential AGR2-interacting protein. AGR2 and EpCAM proteins formed a dose-dependent protein-protein interaction in vitro Proximity ligation assays demonstrated that endogenous AGR2 and EpCAM protein associate in cells. Introducing a single alanine mutation in EpCAM at Tyr251 attenuated its binding to AGR2 in vitro and in cells. Hydrogen-deuterium exchange mass spectrometry was used to identify a stable binding site for AGR2 on EpCAM, adjacent to the TLIYY motif and surrounding EpCAM's detergent binding site. These data define a dominant site on AGR2 that mediates its specific peptide-binding function. EpCAM forms a model client protein for AGR2 to study how an ER-resident chaperone can dock specifically to a peptide motif and regulate the trafficking a protein destined for the secretory pathway. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4).

PubMed

Cunningham, Margaret R; McIntosh, Kathryn A; Pediani, John D; Robben, Joris; Cooke, Alexandra E; Nilsson, Mary; Gould, Gwyn W; Mundell, Stuart; Milligan, Graeme; Plevin, Robin

2012-05-11

Proteinase-activated receptors 4 (PAR(4)) is a class A G protein-coupled receptor (GPCR) recognized through the ability of serine proteases such as thrombin and trypsin to mediate receptor activation. Due to the irreversible nature of activation, a fresh supply of receptor is required to be mobilized to the cell surface for responsiveness to agonist to be sustained. Unlike other PAR subtypes, the mechanisms regulating receptor trafficking of PAR(4) remain unknown. Here, we report novel features of the intracellular trafficking of PAR(4) to the plasma membrane. PAR(4) was poorly expressed at the plasma membrane and largely retained in the endoplasmic reticulum (ER) in a complex with the COPI protein subunit β-COP1. Analysis of the PAR(4) protein sequence identified an arginine-based (RXR) ER retention sequence located within intracellular loop-2 (R(183)AR → A(183)AA), mutation of which allowed efficient membrane delivery of PAR(4). Interestingly, co-expression with PAR(2) facilitated plasma membrane delivery of PAR(4), an effect produced through disruption of β-COP1 binding and facilitation of interaction with the chaperone protein 14-3-3ζ. Intermolecular FRET studies confirmed heterodimerization between PAR(2) and PAR(4). PAR(2) also enhanced glycosylation of PAR(4) and activation of PAR(4) signaling. Our results identify a novel regulatory role for PAR(2) in the anterograde traffic of PAR(4). PAR(2) was shown to both facilitate and abrogate protein interactions with PAR(4), impacting upon receptor localization and cell signal transduction. This work is likely to impact markedly upon the understanding of the receptor pharmacology of PAR(4) in normal physiology and disease.

An inducible ER–Golgi tether facilitates ceramide transport to alleviate lipotoxicity

PubMed Central

Choudhary, Vineet

2017-01-01

Ceramides are key intermediates in sphingolipid biosynthesis and potent signaling molecules. However, excess ceramide is toxic, causing growth arrest and apoptosis. In this study, we identify a novel mechanism by which cells prevent the toxic accumulation of ceramides; they facilitate nonvesicular ceramide transfer from the endoplasmic reticulum (ER) to the Golgi complex, where ceramides are converted to complex sphingolipids. We find that the yeast protein Nvj2p promotes the nonvesicular transfer of ceramides from the ER to the Golgi complex. The protein is a tether that generates close contacts between these compartments and may directly transport ceramide. Nvj2p normally resides at contacts between the ER and other organelles, but during ER stress, it relocalizes to and increases ER–Golgi contacts. ER–Golgi contacts fail to form during ER stress in cells lacking Nvj2p. Our findings demonstrate that cells regulate ER–Golgi contacts in response to stress and reveal that nonvesicular ceramide transfer out of the ER prevents the buildup of toxic amounts of ceramides. PMID:28011845

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

PubMed Central

Liu, Mei-qing; Chen, Zhe; Chen, Lin-xi

2016-01-01

Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS. PMID:26838072

STIM proteins and the endoplasmic reticulum-plasma membrane junctions.

PubMed

Carrasco, Silvia; Meyer, Tobias

2011-01-01

Eukaryotic organelles can interact with each other through stable junctions where the two membranes are kept in close apposition. The junction that connects the endoplasmic reticulum to the plasma membrane (ER-PM junction) is unique in providing a direct communication link between the ER and the PM. In a recently discovered signaling process, STIM (stromal-interacting molecule) proteins sense a drop in ER Ca(2+) levels and directly activate Orai PM Ca(2+) channels across the junction space. In an inverse process, a voltage-gated PM Ca(2+) channel can directly open ER ryanodine-receptor Ca(2+) channels in striated-muscle cells. Although ER-PM junctions were first described 50 years ago, their broad importance in Ca(2+) signaling, as well as in the regulation of cholesterol and phosphatidylinositol lipid transfer, has only recently been realized. Here, we discuss research from different fields to provide a broad perspective on the structures and unique roles of ER-PM junctions in controlling signaling and metabolic processes.

Regulation of Adrenocortical Steroid Hormone Production by RhoA-Diaphanous 1 Signaling and the Cytoskeleton

PubMed Central

Sewer, Marion B.; Li, Donghui

2012-01-01

The production of glucocorticoids and aldosterone in the adrenal cortex is regulated at multiple levels. Biosynthesis of these hormones is initiated when cholesterol, the substrate, enters the inner mitochondrial membrane for conversion to pregnenolone. Unlike most metabolic pathways, the biosynthesis of adrenocortical steroid hormones is unique because some of the enzymes are localized in mitochondria and others in the endoplasmic reticulum (ER). Although much is known about the factors that control the transcription and activities of the proteins that are required for steroid hormone production, the parameters that govern the exchange of substrates between the ER and mitochondria are less well understood. This short review summarizes studies that have begun to provide insight into the role of the cytoskeleton, mitochondrial transport, and the physical interaction of the ER and mitochondria in the production of adrenocortical steroid hormones. PMID:23186810

Liganded and unliganded activation of estrogen receptor and hormone replacement therapies

PubMed Central

Maggi, Adriana

2011-01-01

Over the past two decades, our understanding of estrogen receptor physiology in mammals widened considerably as we acquired a deeper appreciation of the roles of estrogen receptor alpha and beta (ERα and ERβ) in reproduction as well as in bone and metabolic homeostasis, depression, vascular disorders, neurodegenerative diseases and cancer. In addition, our insights on ER transcriptional functions in cells increased considerably with the demonstration that ER activity is not strictly dependent on ligand availability. Indeed, unliganded ERs may be transcriptionally active and post-translational modifications play a major role in this context. The finding that several intracellular transduction molecules may regulate ER transcriptional programs indicates that ERs may act as a hub where several molecular pathways converge: this allows to maintain ER transcriptional activity in tune with all cell functions. Likely, the biological relevant role of ER was favored by evolution as a mean of integration between reproductive and metabolic functions. We here review the post-translational modifications modulating ER transcriptional activity in the presence or in the absence of estrogens and underline their potential role for ER tissue-specific activities. In our opinion, a better comprehension of the variety of molecular events that control ER activity in reproductive and non-reproductive organs is the foundation for the design of safer and more efficacious hormone-based therapies, particularly for menopause. PMID:21605666

A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress.

PubMed

Chaudhari, Namrata; Talwar, Priti; Parimisetty, Avinash; Lefebvre d'Hellencourt, Christian; Ravanan, Palaniyandi

2014-01-01

Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.

Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.

PubMed

Swayne, Theresa C; Zhou, Chun; Boldogh, Istvan R; Charalel, Joseph K; McFaline-Figueroa, José Ricardo; Thoms, Sven; Yang, Christine; Leung, Galen; McInnes, Joseph; Erdmann, Ralf; Pon, Liza A

2011-12-06

Mitochondria accumulate at neuronal and immunological synapses and yeast bud tips and associate with the ER during phospholipid biosynthesis, calcium homeostasis, and mitochondrial fission. Here we show that mitochondria are associated with cortical ER (cER) sheets underlying the plasma membrane in the bud tip and confirm that a deletion in YPT11, which inhibits cER accumulation in the bud tip, also inhibits bud tip anchorage of mitochondria. Time-lapse imaging reveals that mitochondria are anchored at specific sites in the bud tip. Mmr1p, a member of the DSL1 family of tethering proteins, localizes to punctate structures on opposing surfaces of mitochondria and cER sheets underlying the bud tip and is recovered with isolated mitochondria and ER. Deletion of MMR1 impairs bud tip anchorage of mitochondria without affecting mitochondrial velocity or cER distribution. Deletion of the phosphatase PTC1 results in increased Mmr1p phosphorylation, mislocalization of Mmr1p, defects in association of Mmr1p with mitochondria and ER, and defects in bud tip anchorage of mitochondria. These findings indicate that Mmr1p contributes to mitochondrial inheritance as a mediator of anchorage of mitochondria to cER sheets in the yeast bud tip and that Ptc1p regulates Mmr1p phosphorylation, localization, and function. Copyright © 2011 Elsevier Ltd. All rights reserved.

YODA MAP3K kinase regulates plant immune responses conferring broad-spectrum disease resistance.

PubMed

Sopeña-Torres, Sara; Jordá, Lucía; Sánchez-Rodríguez, Clara; Miedes, Eva; Escudero, Viviana; Swami, Sanjay; López, Gemma; Piślewska-Bednarek, Mariola; Lassowskat, Ines; Lee, Justin; Gu, Yangnan; Haigis, Sabine; Alexander, Danny; Pattathil, Sivakumar; Muñoz-Barrios, Antonio; Bednarek, Pawel; Somerville, Shauna; Schulze-Lefert, Paul; Hahn, Michael G; Scheel, Dierk; Molina, Antonio

2018-04-01

Mitogen-activated protein kinases (MAPKs) cascades play essential roles in plants by transducing developmental cues and environmental signals into cellular responses. Among the latter are microbe-associated molecular patterns perceived by pattern recognition receptors (PRRs), which trigger immunity. We found that YODA (YDA) - a MAPK kinase kinase regulating several Arabidopsis developmental processes, like stomatal patterning - also modulates immune responses. Resistance to pathogens is compromised in yda alleles, whereas plants expressing the constitutively active YDA (CA-YDA) protein show broad-spectrum resistance to fungi, bacteria, and oomycetes with different colonization modes. YDA functions in the same pathway as ERECTA (ER) Receptor-Like Kinase, regulating both immunity and stomatal patterning. ER-YDA-mediated immune responses act in parallel to canonical disease resistance pathways regulated by phytohormones and PRRs. CA-YDA plants exhibit altered cell-wall integrity and constitutively express defense-associated genes, including some encoding putative small secreted peptides and PRRs whose impairment resulted in enhanced susceptibility phenotypes. CA-YDA plants show strong reprogramming of their phosphoproteome, which contains protein targets distinct from described MAPKs substrates. Our results suggest that, in addition to stomata development, the ER-YDA pathway regulates an immune surveillance system conferring broad-spectrum disease resistance that is distinct from the canonical pathways mediated by described PRRs and defense hormones. © 2018 Universidad Politécnica de Madrid (UPM) New Phytologist © 2018 New Phytologist Trust.

ERMO3/MVP1/GOLD36 Is Involved in a Cell Type-Specific Mechanism for Maintaining ER Morphology in Arabidopsis thaliana

PubMed Central

Nakano, Ryohei Thomas; Matsushima, Ryo; Nagano, Atsushi J.; Fukao, Yoichiro; Fujiwara, Masayuki; Kondo, Maki; Nishimura, Mikio; Hara-Nishimura, Ikuko

2012-01-01

The endoplasmic reticulum (ER) has a unique, network-like morphology. The ER structures are composed of tubules, cisternae, and three-way junctions. This morphology is highly conserved among eukaryotes, but the molecular mechanism that maintains ER morphology has not yet been elucidated. In addition, certain Brassicaceae plants develop a unique ER-derived organelle called the ER body. This organelle accumulates large amounts of PYK10, a β-glucosidase, but its physiological functions are still obscure. We aimed to identify a novel factor required for maintaining the morphology of the ER, including ER bodies, and employed a forward-genetic approach using transgenic Arabidopsis thaliana (GFP-h) with fluorescently-labeled ER. We isolated and investigated a mutant (designated endoplasmic reticulum morphology3, ermo3) with huge aggregates and abnormal punctate structures of ER. ERMO3 encodes a GDSL-lipase/esterase family protein, also known as MVP1. Here, we showed that, although ERMO3/MVP1/GOLD36 was expressed ubiquitously, the morphological defects of ermo3 were specifically seen in a certain type of cells where ER bodies developed. Coimmunoprecipitation analysis combined with mass spectrometry revealed that ERMO3/MVP1/GOLD36 interacts with the PYK10 complex, a huge protein complex that is thought to be important for ER body-related defense systems. We also found that the depletion of transcription factor NAI1, a master regulator for ER body formation, suppressed the formation of ER-aggregates in ermo3 cells, suggesting that NAI1 expression plays an important role in the abnormal aggregation of ER. Our results suggest that ERMO3/MVP1/GOLD36 is required for preventing ER and other organelles from abnormal aggregation and for maintaining proper ER morphology in a coordinated manner with NAI1. PMID:23155454

Modification of Co/Cu nanoferrites properties via Gd3+/Er3+doping

NASA Astrophysics Data System (ADS)

Ateia, Ebtesam E.; Soliman, Fatma S.

2017-05-01

Pure nanoparticles of the rare earth-substituted cobalt and copper ferrites with general formula Me Gd0.025 Er0.05 Fe1.925 O4 (Me = Co, Cu) were prepared by the chemical citrate method. X-ray diffraction, field emission scanning electron microscopy, BET analysis are utilized to study the effect of rare earth substitution and its impact on the physical properties of the investigated samples. Rare earth-doped cobalt shows type IV isotherm suggesting mesopore structure with its hysteresis loop. The estimated crystallite sizes are found in the range of 21.49 and 36.11 nm for the doped Co and Cu samples, respectively. The magnetic properties of rare earth-substituted cobalt and copper ferrites showed a definite hysteresis loop at room temperature. An increase in coercivity and a decrease in saturation magnetization were detected. This can be explained in view of weaker nature of the Re3+-Fe3+ interaction compared to Fe3+-Fe3+ interaction. Greater than 1.13-fold increase in coercivity (Hc = 2184 Oe) was observed in doped cobalt nanoferrite samples compared to copper (Hc = 1936 Oe). It was found that the decreasing in temperature leads to great improvement in the magnetic properties of the investigated samples. As the magnetic recording performance of the magnetic samples is improved for well-crystallized samples with nano-structural, the effect of rare earth substitution seems to be particularly valuable in this regard.

A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux.

PubMed

Krokowski, Dawid; Han, Jaeseok; Saikia, Mridusmita; Majumder, Mithu; Yuan, Celvie L; Guan, Bo-Jhih; Bevilacqua, Elena; Bussolati, Ovidio; Bröer, Stefan; Arvan, Peter; Tchórzewski, Marek; Snider, Martin D; Puchowicz, Michelle; Croniger, Colleen M; Kimball, Scot R; Pan, Tao; Koromilas, Antonis E; Kaufman, Randal J; Hatzoglou, Maria

2013-06-14

Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2α. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in β-cells in vivo. Paradoxically, chronic ER stress in β-cells induced an anabolic transcription program to overcome translational repression by eIF2α phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in β-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes.

Emotion regulation, emotional eating and the energy-rich dietary pattern. A population-based study in Chinese adolescents.

PubMed

Lu, Qingyun; Tao, Fangbiao; Hou, Fangli; Zhang, Zhaocheng; Ren, Ling-Ling

2016-04-01

Research investigating the influence of emotion regulation (ER) strategies on emotional eating and diet among Chinese adolescents is scarce. The aim of this study was to test associations between two ER strategies (suppression/cognitive reappraisal), emotional eating, and an energy-rich dietary pattern. A total of 4316 adolescents from 10 high schools were surveyed. Dietary patterns were derived using factor analysis. Bivariate correlations were analyzed to examine associations between ER strategies, emotional eating behavior and an energy-rich dietary pattern, by gender. The mediating effect of emotional eating in the relationship between ER and energy-rich food consumption by gender was estimated using structural equation modeling. A higher level of suppression, but no lack of cognitive reappraisal, was associated with emotional eating in boys and girls. A higher level of suppression and lack of cognitive reappraisal were associated with a greater intake of energy-rich foods in girls only. Emotional eating mediated the relationship between a higher level of suppression and a greater intake of energy-rich food in girls. This study revealed significant associations between two ER strategies and an energy-rich dietary pattern in girls, and provided evidence that higher levels of suppression may put girls at risk for emotional eating, potentially affecting the energy-rich dietary pattern. Copyright © 2016 Elsevier Ltd. All rights reserved.

Selenoprotein K Binds Multiprotein Complexes and Is Involved in the Regulation of Endoplasmic Reticulum Homeostasis*

PubMed Central

Shchedrina, Valentina A.; Everley, Robert A.; Zhang, Yan; Gygi, Steven P.; Hatfield, Dolph L.; Gladyshev, Vadim N.

2011-01-01

Selenoprotein K (SelK) is an 11-kDa endoplasmic reticulum (ER) protein of unknown function. Herein, we defined a new eukaryotic protein family that includes SelK, selenoprotein S (SelS), and distantly related proteins. Comparative genomics analyses indicate that this family is the most widespread eukaryotic selenoprotein family. A biochemical search for proteins that interact with SelK revealed ER-associated degradation (ERAD) components (p97 ATPase, Derlins, and SelS). In this complex, SelK showed higher affinity for Derlin-1, whereas SelS had higher affinity for Derlin-2, suggesting that these selenoproteins could determine the nature of the substrate translocated through the Derlin channel. SelK co-precipitated with soluble glycosylated ERAD substrates and was involved in their degradation. Its gene contained a functional ER stress response element, and its expression was up-regulated by conditions that induce the accumulation of misfolded proteins in the ER. Components of the oligosaccharyltransferase complex (ribophorins, OST48, and STT3A) and an ER chaperone, calnexin, were found to bind SelK. A glycosylated form of SelK was also detected, reflecting its association with the oligosaccharyltransferase complex. These data suggest that SelK is involved in the Derlin-dependent ERAD of glycosylated misfolded proteins and that the function defined by the prototypic SelK is the widespread function of selenium in eukaryotes. PMID:22016385

A Self-defeating Anabolic Program Leads to β-Cell Apoptosis in Endoplasmic Reticulum Stress-induced Diabetes via Regulation of Amino Acid Flux*

PubMed Central

Krokowski, Dawid; Han, Jaeseok; Saikia, Mridusmita; Majumder, Mithu; Yuan, Celvie L.; Guan, Bo-Jhih; Bevilacqua, Elena; Bussolati, Ovidio; Bröer, Stefan; Arvan, Peter; Tchórzewski, Marek; Snider, Martin D.; Puchowicz, Michelle; Croniger, Colleen M.; Kimball, Scot R.; Pan, Tao; Koromilas, Antonis E.; Kaufman, Randal J.; Hatzoglou, Maria

2013-01-01

Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2α. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in β-cells in vivo. Paradoxically, chronic ER stress in β-cells induced an anabolic transcription program to overcome translational repression by eIF2α phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in β-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes. PMID:23645676