Ferulic acid attenuates diabetes-induced cognitive impairment in rats via regulation of PTP1B and insulin signaling pathway.

PubMed

Wang, Hao; Sun, Xiaoxu; Zhang, Ning; Ji, Zhouye; Ma, Zhanqiang; Fu, Qiang; Qu, Rong; Ma, Shiping

2017-12-01

Cognitive impairment has been recognized as a typical characteristic of neurodegenerative disease in diabetes mellitus (DM) and this cognitive dysfunction may be a risk factor for Alzheimer's disease (AD). Ferulic acid, a phenolic compound commonly found in a range of plants, has emerged various properties including anti-inflammatory and neuroprotective effects. In the present study, the protective activities and relevant mechanisms of ferulic acid were evaluated in diabetic rats with cognitive deficits, which were induced by a high-glucose-fat (HGF) diet and low dose of streptozotocin (STZ). It was observed that ferulic acid significantly increased body weight and decreased blood glucose levels. Meanwhile, ferulic acid could markedly ameliorate spatial memory of diabetic rats in Morris water maze (MWM) and decrease AD-like pathologic changes (Aβ deposition and Tau phosphorylation) in the hippocampus, which might be correlated with the inhibition of inflammatory cytokines release and reduction of protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, the levels of brain insulin signal molecules p-IRS, p-Akt and p-GSK3β were also investigated. We found that ferulic acid administration restored the alterations in insulin signaling. In conclusion, ferulic acid exhibited beneficial effects on diabetes-induced cognition lesions, which was involved in the regulation of PTP1B and insulin signaling pathway. We suppose that PTP1B inhibition may represent a promising approach to correct abnormal signaling linked to diabetes-induced cognitive impairment. Copyright © 2017. Published by Elsevier Inc.

Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity

PubMed Central

Ryu, Yuhee; Jin, Li; Kee, Hae Jin; Piao, Zhe Hao; Cho, Jae Yeong; Kim, Gwi Ran; Choi, Sin Young; Lin, Ming Quan; Jeong, Myung Ho

2016-01-01

Gallic acid, a type of phenolic acid, has been shown to have beneficial effects in inflammation, vascular calcification, and metabolic diseases. The present study was aimed at determining the effect and regulatory mechanism of gallic acid in cardiac hypertrophy and fibrosis. Cardiac hypertrophy was induced by isoproterenol (ISP) in mice and primary neonatal cardiomyocytes. Gallic acid pretreatment attenuated concentric cardiac hypertrophy. It downregulated the expression of atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain in vivo and in vitro. Moreover, it prevented interstitial collagen deposition and expression of fibrosis-associated genes. Upregulation of collagen type I by Smad3 overexpression was observed in cardiac myoblast H9c2 cells but not in cardiac fibroblasts. Gallic acid reduced the DNA binding activity of phosphorylated Smad3 in Smad binding sites of collagen type I promoter in rat cardiac fibroblasts. Furthermore, it decreased the ISP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) protein in mice. JNK2 overexpression reduced collagen type I and Smad3 expression as well as GATA4 expression in H9c2 cells and cardiac fibroblasts. Gallic acid might be a novel therapeutic agent for the prevention of cardiac hypertrophy and fibrosis by regulating the JNK2 and Smad3 signaling pathway. PMID:27703224

Butyric acid regulates progesterone and estradiol secretion via cAMP signaling pathway in porcine granulosa cells.

PubMed

Lu, Naisheng; Li, Mengjiao; Lei, Hulong; Jiang, Xueyuan; Tu, Weilong; Lu, Yang; Xia, Dong

2017-09-01

Butyric acid (BA), one of the short chain fatty acids (SCFAs), has positive actions on the metabolism, inflammation, etc. However, whether it influences the reproductive physiology and if so the detail mechanism involved has not yet been determined. In this study, the porcine granulosa cells (PGCs) were treated with gradient concentrations of BA. After 24h culture, 0.05mM BA significantly stimulated the progesterone (P 4 ) secretion (P<0.05), 5mM and 10mM BA significantly inhibited the P 4 secretion (P<0.05). Simultaneously, BA up-regulated the estradiol (E 2 ) secretion in a dose dependent manner, 5mM and 10mM BA significantly promoted the E 2 level (P<0.05). In addition, 10mM BA significantly promoted the G-protein-coupled receptor 41/43 mRNA (P<0.05). Interestingly, 5mM BA treatment significantly down-regulated cyclic adenosine monophosphate (cAMP) content (P<0.05), steroidogenic acute regulatory (StAR), steroidogenic factor 1 (SF1), P450scc in the mRNA and/or protein level (P<0.05), and these actions were reversed by cAMP activator forskolin (FK). Moreover, the co-treatment of 5mM BA and bupivacaine (BPC, the cAMP inhibitor) significantly accumulated the inhibition action of BPC on cAMP, the secretion of P 4 , and the abundance of StAR mRNA (P<0.05), inhibited the up-regulation of 5mM BA on the E 2 secretion (P<0.05). Further, the Global Proteome and KEGG pathway analysis found that 5mM BA significantly up-regulated the I3LM80 proteins (P<0.05), which is involved in the steroid biosynthesis signaling pathway. 5mM BA significantly decreased the F2Z5G3 protein level (P<0.05), and the cAMP signaling pathway. In conclusion, present findings for the first time demonstrated that BA could regulate the P 4 and E 2 hormone synthesis in PGCs via the cAMP signaling pathway. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

PubMed

Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

2013-05-01

Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

Nutrient Regulation of the mTOR Complex 1 Signaling Pathway

PubMed Central

Kim, Sang Gyun; Buel, Gwen R.; Blenis, John

2013-01-01

The mammalian target of rapamycin (mTOR) is an evolutionally conserved kinase which exists in two distinct structural and functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Of the two complexes, mTORC1 couples nutrient abundance to cell growth and proliferation by sensing and integrating a variety of inputs arising from amino acids, cellular stresses, energy status, and growth factors. Defects in mTORC1 regulation are implicated in the development of many metabolic diseases, including cancer and diabetes. Over the past decade, significant advances have been made in deciphering the complexity of the signaling processes contributing to mTORC1 regulation and function, but the mechanistic details are still not fully understood. In particular, how amino acid availability is sensed by cells and signals to mTORC1 remains unclear. In this review, we discuss the current understanding of nutrient-dependent control of mTORC1 signaling and will focus on the key components involved in amino acid signaling to mTORC1. PMID:23694989

Retinoic Acid signaling regulates Krt5 and Krt14 independently of stem cell markers in submandibular salivary gland epithelium

PubMed Central

Abashev, Timur M.; Metzler, Melissa A.; Wright, Diana M.; Sandell, Lisa L.

2017-01-01

Background Retinoic Acid (RA), the active metabolite of Vitamin A, has been demonstrated to be important for growth and branching morphogenesis of mammalian embryonic salivary gland epithelium. However, it is not known whether RA functions directly within epithelial cells or in associated tissues that influence morphogenesis of salivary epithelium. Moreover, downstream targets of RA regulation have not been identified. Results Here we show that canonical RA signaling occurs in multiple tissues of embryonic mouse salivary glands, including epithelium, associated parasympathetic ganglion neurons, and non-neuronal mesenchyme. By culturing epithelium explants in isolation from other tissues we demonstrate that RA influences epithelium morphogenesis by direct action in that tissue. Moreover, we demonstrate that inhibition of RA signaling represses cell proliferation and expression of FGF10 signaling targets, and upregulates expression of basal epithelial keratins Krt5 and Krt14. Importantly, we show that the stem cell gene Kit is regulated inversely from Krt5/Krt14 by RA signaling. Conclusions RA regulates Krt5 and Krt14 expression independently of stem cell character in developing salivary epithelium. RA, or chemical inhibitors of RA signaling, could potentially be used for modulating growth and differentiation of epithelial stem cells for the purpose of re-populating damaged glands or generating bioengineered organs. PMID:27884045

An Arabidopsis mitochondria-localized RRL protein mediates abscisic acid signal transduction through mitochondrial retrograde regulation involving ABI4.

PubMed

Yao, Xuan; Li, Juanjuan; Liu, Jianping; Liu, Kede

2015-10-01

The molecular mechanisms of abscisic acid (ABA) signalling have been studied for many years; however, how mitochondria-localized proteins play roles in ABA signalling remains unclear. Here an Arabidopsis mitochondria-localized protein RRL (RETARDED ROOT GROWTH-LIKE) was shown to function in ABA signalling. A previous study had revealed that the Arabidopsis mitochondria-localized protein RRG (RETARDED ROOT GROWTH) is required for cell division in the root meristem. RRL shares 54% and 57% identity at the nucleotide and amino acid sequences, respectively, with RRG; nevertheless, RRL shows a different function in Arabidopsis. In this study, disruption of RRL decreased ABA sensitivity whereas overexpression of RRL increased ABA sensitivity during seed germination and seedling growth. High expression levels of RRL were found in germinating seeds and developing seedlings, as revealed by β-glucuronidase (GUS) staining of ProRRL-GUS transgenic lines. The analyses of the structure and function of mitochondria in the knockout rrl mutant showed that the disruption of RRL causes extensively internally vacuolated mitochondria and reduced ABA-stimulated reactive oxygen species (ROS) production. Previous studies have revealed that the expression of alternative oxidase (AOX) in the alternative respiratory pathway is increased by mitochondrial retrograde regulation to regain ROS levels when the mitochondrial electron transport chain is impaired. The APETALA2 (AP2)-type transcription factor ABI4 is a regulator of ALTERNATIVE OXIDASE1a (AOX1a) in mitochondrial retrograde signalling. This study showed that ABA-induced AOX1a and ABI4 expression was inhibited in the rrl mutant, suggesting that RRL is probably involved in ABI4-mediated mitochondrial retrograde signalling. Furthermore, the results revealed that ABI4 is a downstream regulatory factor in RRL-mediated ABA signalling in seed germination and seedling growth. © The Author 2015. Published by Oxford University Press on behalf of

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

PubMed Central

Bruntz, Ronald C.; Lindsley, Craig W.

2014-01-01

Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein–coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions. PMID:25244928

Regulation of angiogenesis by phospholipid lysophosphatidic acid.

PubMed

Chen, Yiliang; Ramakrishnan, Devi Prasadh; Ren, Bin

2013-06-01

Lysophosphatidic acid (LPA) as a bioactive phospholipid signaling mediator is emerging as an important regulator of endothelial cell functions and angiogenesis. Many studies have shown that LPA is an active player in regulating the processes of endothelial cell migration, proliferation, and differentiation, all essential in angiogenesis. Through modulating angiogenesis associated gene expression, LPA also promotes pathological angiogenesis. Intriguingly, the angiogenic signaling mechanisms mediated by LPA have been linked to specific G-protein coupled receptors and down stream MAPK including Erk1/2, p38 and JNK, protein kinase D (PKD-1), Rho kinase (ROCK), and the NF-kappa B signaling pathways. LPA regulates angiogenic responses via a complex signaling network, and LPA signaling is integrated and transduced to the nucleus to coordinate the transcription of different angiogenic genes. Investigation of these mechanisms will provide novel and valuable insights into the understanding of endothelial cell biology and angiogenic programs. This knowledge will facilitate designs for better therapies for the ischemic cardiovascular diseases and malignant tumors.

Putting the pH into phosphatidic acid signaling

PubMed Central

2011-01-01

The lipid phosphatidic acid (PA) has important roles in cell signaling and metabolic regulation in all organisms. New evidence indicates that PA also has an unprecedented role as a pH biosensor, coupling changes in pH to intracellular signaling pathways. pH sensing is a property of the phosphomonoester headgroup of PA. A number of other potent signaling lipids also contain headgroups with phosphomonoesters, implying that pH sensing by lipids may be widespread in biology. PMID:22136116

Retinoic acid signaling regulates Krt5 and Krt14 independently of stem cell markers in submandibular salivary gland epithelium.

PubMed

Abashev, Timur M; Metzler, Melissa A; Wright, Diana M; Sandell, Lisa L

2017-02-01

Retinoic acid (RA), the active metabolite of vitamin A, has been demonstrated to be important for growth and branching morphogenesis of mammalian embryonic salivary gland epithelium. However, it is not known whether RA functions directly within epithelial cells or in associated tissues that influence morphogenesis of salivary epithelium. Moreover, downstream targets of RA regulation have not been identified. Here, we show that canonical RA signaling occurs in multiple tissues of embryonic mouse salivary glands, including epithelium, associated parasympathetic ganglion neurons, and nonneuronal mesenchyme. By culturing epithelium explants in isolation from other tissues, we demonstrate that RA influences epithelium morphogenesis by direct action in that tissue. Moreover, we demonstrate that inhibition of RA signaling represses cell proliferation and expression of FGF10 signaling targets, and upregulates expression of basal epithelial keratins Krt5 and Krt14. Importantly, we show that the stem cell gene Kit is regulated inversely from Krt5/Krt14 by RA signaling. RA regulates Krt5 and Krt14 expression independently of stem cell character in developing salivary epithelium. RA, or chemical inhibitors of RA signaling, could potentially be used for modulating growth and differentiation of epithelial stem cells for the purpose of re-populating damaged glands or generating bioengineered organs. Developmental Dynamics 246:135-147, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Maternal protein restriction in the rat inhibits placental insulin, mTOR, and STAT3 signaling and down-regulates placental amino acid transporters.

PubMed

Rosario, Fredrick J; Jansson, Nina; Kanai, Yoshikatsu; Prasad, Puttur D; Powell, Theresa L; Jansson, Thomas

2011-03-01

The mechanisms underlying reduced fetal growth in response to maternal protein restriction are not well established. Maternal levels of insulin, IGF-I, and leptin are decreased in rats fed a low protein (LP) diet. Because these hormones stimulate placental amino acid transporters in vitro, we hypothesized that maternal protein restriction inhibits placental leptin, insulin/IGF-I, and mammalian target of rapamycin signaling and down-regulates the expression and activity of placental amino acid transporters. Pregnant rats were fed either an isocaloric low protein (LP, 4% protein) or control diet (18% protein) and studied at gestational day (GD)15, GD19, or GD21 (term 23). At GD19 and GD21, placental expression of phosphorylated eukaryotic initiation factor 4E binding protein 1 (Thr-36/46 or Thr-70) and phosphorylated S6 ribosomal protein (Ser-235/236) was decreased in the LP group. In addition, placental expression of phosphorylated S6 kinase 1 (Thr-389), phosphorylated Akt (Thr-308), and phosphorylated signal transducer and activator of transcription 3 (Tyr-705) was reduced at GD21. In microvillous plasma membranes (MVM) isolated from placentas of LP animals, protein expression of the sodium-coupled neutral amino acid transporter (SNAT)2 and the large neutral amino acid transporters 1 and 2 was reduced at GD19 and GD21. MVM SNAT1 protein expression was reduced at GD21 in LP rats. SNAT4 and 4F2 heavy chain expression in MVM was unaltered. System A and L amino acid transporter activity was decreased in MVM from LP animals at GD19 and GD21. In conclusion, maternal protein restriction inhibits placental insulin, mammalian target of rapamycin signaling, and signal transducer and activator of transcription 3 signaling, which is associated with a down-regulation of placental amino acid transporters. We speculate that maternal endocrine and metabolic control of placental nutrient transport reduces fetal growth in response to protein restriction.

CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling

PubMed Central

Müller, Jennifer; Obermeier, Ingrid; Wöhner, Miriam; Brandl, Carolin; Mrotzek, Sarah; Angermüller, Sieglinde; Maity, Palash C.; Reth, Michael; Nitschke, Lars

2013-01-01

A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can downmodulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in α2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca2+ signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity. PMID:23836650

CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling.

PubMed

Müller, Jennifer; Obermeier, Ingrid; Wöhner, Miriam; Brandl, Carolin; Mrotzek, Sarah; Angermüller, Sieglinde; Maity, Palash C; Reth, Michael; Nitschke, Lars

2013-07-23

A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can downmodulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in α2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca(2+) signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca(2+) signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca(2+) responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity.

Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer.

PubMed

Bruntz, Ronald C; Lindsley, Craig W; Brown, H Alex

2014-10-01

Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein-coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Bile acid metabolism and signaling in cholestasis, inflammation and cancer

PubMed Central

Apte, Udayan

2015-01-01

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis. PMID:26233910

ERK1/2 activation in human taste bud cells regulates fatty acid signaling and gustatory perception of fat in mice and humans.

PubMed

Subramaniam, Selvakumar; Ozdener, Mehmet Hakan; Abdoul-Azize, Souleymane; Saito, Katsuyoshi; Malik, Bilal; Maquart, Guillaume; Hashimoto, Toshihiro; Marambaud, Philippe; Aribi, Mourad; Tordoff, Michael G; Besnard, Philippe; Khan, Naim Akhtar

2016-10-01

Obesity is a major public health problem. An in-depth knowledge of the molecular mechanisms of oro-sensory detection of dietary lipids may help fight it. Humans and rodents can detect fatty acids via lipido-receptors, such as CD36 and GPR120. We studied the implication of the MAPK pathways, in particular, ERK1/2, in the gustatory detection of fatty acids. Linoleic acid, a dietary fatty acid, induced via CD36 the phosphorylation of MEK1/2-ERK1/2-ETS-like transcription factor-1 cascade, which requires Fyn-Src kinase and lipid rafts in human taste bud cells (TBCs). ERK1/2 cascade was activated by Ca 2+ signaling via opening of the calcium-homeostasis modulator-1 (CALHM1) channel. Furthermore, fatty acid-evoked Ca 2+ signaling and ERK1/2 phosphorylation were decreased in both human TBCs after small interfering RNA knockdown of CALHM1 channel and in TBCs from Calhm1 -/- mice. Targeted knockdown of ERK1/2 by small interfering RNA or PD0325901 (MEK1/2 inhibitor) in the tongue and genetic ablation of Erk1 or Calhm1 genes impaired preference for dietary fat in mice. Lingual inhibition of ERK1/2 in healthy volunteers also decreased orogustatory sensitivity for linoleic acid. Our data demonstrate that ERK1/2-MAPK cascade is regulated by the opening of CALHM1 Ca 2+ channel in TBCs to modulate orogustatory detection of dietary lipids in mice and humans.-Subramaniam, S., Ozdener, M. H., Abdoul-Azize, S., Saito, K., Malik, B., Maquart, G., Hashimoto, T., Marambaud, P., Aribi, M., Tordoff, M. G., Besnard, P., Khan, N. A. ERK1/2 activation in human taste bud cells regulates fatty acid signaling and gustatory perception of fat in mice and humans. © FASEB.

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

PubMed

Dyall, S C; Mandhair, H K; Fincham, R E A; Kerr, D M; Roche, M; Molina-Holgado, F

2016-08-01

Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects. EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts.

PubMed

Maeda-Sano, Katsura; Gotoh, Mari; Morohoshi, Toshiro; Someya, Takao; Murofushi, Hiromu; Murakami-Murofushi, Kimiko

2014-09-01

Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator and an analog of the growth factor-like phospholipid lysophosphatidic acid (LPA). cPA has a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We showed before that a metabolically stabilized cPA derivative, 2-carba-cPA, relieved osteoarthritis pathogenesis in vivo and induced hyaluronic acid synthesis in human osteoarthritis synoviocytes in vitro. This study focused on hyaluronic acid synthesis in human fibroblasts, which retain moisture and maintain health in the dermis. We investigated the effects of cPA and LPA on hyaluronic acid synthesis in human fibroblasts (NB1RGB cells). Using particle exclusion and enzyme-linked immunosorbent assays, we found that both cPA and LPA dose-dependently induced hyaluronic acid synthesis. We revealed that the expression of hyaluronan synthase 2 messenger RNA and protein is up-regulated by cPA and LPA treatment time dependently. We then characterized the signaling pathways up-regulating hyaluronic acid synthesis mediated by cPA and LPA in NB1RGB cells. Pharmacological inhibition and reporter gene assays revealed that the activation of the LPA receptor LPAR1, Gi/o protein, phosphatidylinositol-3 kinase (PI3K), extracellular-signal-regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding protein (CREB) but not nuclear factor κB induced hyaluronic acid synthesis by the treatment with cPA and LPA in NB1RGB cells. These results demonstrate for the first time that cPA and LPA induce hyaluronic acid synthesis in human skin fibroblasts mainly through the activation of LPAR1-Gi/o followed by the PI3K, ERK, and CREB signaling pathway. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

γ-Aminobutyric acid (GABA) signalling in plants.

PubMed

Ramesh, Sunita A; Tyerman, Stephen D; Gilliham, Matthew; Xu, Bo

2017-05-01

The role of γ-aminobutyric acid (GABA) as a signal in animals has been documented for over 60 years. In contrast, evidence that GABA is a signal in plants has only emerged in the last 15 years, and it was not until last year that a mechanism by which this could occur was identified-a plant 'GABA receptor' that inhibits anion passage through the aluminium-activated malate transporter family of proteins (ALMTs). ALMTs are multigenic, expressed in different organs and present on different membranes. We propose GABA regulation of ALMT activity could function as a signal that modulates plant growth, development, and stress response. In this review, we compare and contrast the plant 'GABA receptor' with mammalian GABA A receptors in terms of their molecular identity, predicted topology, mode of action, and signalling roles. We also explore the implications of the discovery that GABA modulates anion flux in plants, its role in signal transduction for the regulation of plant physiology, and predict the possibility that there are other GABA interaction sites in the N termini of ALMT proteins through in silico evolutionary coupling analysis; we also explore the potential interactions between GABA and other signalling molecules.

Regulation of intestinal protein metabolism by amino acids.

PubMed

Bertrand, Julien; Goichon, Alexis; Déchelotte, Pierre; Coëffier, Moïse

2013-09-01

Gut homeostasis plays a major role in health and may be regulated by quantitative and qualitative food intake. In the intestinal mucosa, an intense renewal of proteins occurs, at approximately 50% per day in humans. In some pathophysiological conditions, protein turnover is altered and may contribute to intestinal or systemic diseases. Amino acids are key effectors of gut protein turnover, both as constituents of proteins and as regulatory molecules limiting intestinal injury and maintaining intestinal functions. Many studies have focused on two amino acids: glutamine, known as the preferential substrate of rapidly dividing cells, and arginine, another conditionally essential amino acid. The effects of glutamine and arginine on protein synthesis appear to be model and condition dependent, as are the involved signaling pathways. The regulation of gut protein degradation by amino acids has been minimally documented until now. This review will examine recent data, helping to better understand how amino acids regulate intestinal protein metabolism, and will explore perspectives for future studies.

Integrating Retinoic Acid Signaling with Brain Function

ERIC Educational Resources Information Center

Luo, Tuanlian; Wagner, Elisabeth; Drager, Ursula C.

2009-01-01

The vitamin A derivative retinoic acid (RA) regulates the transcription of about a 6th of the human genome. Compelling evidence indicates a role of RA in cognitive activities, but its integration with the molecular mechanisms of higher brain functions is not known. Here we describe the properties of RA signaling in the mouse, which point to…

Redox-regulated growth factor survival signaling.

PubMed

Woolley, John F; Corcoran, Aoife; Groeger, Gillian; Landry, William D; Cotter, Thomas G

2013-11-20

Once the thought of as unwanted byproducts of cellular respiration in eukaryotes, reactive oxygen species (ROS) have been shown to facilitate essential physiological roles. It is now understood that ROS are critical mediators of intracellular signaling. Control of signal transduction downstream of growth factor receptors by ROS is a complex process whose details are only recently coming to light. Indeed, recent evidence points to control of signal propagation by ROS at multiple levels in the typical cascade. Growth factor stimulation activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs) at the membrane, producing superoxide in the extracellular matrix, which is catalyzed to the membrane-permeable hydrogen peroxide (H2O2) that mediates intracellular signaling events. The potential for H2O2, however, to disrupt cellular functions by damaging proteins and nucleic acids demands that its levels are kept in check by receptor-associated peroxiredoxins. This interplay of Nox and peroxiredoxin activity moderates levels of H2O2 sufficiently to modify signaling partners locally. Among the best studied of these partners are redox-controlled phosphatases that are inactivated by H2O2. Phosphatases regulate signal propagation downstream of receptors, and thus their inactivation allows a further level of control. Transmission of information further downstream to targets such as transcription factors, themselves regulated by ROS, completes this pathway. Thus, signal propagation or attenuation can be dictated by ROS at multiple points. Given the complex nature of these processes, we envisage the emerging trends in the field of redox signaling in the context of growth factor stimulation.

Analysis of defense signals in Arabidopsis thaliana leaves by ultra-performance liquid chromatography/tandem mass spectrometry: jasmonates, salicylic acid, abscisic acid.

PubMed

Stingl, Nadja; Krischke, Markus; Fekete, Agnes; Mueller, Martin J

2013-01-01

Defense signaling compounds and phytohormones play an essential role in the regulation of plant responses to various environmental abiotic and biotic stresses. Among the most severe stresses are herbivory, pathogen infection, and drought stress. The major hormones involved in the regulation of these responses are 12-oxo-phytodienoic acid (OPDA), the pro-hormone jasmonic acid (JA) and its biologically active isoleucine conjugate (JA-Ile), salicylic acid (SA), and abscisic acid (ABA). These signaling compounds are present and biologically active at very low concentrations from ng/g to μg/g dry weight. Accurate and sensitive quantification of these signals has made a significant contribution to the understanding of plant stress responses. Ultra-performance liquid chromatography (UPLC) coupled with a tandem quadrupole mass spectrometer (MS/MS) has become an essential technique for the analysis and quantification of these compounds.

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

PubMed Central

Nagahashi, Masayuki; Yuza, Kizuki; Hirose, Yuki; Nakajima, Masato; Ramanathan, Rajesh; Hait, Nitai C.; Hylemon, Phillip B.; Zhou, Huiping; Takabe, Kazuaki; Wakai, Toshifumi

2016-01-01

Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases. PMID:27459945

The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway.

PubMed

Su, Ke; Wang, Chun-Fang; Zhang, Ying; Cai, Yu-Jie; Zhang, Yan-Yan; Zhao, Qian

2016-08-01

Cervical cancer has been the fourth most common cancer killing many women across the world. Carnosic acid (CA), as a phenolic diterpene, has been suggested to against cancer, exerting protective effects associated with inflammatory cytokines. It is aimed to demonstrate the therapeutic role of carnosic acid against cervical cancer and indicate its underlying molecular mechanisms. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was performed to assess the possible anti-proliferative effects of carnosic acid. And also, colony formation was used to further estimate carnosic acid's ability in suppressing cervical cancer cells proliferation. Flow cytometry assays were performed here to indicate the alterations of cervical cancer cells cycle and the development of apoptosis. Western blot assays and RT-PCR were also applied to clarify the apoptosis-associated signaling pathways affected by reactive oxygen species (ROS) generation. And immunofluorescence was used to detect ROS-positive cells. In vivo experiments, CaSki xenograft model samples of nude mice were involved to further elucidate the effects of carnosic acid. In our results, we found that carnosic acid exerted anti-tumor ability in vitro supported by up-regulation of apoptosis and ROS production in cervical cancer cells. Also, acceleration of ROS led to the phospharylation of (c-Jun N-terminal kinase (JNK) and its-related signals, as well as activation of Endoplasmic Reticulum (ER) stress, promoting the progression of apoptosis via stimulating Caspase3 expression. The development and growth of xenograft tumors in nude mice were found to be inhibited by the administration of carnosic acid for five weeks. And the suppressed role of carnosic acid in proliferation of cervical cancer cells and apoptosis of nude mice with tumor tissues were observed in our study. Taken together, our data indicated that carnosic acid resulted in apoptosis both in vitro and vivo experiments via promoting ROS and

WRKY Transcription Factors: Key Components in Abscisic Acid Signaling

DTIC Science & Technology

2011-01-01

Review article WRKY transcription factors : key components in abscisic acid signalling Deena L. Rushton1, Prateek Tripathi1, Roel C. Rabara1, Jun Lin1...May 2011. *Correspondence (Tel +605 688 5749; fax +605 688 5624; email paul.rushton@sdstate.edu) Keywords: abscisic acid, WRKY transcription factor ...seed germination, drought, abiotic stress. Summary WRKY transcription factors (TFs) are key regulators of many plant processes, including the responses

Chlorogenic acid inhibits cholestatic liver injury induced by α-naphthylisothiocyanate: involvement of STAT3 and NFκB signalling regulation.

PubMed

Tan, Zhen; Luo, Min; Yang, Julin; Cheng, Yuqing; Huang, Jing; Lu, Caide; Song, Danjun; Ye, Meiling; Dai, Manyun; Gonzalez, Frank J; Liu, Aiming; Guo, Bin

2016-09-01

Chlorogenic acid (CGA) is one of the most widely consumed polyphenols in diets and is recognized to be a natural hepatoprotective agent. Here, we evaluated the protective effect and the potential mechanism of CGA against ɑ-naphthylisothiocyanate (ANIT)-induced cholestasis and liver injury. Twenty-five male 129/Sv mice were administered with CGA, and ANIT challenge was performed at 75 mg/kg on the 4th day. Blood was collected and subjected to biochemical analysis; the liver tissues were examined using histopathological analysis and signalling pathways. Chlorogenic acid almost totally attenuated the ANIT-induced liver damage and cholestasis, compared with the ANIT group. Dose of 50 mg/kg of CGA significantly prevented ANIT-induced changes in serum levels of alanine aminotransferase, alkaline phosphatases, total bile acid, direct bilirubin, indirect bilirubin (5.3-, 6.3-, 18.8-, 158-, 41.4-fold, P<0.001) and aspartate aminotransferase (4.6-fold, P<0.01). Expressions of the altered bile acid metabolism and transport-related genes were normalized by cotreatment with CGA. The expressions of interleukin 6, tumour necrosis factor-α and suppressor of cytokine signalling 3 were found to be significantly decreased (1.2-fold, ns; 11.0-fold, P<0.01; 4.4-fold, P<0.05) in the CGA/ANIT group. Western blot revealed that CGA inhibited the activation and expression of signal transducer and activator of transcription 3 and NFκB. These data suggest that CGA inhibits both ANIT-induced intrahepatic cholestasis and the liver injury. This protective effect involves down-regulation of STAT3 and NFκB signalling. © 2016 Royal Pharmaceutical Society.

SPINDLY, a Negative Regulator of Gibberellic Acid Signaling, Is Involved in the Plant Abiotic Stress Response1[W][OA

PubMed Central

Qin, Feng; Kodaira, Ken-Suke; Maruyama, Kyonoshin; Mizoi, Junya; Tran, Lam-Son Phan; Fujita, Yasunari; Morimoto, Kyoko; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

2011-01-01

The SPINDLY (SPY) gene was first identified as a negative regulator of plant gibberellic acid (GA) signaling because mutation of this gene phenocopies plants treated with an overdose of bioactive GA and results in insensitivity to a GA inhibitor during seed germination. The SPY gene encodes an O-linked N-acetylglucosamine transferase that can modify the target protein and modulate the protein activity in cells. In this study, we describe the strong salt and drought tolerance phenotypes of Arabidopsis (Arabidopsis thaliana) spy-1 and spy-3 mutants in addition to their GA-related phenotypes. SPY gene expression was found to be drought stress inducible and slightly responsive to salt stress. Transcriptome analysis of spy-3 revealed that many GA-responsive genes were up-regulated, which could explain the GA-overdosed phenotype of spy-3. Some stress-inducible genes were found to be up-regulated in spy-3, such as genes encoding late embryogenesis abundant proteins, Responsive to Dehydration20, and AREB1-like transcription factor, which may confer stress tolerance on spy-3. CKX3, a cytokinin (CK) catabolism gene, was up-regulated in spy-3; this up-regulation indicates that the mutant possesses reduced CK signaling, which is consistent with a positive role for SPY in CK signaling. Moreover, overexpression of SPY in transgenics (SPY overexpressing [SPY-OX]) impaired plant drought stress tolerance, opposite to the phenotype of spy. The expression levels of several genes, such as DREB1E/DDF1 and SNH1/WIN1, were decreased in SPY-OX but increased in spy-3. Taken together, these data indicate that SPY plays a negative role in plant abiotic stress tolerance, probably by integrating environmental stress signals via GA and CK cross talk. PMID:22013217

Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

PubMed Central

Zhou, Yang; Fang, Li; Jiang, Lei; Wen, Ping; Cao, Hongdi; He, Weichun; Dai, Chunsun; Yang, Junwei

2012-01-01

Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling. PMID:22761883

Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids.

PubMed

Lager, Susanne; Jansson, Thomas; Powell, Theresa L

2014-10-15

Fatty acids are critical for normal fetal development but may also influence placental function. We have previously reported that oleic acid (OA) stimulates amino acid transport in primary human trophoblasts (PHTs). In other tissues, saturated and unsaturated fatty acids have distinct effects on cellular signaling, for instance, palmitic acid (PA) but not OA reduces IκBα expression. We hypothesized that saturated and unsaturated fatty acids differentially affect trophoblast amino acid transport and cellular signaling. To test this hypothesis, PHTs were cultured in docosahexaenoic acid (DHA; 50 μM), OA (100 μM), or PA (100 μM). DHA and OA were also combined to test whether DHA could counteract the OA stimulatory effect on amino acid transport. The effects of fatty acids were compared against a vehicle control. Amino acid transport was measured by isotope-labeled tracers. Activation of inflammatory-related signaling pathways and the mechanistic target of rapamycin (mTOR) pathway were determined by Western blot analysis. Exposure of PHTs to DHA for 24 h reduced amino acid transport and phosphorylation of p38 MAPK, STAT3, mTOR, eukaryotic initiation factor 4E-binding protein 1, and ribosomal protein (rp)S6. In contrast, OA increased amino acid transport and phosphorylation of ERK, mTOR, S6 kinase 1, and rpS6. The combination of DHA with OA increased amino acid transport and rpS6 phosphorylation. PA did not affect amino acid transport but reduced IκBα expression. In conclusion, these fatty acids differentially regulated placental amino acid transport and cellular signaling. Taken together, these findings suggest that dietary fatty acids could alter the intrauterine environment by modifying placental function, thereby having long-lasting effects on the developing fetus. Copyright © 2014 the American Physiological Society.

Abscisic Acid Is a Major Regulator of Grape Berry Ripening Onset: New Insights into ABA Signaling Network

PubMed Central

Pilati, Stefania; Bagagli, Giorgia; Sonego, Paolo; Moretto, Marco; Brazzale, Daniele; Castorina, Giulia; Simoni, Laura; Tonelli, Chiara; Guella, Graziano; Engelen, Kristof; Galbiati, Massimo; Moser, Claudio

2017-01-01

Grapevine is a world-wide cultivated economically relevant crop. The process of berry ripening is non-climacteric and does not rely on the sole ethylene signal. Abscisic acid (ABA) is recognized as an important hormone of ripening inception and color development in ripening berries. In order to elucidate the effect of this signal at the molecular level, pre-véraison berries were treated ex vivo for 20 h with 0.2 mM ABA and berry skin transcriptional modulation was studied by RNA-seq after the treatment and 24 h later, in the absence of exogenous ABA. This study highlighted that a small amount of ABA triggered its own biosynthesis and had a transcriptome-wide effect (1893 modulated genes) characterized by the amplification of the transcriptional response over time. By comparing this dataset with the many studies on ripening collected within the grapevine transcriptomic compendium Vespucci, an extended overlap between ABA- and ripening modulated gene sets was observed (71% of the genes), underpinning the role of this hormone in the regulation of berry ripening. The signaling network of ABA, encompassing ABA metabolism, transport and signaling cascade, has been analyzed in detail and expanded based on knowledge from other species in order to provide an integrated molecular description of this pathway at berry ripening onset. Expression data analysis was combined with in silico promoter analysis to identify candidate target genes of ABA responsive element binding protein 2 (VvABF2), a key upstream transcription factor of the ABA signaling cascade which is up-regulated at véraison and also by ABA treatments. Two transcription factors, VvMYB143 and VvNAC17, and two genes involved in protein degradation, Armadillo-like and Xerico-like genes, were selected for in vivo validation by VvABF2-mediated promoter trans-activation in tobacco. VvNAC17 and Armadillo-like promoters were induced by ABA via VvABF2, while VvMYB143 responded to ABA in a VvABF2-independent manner. This

Bile acid receptors link nutrient sensing to metabolic regulation

PubMed Central

Li, Jibiao; Li, Tiangang

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in Western populations. Non-alcoholic steatohepatitis (NASH) is a more debilitating form of NAFLD characterized by hepatocellular injury and inflammation, which significantly increase the risk of end-stage liver and cardiovascular diseases. Unfortunately, there are no available drug therapies for NASH. Bile acids are physiological detergent molecules that are synthesized from cholesterol exclusively in the hepatocytes. Bile acids circulate between the liver and intestine, where they are required for cholesterol solubilization in the bile and dietary fat emulsification in the gut. Bile acids also act as signaling molecules that regulate metabolic homeostasis and inflammatory processes. Many of these effects are mediated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. Nutrient signaling regulates hepatic bile acid synthesis and circulating plasma bile acid concentrations, which in turn control metabolic homeostasis. The FXR agonist obeticholic acid has had beneficial effects on NASH in recent clinical trials. Preclinical studies have suggested that the TGR5 agonist and the FXR/TGR5 dual agonist are also potential therapies for metabolic liver diseases. Extensive studies in the past few decades have significantly improved our understanding of the metabolic regulatory function of bile acids, which has provided the molecular basis for developing promising bile acid-based therapeutic agents for NASH treatment. PMID:29098111

GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters.

PubMed

Ramesh, Sunita A; Tyerman, Stephen D; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A; Ryan, Peter R; Gilliham, Matthew; Gillham, Matthew

2015-07-29

The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms.

GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters

PubMed Central

Ramesh, Sunita A.; Tyerman, Stephen D.; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A.; Ryan, Peter R.; Gillham, Matthew

2015-01-01

The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms. PMID:26219411

Regulation of the proteome by amino acids.

PubMed

Bourgoin-Voillard, Sandrine; Goron, Arthur; Seve, Michel; Moinard, Christophe

2016-03-01

Besides their main contribution as substrates for protein synthesis, amino acids as signaling molecules could exert some regulatory functions on protein synthesis and/or proteolysis that have been emphasized in a number of recent studies. Several publications have highlighted supplemental roles of those amino acids in protein metabolism as well as in immunity, heat shock response, or apoptosis processes. In this way, via their regulatory properties, selected amino acids (such as leucine, glutamine, arginine, citrulline, or methionine) directly influence the proteome. In this review, we are proposing an overview of the regulation of the proteome by amino acids in mammals. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy.

PubMed

Cabezas-Wallscheid, Nina; Buettner, Florian; Sommerkamp, Pia; Klimmeck, Daniel; Ladel, Luisa; Thalheimer, Frederic B; Pastor-Flores, Daniel; Roma, Leticia P; Renders, Simon; Zeisberger, Petra; Przybylla, Adriana; Schönberger, Katharina; Scognamiglio, Roberta; Altamura, Sandro; Florian, Carolina M; Fawaz, Malak; Vonficht, Dominik; Tesio, Melania; Collier, Paul; Pavlinic, Dinko; Geiger, Hartmut; Schroeder, Timm; Benes, Vladimir; Dick, Tobias P; Rieger, Michael A; Stegle, Oliver; Trumpp, Andreas

2017-05-18

Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT. Copyright © 2017. Published by Elsevier Inc.

The plastidial retrograde signal methyl erythritol cyclopyrophosphate is a regulator of salicylic acid and jasmonic acid crosstalk

PubMed Central

Lemos, Mark; Xiao, Yanmei; Bjornson, Marta; Wang, Jin-zheng; Hicks, Derrick; de Souza, Amancio; Wang, Chang-Quan; Yang, Panyu; Ma, Shisong; Dinesh-Kumar, Savithramma; Dehesh, Katayoon

2016-01-01

The exquisite harmony between hormones and their corresponding signaling pathways is central to prioritizing plant responses to simultaneous and/or successive environmental trepidations. The crosstalk between jasmonic acid (JA) and salicylic acid (SA) is an established effective mechanism that optimizes and tailors plant adaptive responses. However, the underlying regulatory modules of this crosstalk are largely unknown. Global transcriptomic analyses of mutant plants (ceh1) with elevated levels of the stress-induced plastidial retrograde signaling metabolite 2-C-methyl-D-erythritol cyclopyrophosphate (MEcPP) revealed robustly induced JA marker genes, expected to be suppressed by the presence of constitutively high SA levels in the mutant background. Analyses of a range of genotypes with varying SA and MEcPP levels established the selective role of MEcPP-mediated signal(s) in induction of JA-responsive genes in the presence of elevated SA. Metabolic profiling revealed the presence of high levels of the JA precursor 12-oxo-phytodienoic acid (OPDA), but near wild type levels of JA in the ceh1 mutant plants. Analyses of coronatine-insensitive 1 (coi1)/ceh1 double mutant plants confirmed that the MEcPP-mediated induction is JA receptor COI1 dependent, potentially through elevated OPDA. These findings identify MEcPP as a previously unrecognized central regulatory module that induces JA-responsive genes in the presence of high SA, thereby staging a multifaceted plant response within the environmental context. PMID:26733689

Transcriptional regulation of abscisic acid signal core components during cucumber seed germination and under Cu²⁺, Zn²⁺, NaCl and simulated acid rain stresses.

PubMed

Wang, Yanping; Wang, Ya; Kai, Wenbin; Zhao, Bo; Chen, Pei; Sun, Liang; Ji, Kai; Li, Qian; Dai, Shengjie; Sun, Yufei; Wang, Yidong; Pei, Yuelin; Leng, Ping

2014-03-01

Abscisic acid (ABA) is an important phytohormone that regulates lots of physiological and biochemical processes in plant life cycle, especially in seed germination and stress responses. For exploring the transcriptional regulation of ABA signal transduction during cucumber (Cucumis sativus L.) seed germination and under Cu(2+), Zn(2+), NaCl and simulated acid rain stresses, nine CsPYLs, three group A CsPP2Cs and two subclass III CsSnRK2s were identified from cucumber genome, which respectively showed high sequence similarities and highly conserved domains with homologous genes in Arabidopsis. Based on Real-time PCR analysis, most of the tested genes' expression decreased during cucumber seed germination, which was in accordance with the ABA level variation. In addition, according to the absolute expression, CsPYL1, CsPYL3, CsPP2C5, CsABI1, CsSnRK2.3 and CsSnRK2.4 were highly expressed, indicating that they may play more important roles in ABA signaling during cucumber seed germination. Moreover, most of these highly expressed genes, except CsPYL3, were up-regulated by ABA treatment. Meanwhile, most of the tested genes' expression dramatically changed at the initial water uptake phase, indicating that this period may be critical in the regulation of ABA on seed germination. Under Cu(2+), Zn(2+), NaCl and simulated acid rain stresses, cucumber seed germination percentage decreased and ABA content increased. Meanwhile, the expression of ABA signal transduction core components genes showed specific response to a particular stress and was not always consist with ABA variation. Generally, the expression of CsPYL1, CsPYL3, CsABI1, CsSnRK2.3 and CsSnRK2.4 was sensitive to 120 mM NaCl and 0.5 mM Cu(2+) treatments. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Tetraspanin 6 (TSPAN6) Negatively Regulates Retinoic Acid-inducible Gene I-like Receptor-mediated Immune Signaling in a Ubiquitination-dependent Manner*

PubMed Central

Wang, Yetao; Tong, Xiaomei; Omoregie, Ehimwenma Sheena; Liu, Wenjun; Meng, Songdong; Ye, Xin

2012-01-01

The recognition between retinoic acid-inducible gene I-like receptors (RLRs) and viral RNA triggers an intracellular cascade of signaling to induce the expression of type I IFNs. Both positive and negative regulation of the RLR signaling pathway are important for the host antiviral immune response. Here, we demonstrate that the tetraspanin protein TSPAN6 inhibits RLR signaling by affecting the formation of the adaptor MAVS (mitochondrial antiviral signaling)-centered signalosome. We found that overexpression of TSPAN6 impaired RLR-mediated activation of IFN-stimulated response element, NF-κB, and IFN-β promoters, whereas knockdown of TSPAN6 enhanced the RLR-mediated signaling pathway. Interestingly, as the RLR pathway was activated, TSPAN6 underwent Lys-63-linked ubiquitination, which promoted its association with MAVS. The interaction of TSPAN6 and MAVS interfered with the recruitment of RLR downstream molecules TRAF3, MITA, and IRF3 to MAVS. Further study revealed that the first transmembrane domain of TSPAN6 is critical for its ubiquitination and association with MAVS as well as its inhibitory effect on RLR signaling. We concluded that TSPAN6 functions as a negative regulator of the RLR pathway by interacting with MAVS in a ubiquitination-dependent manner. PMID:22908223

Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster

PubMed Central

Ghosh, Arpan C.; O’Connor, Michael B.

2014-01-01

The ability to maintain cellular and physiological metabolic homeostasis is key for the survival of multicellular organisms in changing environmental conditions. However, our understanding of extracellular signaling pathways that modulate metabolic processes remains limited. In this study we show that the Activin-like ligand Dawdle (Daw) is a major regulator of systemic metabolic homeostasis and cellular metabolism in Drosophila. We find that loss of canonical Smad signaling downstream of Daw leads to defects in sugar and systemic pH homeostasis. Although Daw regulates sugar homeostasis by positively influencing insulin release, we find that the effect of Daw on pH balance is independent of its role in insulin signaling and is caused by accumulation of organic acids that are primarily tricarboxylic acid (TCA) cycle intermediates. RNA sequencing reveals that a number of TCA cycle enzymes and nuclear-encoded mitochondrial genes including genes involved in oxidative phosphorylation and β-oxidation are up-regulated in the daw mutants, indicating either a direct or indirect role of Daw in regulating these genes. These findings establish Activin signaling as a major metabolic regulator and uncover a functional link between TGF-β signaling, insulin signaling, and metabolism in Drosophila. PMID:24706779

Regulation of Hippo signalling by p38 signalling

PubMed Central

Huang, Dashun; Li, Xiaojiao; Sun, Li; Huang, Ping; Ying, Hao; Wang, Hui; Wu, Jiarui; Song, Haiyun

2016-01-01

The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts. We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation. PMID:27402810

TXNIP regulates myocardial fatty acid oxidation via miR-33a signaling.

PubMed

Chen, Junqin; Young, Martin E; Chatham, John C; Crossman, David K; Dell'Italia, Louis J; Shalev, Anath

2016-07-01

Myocardial fatty acid β-oxidation is critical for the maintenance of energy homeostasis and contractile function in the heart, but its regulation is still not fully understood. While thioredoxin-interacting protein (TXNIP) has recently been implicated in cardiac metabolism and mitochondrial function, its effects on β-oxidation have remained unexplored. Using a new cardiomyocyte-specific TXNIP knockout mouse and working heart perfusion studies, as well as loss- and gain-of-function experiments in rat H9C2 and human AC16 cardiomyocytes, we discovered that TXNIP deficiency promotes myocardial β-oxidation via signaling through a specific microRNA, miR-33a. TXNIP deficiency leads to increased binding of nuclear factor Y (NFYA) to the sterol regulatory element binding protein 2 (SREBP2) promoter, resulting in transcriptional inhibition of SREBP2 and its intronic miR-33a. This allows for increased translation of the miR-33a target genes and β-oxidation-promoting enzymes, carnitine octanoyl transferase (CROT), carnitine palmitoyl transferase 1 (CPT1), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase-β (HADHB), and AMPKα and is associated with an increase in phospho-AMPKα and phosphorylation/inactivation of acetyl-CoA-carboxylase. Thus, we have identified a novel TXNIP-NFYA-SREBP2/miR-33a-AMPKα/CROT/CPT1/HADHB pathway that is conserved in mouse, rat, and human cardiomyocytes and regulates myocardial β-oxidation. Copyright © 2016 the American Physiological Society.

The homeodomain-leucine zipper (HD-Zip) class I transcription factors ATHB7 and ATHB12 modulate abscisic acid signalling by regulating protein phosphatase 2C and abscisic acid receptor gene activities.

PubMed

Valdés, Ana Elisa; Overnäs, Elin; Johansson, Henrik; Rada-Iglesias, Alvaro; Engström, Peter

2012-11-01

Plants perceiving drought activate multiple responses to improve survival, including large-scale alterations in gene expression. This article reports on the roles in the drought response of two Arabidopsis thaliana homeodomain-leucine zipper class I genes; ATHB7 and ATHB12, both strongly induced by water-deficit and abscisic acid (ABA). ABA-mediated transcriptional regulation of both genes is shown to depend on the activity of protein phosphatases type 2C (PP2C). ATHB7 and ATHB12 are, thus, targets of the ABA signalling mechanism defined by the PP2Cs and the PYR/PYL family of ABA receptors, with which the PP2C proteins interact. Our results from chromatin immunoprecipitation and gene expression analyses demonstrate that ATHB7 and ATHB12 act as positive transcriptional regulators of PP2C genes, and thereby as negative regulators of abscisic acid signalling. In support of this notion, our results also show that ATHB7 and ATHB12 act to repress the transcription of genes encoding the ABA receptors PYL5 and PYL8 in response to an ABA stimulus. In summary, we demonstrate that ATHB7 and ATHB12 have essential functions in the primary response to drought, as mediators of a negative feedback effect on ABA signalling in the plant response to water deficit.

The plastidial retrograde signal methyl erythritol cyclopyrophosphate is a regulator of salicylic acid and jasmonic acid crosstalk.

PubMed

Lemos, Mark; Xiao, Yanmei; Bjornson, Marta; Wang, Jin-Zheng; Hicks, Derrick; Souza, Amancio de; Wang, Chang-Quan; Yang, Panyu; Ma, Shisong; Dinesh-Kumar, Savithramma; Dehesh, Katayoon

2016-03-01

The exquisite harmony between hormones and their corresponding signaling pathways is central to prioritizing plant responses to simultaneous and/or successive environmental trepidations. The crosstalk between jasmonic acid (JA) and salicylic acid (SA) is an established effective mechanism that optimizes and tailors plant adaptive responses. However, the underlying regulatory modules of this crosstalk are largely unknown. Global transcriptomic analyses of mutant plants (ceh1) with elevated levels of the stress-induced plastidial retrograde signaling metabolite 2-C-methyl-D-erythritol cyclopyrophosphate (MEcPP) revealed robustly induced JA marker genes, expected to be suppressed by the presence of constitutively high SA levels in the mutant background. Analyses of a range of genotypes with varying SA and MEcPP levels established the selective role of MEcPP-mediated signal(s) in induction of JA-responsive genes in the presence of elevated SA. Metabolic profiling revealed the presence of high levels of the JA precursor 12-oxo-phytodienoic acid (OPDA), but near wild type levels of JA in the ceh1 mutant plants. Analyses of coronatine-insensitive 1 (coi1)/ceh1 double mutant plants confirmed that the MEcPP-mediated induction is JA receptor COI1 dependent, potentially through elevated OPDA. These findings identify MEcPP as a previously unrecognized central regulatory module that induces JA-responsive genes in the presence of high SA, thereby staging a multifaceted plant response within the environmental context. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

A MAP4 kinase related to Ste20 is a nutrient-sensitive regulator of mTOR signalling

PubMed Central

Findlay, Greg M.; Yan, Lijun; Procter, Julia; Mieulet, Virginie; Lamb, Richard F.

2007-01-01

The mTOR (mammalian target of rapamycin) signalling pathway is a key regulator of cell growth and is controlled by growth factors and nutrients such as amino acids. Although signalling pathways from growth factor receptors to mTOR have been elucidated, the pathways mediating signalling by nutrients are poorly characterized. Through a screen for protein kinases active in the mTOR signalling pathway in Drosophila we have identified a Ste20 family member (MAP4K3) that is required for maximal S6K (S6 kinase)/4E-BP1 [eIF4E (eukaryotic initiation factor 4E)-binding protein 1] phosphorylation and regulates cell growth. Importantly, MAP4K3 activity is regulated by amino acids, but not the growth factor insulin and is not regulated by the mTORC1 inhibitor rapamycin. Our results therefore suggest a model whereby nutrients signal to mTORC1 via activation of MAP4K3. PMID:17253963

Regulation of Hippo signalling by p38 signalling.

PubMed

Huang, Dashun; Li, Xiaojiao; Sun, Li; Huang, Ping; Ying, Hao; Wang, Hui; Wu, Jiarui; Song, Haiyun

2016-08-01

The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

Phosphatidic acid regulates signal output by G protein coupled receptors through direct interaction with phospholipase C-beta(1).

PubMed

Litosch, Irene; Pujari, Rajeshree; Lee, Shawn J

2009-09-01

Phosphatidic acid (PA), generated downstream of monomeric Rho GTPases via phospholipase D (PLD) and additionally by diacylglycerol kinases (DGK), both stimulates phospholipase C-beta(1) (PLC-beta(1)) and potentiates stimulation of PLC-beta(1) activity by Galpha(q) in vitro. PA is a potential candidate for integrating signaling by monomeric and heterotrimeric G proteins to regulate signal output by G protein coupled receptors (GPCR), and we have sought to understand the mechanisms involved. We previously identified the region spanning residues 944-957, lying within the PLC-beta(1) C-terminus alphaA helix and flexible loop of the Galpha(q) binding domain, as required for stimulation of lipase activity by PA in vitro. Regulation by PA does not require residues essential for stimulation by Galpha(q) or GTPase activating activity. The present studies evaluated shorter alanine/glycine replacement mutants and finally point mutations to identify Tyr(952) and Ile(955) as key determinants for regulation by PA, assessed by both in vitro enzymatic and cell-based co-transfection assays. Replacement of Tyr(952) and Ile(955), PLC-beta(1) (Y952G/I955G), results in an 85% loss in stimulation by PA relative to WT-PLC-beta(1) in vitro. COS 7 cells co-transfected with PLC-beta(1) (Y952G/I955G) demonstrate a 10-fold increase in the EC(50) for stimulation and a 60% decrease in maximum stimulation by carbachol via Galpha(q) linked m1 muscarinic receptors, relative to cells co-transfected with WT-PLC-beta(1) but otherwise similar conditions. Residues required for regulation by PA are not essential for stimulation by G protein subunits. WT-PLC-beta(1) and PLC-beta(1) (Y952G/I955G) activity is increased comparably by co-transfection with Galpha(q) and neither is markedly affected by co-transfection with Gbeta(1)gamma(2). Inhibiting PLD-generated PA production by 1-butanol has little effect on maximum stimulation, but shifts the EC(50) for agonist stimulation of WT-PLC-beta(1) by 10-fold

AtWRKY22 promotes susceptibility to aphids and modulates salicylic acid and jasmonic acid signalling

PubMed Central

Kloth, Karen J.; Wiegers, Gerrie L.; Busscher-Lange, Jacqueline; van Haarst, Jan C.; Kruijer, Willem; Bouwmeester, Harro J.; Dicke, Marcel; Jongsma, Maarten A.

2016-01-01

Aphids induce many transcriptional perturbations in their host plants, but the signalling cascades responsible and the effects on plant resistance are largely unknown. Through a genome-wide association (GWA) mapping study in Arabidopsis thaliana, we identified WRKY22 as a candidate gene associated with feeding behaviour of the green peach aphid, Myzus persicae. The transcription factor WRKY22 is known to be involved in pathogen-triggered immunity, and WRKY22 gene expression has been shown to be induced by aphids. Assessment of aphid population development and feeding behaviour on knockout mutants and overexpression lines showed that WRKY22 increases susceptibility to M. persicae via a mesophyll-located mechanism. mRNA sequencing analysis of aphid-infested wrky22 knockout plants revealed the up-regulation of genes involved in salicylic acid (SA) signalling and down-regulation of genes involved in plant growth and cell-wall loosening. In addition, mechanostimulation of knockout plants by clip cages up-regulated jasmonic acid (JA)-responsive genes, resulting in substantial negative JA–SA crosstalk. Based on this and previous studies, WRKY22 is considered to modulate the interplay between the SA and JA pathways in response to a wide range of biotic and abiotic stimuli. Its induction by aphids and its role in suppressing SA and JA signalling make WRKY22 a potential target for aphids to manipulate host plant defences. PMID:27107291

A negative regulator encoded by a rice WRKY gene represses both abscisic acid and gibberellins signaling in aleurone cells.

PubMed

Zhang, Zhong-Lin; Shin, Margaret; Zou, Xiaolu; Huang, Jianzhi; Ho, Tun-hua David; Shen, Qingxi J

2009-05-01

Abscisic acid (ABA) and gibberellins (GAs) control several developmental processes including seed maturation, dormancy, and germination. The antagonism of these two hormones is well-documented. However, recent data from transcription profiling studies indicate that they can function as agonists in regulating the expression of many genes although the underlying mechanism is unclear. Here we report a rice WRKY gene, OsWRKY24, which encodes a protein that functions as a negative regulator of both GA and ABA signaling. Overexpression of OsWRKY24 via particle bombardment-mediated transient expression in aleurone cells represses the expression of two reporter constructs: the beta-glucuronidase gene driven by the GA-inducible Amy32b alpha-amylase promoter (Amy32b-GUS) and the ABA-inducible HVA22 promoter (HVA22-GUS). OsWRKY24 is unlikely a general repressor because it has little effect on the expression of the luciferase reporter gene driven by a constitutive ubiquitin promoter (UBI-Luciferase). As to the GA signaling, OsWRKY24 differs from OsWRKY51 and -71, two negative regulators specifically function in the GA signaling pathway, in several ways. First, OsWRKY24 contains two WRKY domains while OsWRKY51 and -71 have only one; both WRKY domains are essential for the full repressing activity of OsWRKY24. Second, binding of OsWRKY24 to the Amy32b promoter appears to involve sequences in addition to the TGAC cores of the W-boxes. Third, unlike OsWRKY71, OsWRKY24 is stable upon GA treatment. Together, these data demonstrate that OsWRKY24 is a novel type of transcriptional repressor that inhibits both GA and ABA signaling.

Negative regulators of the RIG-I-like receptor signaling pathway

PubMed Central

Quicke, Kendra M.; Diamond, Michael S.; Suthar, Mehul S.

2017-01-01

SUMMARY Upon recognition of specific molecular patterns on viruses, bacteria and fungi, host cells trigger an innate immune response, which culminates in the production of type I interferons (IFN), pro-inflammatory cytokines and chemokines, and restricts pathogen replication and spread within the host. At each stage of the immune response, there are stimulatory and inhibitory signals that regulate the magnitude, quality, and character of the response. Positive regulation promotes an antiviral state to control and eventually clear infection whereas negative regulation dampens inflammation and prevents immune-mediated tissue damage. An over-exuberant innate immune response can lead to the destruction of cells and tissues, and the development of spontaneous autoimmunity. The RIG-I-like receptors (RLRs) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) belong to a family of cytosolic host RNA helicases that recognize distinct non-self RNA signatures and trigger innate immune responses against several RNA virus infections. The RLR signaling pathway is tightly regulated to achieve a well-orchestrated response aimed at maximizing antiviral immunity and minimizing immune-mediated pathology. This review highlights contemporary findings on negative regulators of the RLR signaling pathway, with specific focus on the proteins and biological processes that directly regulate RIG-I, MDA5 and MAVS function. PMID:28295214

Ethylene signaling triggered by low concentrations of ascorbic acid regulates biomass accumulation in Arabidopsis thaliana.

PubMed

Caviglia, M; Mazorra Morales, L M; Concellón, A; Gergoff Grozeff, G E; Wilson, M; Foyer, C H; Bartoli, C G

2018-02-02

Ascorbic acid (AA) is a major redox buffer in plant cells. The role of ethylene in the redox signaling pathways that influence photosynthesis and growth was explored in two independent AA deficient Arabidopsis thaliana mutants (vtc2-1 and vtc2-4). Both mutants, which are defective in the AA biosynthesis gene GDP-L-galactose phosphorylase, produce higher amounts of ethylene than wt plants. In contrast to the wt, the inhibition of ethylene signaling increased leaf conductance, photosynthesis and dry weight in both vtc2 mutant lines. The AA-deficient mutants showed altered expression of genes encoding proteins involved in the synthesis/responses to phytohormones that control growth, particularly auxin, cytokinins, abscisic acid, brassinosterioids, ethylene and salicylic acid. These results demonstrate that AA deficiency modifies hormone signaling in plants, redox-ethylene interactions providing a regulatory node controlling shoot biomass accumulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling

PubMed Central

Norris, Megan L; Pauli, Andrea; Gagnon, James A; Lord, Nathan D; Rogers, Katherine W; Mosimann, Christian; Zon, Leonard I

2017-01-01

Toddler/Apela/Elabela is a conserved secreted peptide that regulates mesendoderm development during zebrafish gastrulation. Two non-exclusive models have been proposed to explain Toddler function. The ‘specification model’ postulates that Toddler signaling enhances Nodal signaling to properly specify endoderm, whereas the ‘migration model’ posits that Toddler signaling regulates mesendodermal cell migration downstream of Nodal signaling. Here, we test key predictions of both models. We find that in toddler mutants Nodal signaling is initially normal and increasing endoderm specification does not rescue mesendodermal cell migration. Mesodermal cell migration defects in toddler mutants result from a decrease in animal pole-directed migration and are independent of endoderm. Conversely, endodermal cell migration defects are dependent on a Cxcr4a-regulated tether of the endoderm to mesoderm. These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling. PMID:29117894

Bile Acid Signaling in Metabolic Disease and Drug Therapy

PubMed Central

Li, Tiangang

2014-01-01

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

Cell Identity Switching Regulated by Retinoic Acid Signaling Maintains Homogeneous Segments in the Hindbrain.

PubMed

Addison, Megan; Xu, Qiling; Cayuso, Jordi; Wilkinson, David G

2018-06-04

The patterning of tissues to form subdivisions with distinct and homogeneous regional identity is potentially disrupted by cell intermingling. Transplantation studies suggest that homogeneous segmental identity in the hindbrain is maintained by identity switching of cells that intermingle into another segment. We show that switching occurs during normal development and is mediated by feedback between segment identity and the retinoic acid degrading enzymes, cyp26b1 and cyp26c1. egr2, which specifies the segmental identity of rhombomeres r3 and r5, underlies the lower expression level of cyp26b1 and cyp26c1 in r3 and r5 compared with r2, r4, and r6. Consequently, r3 or r5 cells that intermingle into adjacent segments encounter cells with higher cyp26b1/c1 expression, which we find is required for downregulation of egr2b expression. Furthermore, egr2b expression is regulated in r2, r4, and r6 by non-autonomous mechanisms that depend upon the number of neighbors that express egr2b. These findings reveal that a community regulation of retinoid signaling maintains homogeneous segmental identity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Metabolic regulation of manganese superoxide dismutase expression via essential amino acid deprivation.

PubMed

Aiken, Kimberly J; Bickford, Justin S; Kilberg, Michael S; Nick, Harry S

2008-04-18

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging.

Karrikins: Regulators Involved in Phytohormone Signaling Networks during Seed Germination and Seedling Development

PubMed Central

Meng, Yongjie; Shuai, Haiwei; Luo, Xiaofeng; Chen, Feng; Zhou, Wenguan; Yang, Wenyu; Shu, Kai

2017-01-01

Seed germination and early seedling establishment are critical stages during a plant’s life cycle. These stages are precisely regulated by multiple internal factors, including phytohormones and environmental cues such as light. As a family of small molecules discovered in wildfire smoke, karrikins (KARs) play a key role in various biological processes, including seed dormancy release, germination regulation, and seedling establishment. KARs show a high similarity with strigolactone (SL) in both chemical structure and signaling transduction pathways. Current evidence shows that KARs may regulate seed germination by mediating the biosynthesis and/or signaling transduction of abscisic acid (ABA), gibberellin (GA) and auxin [indoleacetic acid (IAA)]. Interestingly, KARs regulate seed germination differently in different species. Furthermore, the promotion effect on seedling establishment implies that KARs have a great potential application in alleviating shade avoidance response, which attracts more and more attention in plant molecular biology. In these processes, KARs may have complicated interactions with phytohormones, especially with IAA. In this updated review, we summarize the current understanding of the relationship between KARs and SL in the chemical structure, signaling pathway and the regulation of plant growth and development. Further, the crosstalk between KARs and phytohormones in regulating seed germination and seedling development and that between KARs and IAA during shade responses are discussed. Finally, future challenges and research directions for the KAR research field are suggested. PMID:28174573

Retinoic Acid Signaling Affects Cortical Synchrony During Sleep

NASA Astrophysics Data System (ADS)

Maret, Stéphanie; Franken, Paul; Dauvilliers, Yves; Ghyselinck, Norbert B.; Chambon, Pierre; Tafti, Mehdi

2005-10-01

Delta oscillations, characteristic of the electroencephalogram (EEG) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remain elusive. Here we demonstrate in the mouse that the gene encoding the retinoic acid receptor beta determines the contribution of delta oscillations to the sleep EEG. Thus, retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult.

Jasmonic acid signaling modulates ozone-induced hypersensitive cell death.

PubMed

Rao, M V; Lee, H; Creelman, R A; Mullet, J E; Davis, K R

2000-09-01

Recent studies suggest that cross-talk between salicylic acid (SA)-, jasmonic acid (JA)-, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O(3)) exposure activates a hypersensitive response (HR)-like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O(3)-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O(3)-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O(3)-induced H(2)O(2) content and SA concentrations and completely abolished O(3)-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O(3) exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O(3) of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O(3)-induced HR-like cell death.

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy.

PubMed

Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

2017-03-16

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5' adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

Ferulic acid attenuates the down-regulation of MEK/ERK/p90RSK signaling pathway in focal cerebral ischemic injury.

PubMed

Koh, Phil-Ok

2015-02-19

Ferulic acid provides neuroprotective effects against a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia. Mitogen-activated protein kinases can regulate extensive intracellular processes including cell differentiation, growth, and death. This study further investigated whether ferulic acid modulates a protective mechanism through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad during cerebral ischemic injury. Male Sprague-Dawley rats were treated with ferulic acid (100mg/kg) or vehicle after the onset of MCAO and brain tissues were collected 24h after MCAO. These results indicated that ferulic acid decreases the volume of the infarct area and the number of cells positive in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Although MCAO injury induces a decrease in the phosphorylation of Raf-1, MEK1/2, and ERK1/2, ferulic acid treatment prevents the injury-induced decrease in these phosphorylation levels. Ferulic acid also attenuates the injury-induced decrease in p90RSK and Bad phosphorylation levels. These findings suggest that ferulic acid prevents MCAO-induced neuronal cell death and that the MEK-ERK-p90RSK-Bad signaling pathway is involved in these neuroprotective effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Key mediators of intracellular amino acids signaling to mTORC1 activation.

PubMed

Duan, Yehui; Li, Fengna; Tan, Kunrong; Liu, Hongnan; Li, Yinghui; Liu, Yingying; Kong, Xiangfeng; Tang, Yulong; Wu, Guoyao; Yin, Yulong

2015-05-01

Mammalian target of rapamycin complex 1 (mTORC1) is activated by amino acids to promote cell growth via protein synthesis. Specifically, Ras-related guanosine triphosphatases (Rag GTPases) are activated by amino acids, and then translocate mTORC1 to the surface of late endosomes and lysosomes. Ras homolog enriched in brain (Rheb) resides on this surface and directly activates mTORC1. Apart from the presence of intracellular amino acids, Rag GTPases and Rheb, other mediators involved in intracellular amino acid signaling to mTORC1 activation include human vacuolar sorting protein-34 (hVps34) and mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3). Those molecular links between mTORC1 and its mediators form a complicate signaling network that controls cellular growth, proliferation, and metabolism. Moreover, it is speculated that amino acid signaling to mTORC1 may start from the lysosomal lumen. In this review, we discussed the function of these mediators in mTORC1 pathway and how these mediators are regulated by amino acids in details.

AtWRKY22 promotes susceptibility to aphids and modulates salicylic acid and jasmonic acid signalling.

PubMed

Kloth, Karen J; Wiegers, Gerrie L; Busscher-Lange, Jacqueline; van Haarst, Jan C; Kruijer, Willem; Bouwmeester, Harro J; Dicke, Marcel; Jongsma, Maarten A

2016-05-01

Aphids induce many transcriptional perturbations in their host plants, but the signalling cascades responsible and the effects on plant resistance are largely unknown. Through a genome-wide association (GWA) mapping study in Arabidopsis thaliana, we identified WRKY22 as a candidate gene associated with feeding behaviour of the green peach aphid, Myzus persicae The transcription factor WRKY22 is known to be involved in pathogen-triggered immunity, and WRKY22 gene expression has been shown to be induced by aphids. Assessment of aphid population development and feeding behaviour on knockout mutants and overexpression lines showed that WRKY22 increases susceptibility to M. persicae via a mesophyll-located mechanism. mRNA sequencing analysis of aphid-infested wrky22 knockout plants revealed the up-regulation of genes involved in salicylic acid (SA) signalling and down-regulation of genes involved in plant growth and cell-wall loosening. In addition, mechanostimulation of knockout plants by clip cages up-regulated jasmonic acid (JA)-responsive genes, resulting in substantial negative JA-SA crosstalk. Based on this and previous studies, WRKY22 is considered to modulate the interplay between the SA and JA pathways in response to a wide range of biotic and abiotic stimuli. Its induction by aphids and its role in suppressing SA and JA signalling make WRKY22 a potential target for aphids to manipulate host plant defences. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Fibroblast growth factor (Fgf) signaling pathway regulates liver homeostasis in zebrafish.

PubMed

Tsai, Su-Mei; Liu, Da-Wei; Wang, Wen-Pin

2013-04-01

In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. FGF signaling also promotes hepatocyte proliferation, and helps detoxify hepatotoxin during liver regeneration after partial hepatectomy. However, the function of Fgf in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. The current study analyzed the expression of fgf receptors (fgfrs) in the liver of zebrafish. We then investigated the function of Fgf signaling in the zebrafish liver by expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). Histological analysis showed that our genetic intervention resulted in a small liver size with defected medial expansion of developing livers in transgenic (Tg) larvae. Morphologically, the liver lobe of lf:dnfr adult fish was shorter than that of control. Ballooning degeneration of hepatocytes was observed in fish as young as 3 months. Further examination revealed the development of hepatic steatosis and cholestasis. In adult Tg fish, we unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Considering all these findings, we concluded that as in mammals, in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling. Disruption of the Fgf signal-mediated metabolism might indirectly affect hepatocyte proliferation.

Plasmodesmata localizing proteins regulate transport and signaling during systemic acquired immunity in plants

USDA-ARS?s Scientific Manuscript database

Systemic acquired resistance (SAR) in plants is mediated by the signaling molecules azelaic acid (AzA),glycerol-3-phosphate (G3P), and salicylic acid (SA).Here, we show that AzA and G3P transport occurs via the symplastic route, which is regulated by channels known as plasmodesmata (PD). In contrast...

A chloroplast retrograde signal, 3'-phosphoadenosine 5'-phosphate, acts as a secondary messenger in abscisic acid signaling in stomatal closure and germination.

PubMed

Pornsiriwong, Wannarat; Estavillo, Gonzalo M; Chan, Kai Xun; Tee, Estee E; Ganguly, Diep; Crisp, Peter A; Phua, Su Yin; Zhao, Chenchen; Qiu, Jiaen; Park, Jiyoung; Yong, Miing Tiem; Nisar, Nazia; Yadav, Arun Kumar; Schwessinger, Benjamin; Rathjen, John; Cazzonelli, Christopher I; Wilson, Philippa B; Gilliham, Matthew; Chen, Zhong-Hua; Pogson, Barry J

2017-03-21

Organelle-nuclear retrograde signaling regulates gene expression, but its roles in specialized cells and integration with hormonal signaling remain enigmatic. Here we show that the SAL1-PAP (3'-phosphoadenosine 5'- phosphate) retrograde pathway interacts with abscisic acid (ABA) signaling to regulate stomatal closure and seed germination in Arabidopsis . Genetically or exogenously manipulating PAP bypasses the canonical signaling components ABA Insensitive 1 (ABI1) and Open Stomata 1 (OST1); priming an alternative pathway that restores ABA-responsive gene expression, ROS bursts, ion channel function, stomatal closure and drought tolerance in ost1 -2. PAP also inhibits wild type and abi1 -1 seed germination by enhancing ABA sensitivity. PAP-XRN signaling interacts with ABA, ROS and Ca 2+ ; up-regulating multiple ABA signaling components, including lowly-expressed Calcium Dependent Protein Kinases (CDPKs) capable of activating the anion channel SLAC1. Thus, PAP exhibits many secondary messenger attributes and exemplifies how retrograde signals can have broader roles in hormone signaling, allowing chloroplasts to fine-tune physiological responses.

The Arabidopsis Mitochondrial Protease FtSH4 Is Involved in Leaf Senescence via Regulation of WRKY-Dependent Salicylic Acid Accumulation and Signaling.

PubMed

Zhang, Shengchun; Li, Cui; Wang, Rui; Chen, Yaxue; Shu, Si; Huang, Ruihua; Zhang, Daowei; Li, Jian; Xiao, Shi; Yao, Nan; Yang, Chengwei

2017-04-01

Mitochondria and autophagy play important roles in the networks that regulate plant leaf senescence and cell death. However, the molecular mechanisms underlying the interactions between mitochondrial signaling and autophagy are currently not well understood. This study characterized the function of the Arabidopsis ( Arabidopsis thaliana ) mitochondrial AAA-protease gene FtSH4 in regulating autophagy and senescence, finding that FtSH4 mediates WRKY-dependent salicylic acid (SA) accumulation and signaling. Knockout of FtSH4 in the ftsh4-4 mutant resulted in severe leaf senescence, cell death, and high autophagy levels. The level of SA increased dramatically in the ftsh4-4 mutant. Expression of nahG in the ftsh4-4 mutant led to decreased SA levels and suppressed the leaf senescence and cell death phenotypes. The transcript levels of several SA synthesis and signaling genes, including SALICYLIC ACID INDUCTION DEFICIENT2 ( SID2 ), NON-RACE-SPECIFIC DISEASE RESISTANCE1 ( NDR1 ), and NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 ( NPR1 ), increased significantly in the ftsh4-4 mutants compared with the wild type. Loss of function of SID2 , NDR1 , or NPR1 in the ftsh4-4 mutant reversed the ftsh4-4 senescence and autophagy phenotypes. Furthermore, ftsh4-4 mutants had elevated levels of transcripts of several WRKY genes, including WRKY40 , WRKY46 , WRKY51 , WRKY60 , WRKY63 , and WRKY75 ; all of these WRKY proteins can bind to the promoter of SID2 Loss of function of WRKY75 in the ftsh4-4 mutants decreased the levels of SA and reversed the senescence phenotype. Taken together, these results suggest that the mitochondrial ATP-dependent protease FtSH4 may regulate the expression of WRKY genes by modifying the level of reactive oxygen species and the WRKY transcription factors that control SA synthesis and signaling in autophagy and senescence. © 2017 American Society of Plant Biologists. All Rights Reserved.

Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue

PubMed Central

Landrier, Jean-Francois; Kasiri, Elnaz; Karkeni, Esma; Mihály, Johanna; Béke, Gabriella; Weiss, Kathrin; Lucas, Renata; Aydemir, Gamze; Salles, Jérome; Walrand, Stéphane; de Lera, Angel R.; Rühl, Ralph

2017-01-01

Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue. PMID:27729412

Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation*

PubMed Central

Aiken, Kimberly J.; Bickford, Justin S.; Kilberg, Michael S.; Nick, Harry S.

2008-01-01

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging. PMID:18187411

Analysis of a developmentally regulated nuclear localization signal in Xenopus

PubMed Central

1992-01-01

The 289 residue nuclear oncoprotein encoded by the adenovirus 5 Ela gene contains two peptide sequences that behave as nuclear localization signals (NLS). One signal, located at the carboxy terminus, is like many other known NLSs in that it consists of a short stretch of basic residues (KRPRP) and is constitutively active in cells. The second signal resides within an internal 45 residue region of E1a that contains few basic residues or sequences that resemble other known NLSs. Moreover, this internal signal functions in injected Xenopus oocytes, but not in transfected Xenopus A6 cells, suggesting that it could be regulated developmentally (Slavicek et al. 1989. J. Virol. 63:4047). In this study, we show that the activity of this signal is sensitive to ATP depletion in vivo, efficiently directs the import of a 50 kD fusion protein and can compete with the E1a carboxy-terminal NLS for nuclear import. In addition, we have delineated the precise amino acid residues that comprise the second E1a NLS, and have assessed its utilization during Xenopus embryogenesis. Using amino acid deletion and substitution analyses, we show that the signal consists of the sequence FV(X)7-20MXSLXYM(X)4MF. By expressing in Xenopus embryos a truncated E1a protein that contains only the second NLS and by monitoring its cytoplasmic/nuclear distribution during development with indirect immunofluorescence, we find that the second NLS is utilized up to the early neurula stage. In addition, there appears to be a hierarchy among the embryonic germ layers as to when the second NLS becomes nonfunctional. For this reason, we refer to this NLS as the developmentally regulated nuclear localization signal (drNLS). The implications of these findings for early development are discussed. PMID:1387407

Dancing with Hormones: A Current Perspective of Nitrate Signaling and Regulation in Arabidopsis

PubMed Central

Guan, Peizhu

2017-01-01

In nature and agriculture, nitrate availability is a main environmental cue for plant growth, development and stress responses. Nitrate signaling and regulation are hence at the center of communications between plant intrinsic programs and the environment. It is also well known that endogenous phytohormones play numerous critical roles in integrating extrinsic cues and intrinsic responses, regulating and refining almost all aspects of plant growth, development and stress responses. Therefore, interaction between nitrate and phytohormones, such as auxins, cytokinins, abscisic acid, gibberellins, and ethylene, is prevalent. The growing evidence indicates that biosynthesis, de-conjugation, transport, and signaling of hormones are partly controlled by nitrate signaling. Recent advances with nitrate signaling and transcriptional regulation in Arabidopsis give rise to new paradigms. Given the comprehensive nitrate transport, sensing, signaling and regulations at the level of the cell and organism, nitrate itself is a local and long-distance signal molecule, conveying N status at the whole-plant level. A direct molecular link between nitrate signaling and cell cycle progression was revealed with TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1-20 (TCP20) – NIN-LIKE PROTEIN 6/7 (NLP6/7) regulatory nexus. NLPs are key regulators of nitrogen responses in plants. TCPs function as the main regulators of plant morphology and architecture, with the emerging role as integrators of plant developmental responses to the environment. By analogy with auxin being proposed as a plant morphogen, nitrate may be an environmental morphogen. The morphogen-gradient-dependent and cell-autonomous mechanisms of nitrate signaling and regulation are an integral part of cell growth and cell identification. This is especially true in root meristem growth that is regulated by intertwined nitrate, phytohormones, and glucose-TOR signaling pathways. Furthermore, the nitrate transcriptional

Jasmonic Acid Signaling Modulates Ozone-Induced Hypersensitive Cell Death

PubMed Central

Rao, Mulpuri V.; Lee, Hyung-il; Creelman, Robert A.; Mullet, John E.; Davis, Keith R.

2000-01-01

Recent studies suggest that cross-talk between salicylic acid (SA)–, jasmonic acid (JA)–, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O3) exposure activates a hypersensitive response (HR)–like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O3-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O3-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O3-induced H2O2 content and SA concentrations and completely abolished O3-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O3 exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O3 of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O3-induced HR-like cell death. PMID:11006337

Disruption of Abscisic Acid Signaling Constitutively Activates Arabidopsis Resistance to the Necrotrophic Fungus Plectosphaerella cucumerina1[W

PubMed Central

Sánchez-Vallet, Andrea; López, Gemma; Ramos, Brisa; Delgado-Cerezo, Magdalena; Riviere, Marie-Pierre; Llorente, Francisco; Fernández, Paula Virginia; Miedes, Eva; Estevez, José Manuel; Grant, Murray; Molina, Antonio

2012-01-01

Plant resistance to necrotrophic fungi is regulated by a complex set of signaling pathways that includes those mediated by the hormones salicylic acid (SA), ethylene (ET), jasmonic acid (JA), and abscisic acid (ABA). The role of ABA in plant resistance remains controversial, as positive and negative regulatory functions have been described depending on the plant-pathogen interaction analyzed. Here, we show that ABA signaling negatively regulates Arabidopsis (Arabidopsis thaliana) resistance to the necrotrophic fungus Plectosphaerella cucumerina. Arabidopsis plants impaired in ABA biosynthesis, such as the aba1-6 mutant, or in ABA signaling, like the quadruple pyr/pyl mutant (pyr1pyl1pyl2pyl4), were more resistant to P. cucumerina than wild-type plants. In contrast, the hab1-1abi1-2abi2-2 mutant impaired in three phosphatases that negatively regulate ABA signaling displayed an enhanced susceptibility phenotype to this fungus. Comparative transcriptomic analyses of aba1-6 and wild-type plants revealed that the ABA pathway negatively regulates defense genes, many of which are controlled by the SA, JA, or ET pathway. In line with these data, we found that aba1-6 resistance to P. cucumerina was partially compromised when the SA, JA, or ET pathway was disrupted in this mutant. Additionally, in the aba1-6 plants, some genes encoding cell wall-related proteins were misregulated. Fourier transform infrared spectroscopy and biochemical analyses of cell walls from aba1-6 and wild-type plants revealed significant differences in their Fourier transform infrared spectratypes and uronic acid and cellulose contents. All these data suggest that ABA signaling has a complex function in Arabidopsis basal resistance, negatively regulating SA/JA/ET-mediated resistance to necrotrophic fungi. PMID:23037505

Negative Regulation of Abscisic Acid Signaling by the Fagus sylvatica FsPP2C1 Plays A Role in Seed Dormancy Regulation and Promotion of Seed Germination1

PubMed Central

González-García, Mary Paz; Rodríguez, Dolores; Nicolás, Carlos; Rodríguez, Pedro Luis; Nicolás, Gregorio; Lorenzo, Oscar

2003-01-01

FsPP2C1 was previously isolated from beech (Fagus sylvatica) seeds as a functional protein phosphatase type-2C (PP2C) with all the conserved features of these enzymes and high homology to ABI1, ABI2, and PP2CA, PP2Cs identified as negative regulators of ABA signaling. The expression of FsPP2C1 was induced upon abscisic acid (ABA) treatment and was also up-regulated during early weeks of stratification. Furthermore, this gene was specifically expressed in ABA-treated seeds and was hardly detectable in vegetative tissues. In this report, to provide genetic evidence on FsPP2C1 function in seed dormancy and germination, we used an overexpression approach in Arabidopsis because transgenic work is not feasible in beech. Constitutive expression of FsPP2C1 under the cauliflower mosaic virus 35S promoter confers ABA insensitivity in Arabidopsis seeds and, consequently, a reduced degree of seed dormancy. Additionally, transgenic 35S:FsPP2C1 plants are able to germinate under unfavorable conditions, as inhibitory concentrations of mannitol, NaCl, or paclobutrazol. In vegetative tissues, Arabidopsis FsPP2C1 transgenic plants show ABA-resistant early root growth and diminished induction of the ABA-response genes RAB18 and KIN2, but no effect on stomatal closure regulation. Seed and vegetative phenotypes of Arabidopsis 35S:FsPP2C1 plants suggest that FsPP2C1 negatively regulates ABA signaling. The ABA inducibility of FsPP2C1 expression, together with the transcript accumulation mainly in seeds, suggest that it could play an important role modulating ABA signaling in beechnuts through a negative feedback loop. Finally, we suggest that negative regulation of ABA signaling by FsPP2C1 is a factor contributing to promote the transition from seed dormancy to germination during early weeks of stratification. PMID:12970481

Retinoic acid signaling pathways in development and diseases.

PubMed

Das, Bhaskar C; Thapa, Pritam; Karki, Radha; Das, Sasmita; Mahapatra, Sweta; Liu, Ting-Chun; Torregroza, Ingrid; Wallace, Darren P; Kambhampati, Suman; Van Veldhuizen, Peter; Verma, Amit; Ray, Swapan K; Evans, Todd

2014-01-15

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging. Copyright © 2013 Elsevier Ltd. All rights reserved.

Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

PubMed Central

Carroll, Bernadette; Maetzel, Dorothea; Maddocks, Oliver DK; Otten, Gisela; Ratcliff, Matthew; Smith, Graham R; Dunlop, Elaine A; Passos, João F; Davies, Owen R; Jaenisch, Rudolf; Tee, Andrew R; Sarkar, Sovan; Korolchuk, Viktor I

2016-01-01

The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling. DOI: http://dx.doi.org/10.7554/eLife.11058.001 PMID:26742086

The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling.

PubMed

Shang, Peng; Valapala, Mallika; Grebe, Rhonda; Hose, Stacey; Ghosh, Sayan; Bhutto, Imran A; Handa, James T; Lutty, Gerard A; Lu, Lixia; Wan, Jun; Qian, Jiang; Sergeev, Yuri; Puertollano, Rosa; Zigler, J Samuel; Xu, Guo-Tong; Sinha, Debasish

2017-04-01

The dry (nonneovascular) form of age-related macular degeneration (AMD), a leading cause of blindness in the elderly, has few, if any, treatment options at present. It is characterized by early accumulation of cellular waste products in the retinal pigmented epithelium (RPE); rejuvenating impaired lysosome function in RPE is a well-justified target for treatment. It is now clear that amino acids and vacuolar-type H + -ATPase (V-ATPase) regulate the mechanistic target of rapamycin, complex 1 (mTORC1) signaling in lysosomes. Here, we provide evidence for the first time that the amino acid transporter SLC36A4/proton-dependent amino acid transporter (PAT4) regulates the amino acid pool in the lysosomes of RPE. In Cryba1 (gene encoding βA3/A1-crystallin) KO (knockout) mice, where PAT4 and amino acid levels are increased in the RPE, the transcription factors EB (TFEB) and E3 (TFE3) are retained in the cytoplasm, even after 24 h of fasting. Consequently, genes in the coordinated lysosomal expression and regulation (CLEAR) network are not activated, and lysosomal function remains low. As these mice age, expression of RPE65 and lecithin retinol acyltransferase (LRAT), two vital visual cycle proteins, decreases in the RPE. A defective visual cycle would possibly slow down the regeneration of new photoreceptor outer segments (POS). Further, photoreceptor degeneration also becomes obvious during aging, reminiscent of human dry AMD disease. Electron microscopy shows basal laminar deposits in Bruch's membrane, a hallmark of development of AMD. For dry AMD patients, targeting PAT4/V-ATPase in the lysosomes of RPE cells may be an effective means of preventing or delaying disease progression. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Phospholipase D and phosphatidic acid in plant defence response: from protein–protein and lipid–protein interactions to hormone signalling

PubMed Central

Zhao, Jian

2015-01-01

Phospholipase Ds (PLDs) and PLD-derived phosphatidic acids (PAs) play vital roles in plant hormonal and environmental responses and various cellular dynamics. Recent studies have further expanded the functions of PLDs and PAs into plant–microbe interaction. The molecular diversities and redundant functions make PLD–PA an important signalling complex regulating lipid metabolism, cytoskeleton dynamics, vesicle trafficking, and hormonal signalling in plant defence through protein–protein and protein–lipid interactions or hormone signalling. Different PLD–PA signalling complexes and their targets have emerged as fast-growing research topics for understanding their numerous but not yet established roles in modifying pathogen perception, signal transduction, and downstream defence responses. Meanwhile, advanced lipidomics tools have allowed researchers to reveal further the mechanisms of PLD–PA signalling complexes in regulating lipid metabolism and signalling, and their impacts on jasmonic acid/oxylipins, salicylic acid, and other hormone signalling pathways that essentially mediate plant defence responses. This review attempts to summarize the progress made in spatial and temporal PLD/PA signalling as well as PLD/PA-mediated modification of plant defence. It presents an in-depth discussion on the functions and potential mechanisms of PLD–PA complexes in regulating actin filament/microtubule cytoskeleton, vesicle trafficking, and hormonal signalling, and in influencing lipid metabolism-derived metabolites as critical signalling components in plant defence responses. The discussion puts PLD–PA in a broader context in order to guide future research. PMID:25680793

WRKY transcription factors: key components in abscisic acid signalling.

PubMed

Rushton, Deena L; Tripathi, Prateek; Rabara, Roel C; Lin, Jun; Ringler, Patricia; Boken, Ashley K; Langum, Tanner J; Smidt, Lucas; Boomsma, Darius D; Emme, Nicholas J; Chen, Xianfeng; Finer, John J; Shen, Qingxi J; Rushton, Paul J

2012-01-01

WRKY transcription factors (TFs) are key regulators of many plant processes, including the responses to biotic and abiotic stresses, senescence, seed dormancy and seed germination. For over 15 years, limited evidence has been available suggesting that WRKY TFs may play roles in regulating plant responses to the phytohormone abscisic acid (ABA), notably some WRKY TFs are ABA-inducible repressors of seed germination. However, the roles of WRKY TFs in other aspects of ABA signalling, and the mechanisms involved, have remained unclear. Recent significant progress in ABA research has now placed specific WRKY TFs firmly in ABA-responsive signalling pathways, where they act at multiple levels. In Arabidopsis, WRKY TFs appear to act downstream of at least two ABA receptors: the cytoplasmic PYR/PYL/RCAR-protein phosphatase 2C-ABA complex and the chloroplast envelope-located ABAR-ABA complex. In vivo and in vitro promoter-binding studies show that the target genes for WRKY TFs that are involved in ABA signalling include well-known ABA-responsive genes such as ABF2, ABF4, ABI4, ABI5, MYB2, DREB1a, DREB2a and RAB18. Additional well-characterized stress-inducible genes such as RD29A and COR47 are also found in signalling pathways downstream of WRKY TFs. These new insights also reveal that some WRKY TFs are positive regulators of ABA-mediated stomatal closure and hence drought responses. Conversely, many WRKY TFs are negative regulators of seed germination, and controlling seed germination appears a common function of a subset of WRKY TFs in flowering plants. Taken together, these new data demonstrate that WRKY TFs are key nodes in ABA-responsive signalling networks. © 2011 The Authors. Plant Biotechnology Journal © 2011 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

GLABROUS INFLORESCENCE STEMS (GIS) is required for trichome branching through gibberellic acid signaling in Arabidopsis.

PubMed

An, Lijun; Zhou, Zhongjing; Su, Sha; Yan, An; Gan, Yinbo

2012-02-01

Cell differentiation generally corresponds to the cell cycle, typically forming a non-dividing cell with a unique differentiated morphology, and Arabidopsis trichome is an excellent model system to study all aspects of cell differentiation. Although gibberellic acid is reported to be involved in trichome branching in Arabidopsis, the mechanism for such signaling is unclear. Here, we demonstrated that GLABROUS INFLORESCENCE STEMS (GIS) is required for the control of trichome branching through gibberellic acid signaling. The phenotypes of a loss-of-function gis mutant and an overexpressor showed that GIS acted as a repressor to control trichome branching. Our results also show that GIS is not required for cell endoreduplication, and our molecular and genetic study results have shown that GIS functions downstream of the key regulator of trichome branching, STICHEL (STI), to control trichome branching through the endoreduplication-independent pathway. Furthermore, our results also suggest that GIS controls trichome branching in Arabidopsis through two different pathways and acts either upstream or downstream of the negative regulator of gibbellic acid signaling SPINDLY (SPY).

Roles of chemical signals in regulation of the adaptive responses to iron deficiency.

PubMed

Liu, Xing Xing; He, Xiao Lin; Jin, Chong Wei

2016-05-03

Iron is an essential micronutrient for plants but is not readily accessible in most calcareous soils. Although the adaptive responses of plants to iron deficiency have been well documented, the signals involved in the regulatory cascade leading to their activation are not well understood to date. Recent studies revealed that chemical compounds, including sucrose, auxin, ethylene and nitric oxide, positively regulated the Fe-deficiency-induced Fe uptake processes in a cooperative manner. Nevertheless, cytokinins, jasmonate and abscisic acid were shown to act as negative signals in transmitting the iron deficiency information. The present mini review is to briefly address the roles of chemical signals in regulation of the adaptive responses to iron deficiency based on the literatures published in recent years.

CKB1 is involved in abscisic acid and gibberellic acid signaling to regulate stress responses in Arabidopsis thaliana.

PubMed

Yuan, Congying; Ai, Jianping; Chang, Hongping; Xiao, Wenjun; Liu, Lu; Zhang, Cheng; He, Zhuang; Huang, Ji; Li, Jinyan; Guo, Xinhong

2017-05-01

Casein kinase II (CK2), an evolutionarily well-conserved Ser/Thr kinase, plays critical roles in all higher organisms including plants. CKB1 is a regulatory subunit beta of CK2. In this study, homozygous T-DNA mutants (ckb1-1 and ckb1-2) and over-expression plants (35S:CKB1-1, 35S:CKB1-2) of Arabidopsis thaliana were studied to understand the role of CKB1 in abiotic stress and gibberellic acid (GA) signaling. Histochemical staining showed that although CKB1 was expressed in all organs, it had a relatively higher expression in conducting tissues. The ckb1 mutants showed reduced sensitivity to abscisic acid (ABA) during seed germination and seedling growth. The increased stomatal aperture, leaf water loss and proline accumulation were observed in ckb1 mutants. In contrast, the ckb1 mutant had increased sensitivity to polyaluminum chloride during seed germination and hypocotyl elongation. We obtained opposite results in over-expression plants. The expression levels of a number of genes in the ABA and GA regulatory network had changed. This study demonstrates that CKB1 is an ABA signaling-related gene, which subsequently influences GA metabolism, and may play a positive role in ABA signaling.

N-3 polyunsaturated fatty acid regulation of hepatic gene transcription

PubMed Central

Jump, Donald B.

2009-01-01

Purpose of review The liver plays a central role in whole body lipid metabolism and adapts rapidly to changes in dietary fat composition. This adaption involves changes in the expression of genes involved in glycolysis, de-novo lipogenesis, fatty acid elongation, desaturation and oxidation. This review brings together metabolic and molecular studies that help explain n-3 (omega-3) polyunsaturated fatty acid regulation of hepatic gene transcription. Recent findings Dietary n-3 polyunsaturated fatty acid regulates hepatic gene expression by targeting three major transcriptional regulatory networks: peroxisome proliferator-activated receptor α, sterol regulatory element binding protein-1 and the carbohydrate regulatory element binding protein/Max-like factor X heterodimer. 22 : 6,n-3, the most prominent n-3 polyunsaturated fatty acid in tissues, is a weak activator of peroxisome proliferator-activated receptor α. Hepatic metabolism of 22 : 6,n-3, however, generates 20 : 5,n-3, a strong peroxisome proliferator-activated receptor α activator. In contrast to peroxisome proliferator-activated receptor α, 22 : 6,n-3 is the most potent fatty acid regulator of hepatic sterol regulatory element binding protein-1. 22 : 6,n-3 suppresses sterol regulatory element binding protein-1 gene expression while enhancing degradation of nuclear sterol regulatory element binding protein-1 through 26S proteasome and Erk1/2-dependent mechanisms. Both n-3 and n-6 polyunsaturated fatty acid suppress carbohydrate regulatory element binding protein and Max-like factor X nuclear abundance and interfere with glucose-regulated hepatic metabolism. Summary These studies have revealed unique mechanisms by which specific polyunsaturated fatty acids control peroxisome proliferator activated receptor α, sterol regulatory element binding protein-1 and carbohydrate regulatory element binding protein/Max-like factor X function. As such, specific metabolic and signal transduction pathways contribute

Cross regulation between mTOR signaling and O-GlcNAcylation.

PubMed

Very, Ninon; Steenackers, Agata; Dubuquoy, Caroline; Vermuse, Jeanne; Dubuquoy, Laurent; Lefebvre, Tony; El Yazidi-Belkoura, Ikram

2018-06-01

The hexosamine biosynthetic pathway (HBP) integrates glucose, amino acids, fatty acids and nucleotides metabolisms for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is the nucleotide sugar donor for O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) processes. O-GlcNAc transferase (OGT) is the enzyme which transfers the N-acetylglucosamine (O-GlcNAc) residue onto target proteins. Several studies previously showed that glucose metabolism dysregulations associated with obesity, diabetes or cancer correlated with an increase of OGT expression and global O-GlcNAcylation levels. Moreover, these diseases present an increased activation of the nutrient sensing mammalian target of rapamycin (mTOR) pathway. Other works demonstrate that mTOR regulates protein O-GlcNAcylation in cancer cells through stabilization of OGT. In this context, we studied the cross-talk between these two metabolic sensors in vivo in obese mice predisposed to diabetes and in vitro in normal and colon cancer cells. We report that levels of OGT and O-GlcNAcylation are increased in obese mice colon tissues and colon cancer cells and are associated with a higher activation of mTOR signaling. In parallel, treatments with mTOR regulators modulate OGT and O-GlcNAcylation levels in both normal and colon cancer cells. However, deregulation of O-GlcNAcylation affects mTOR signaling activation only in cancer cells. Thus, a crosstalk exists between O-GlcNAcylation and mTOR signaling in contexts of metabolism dysregulation associated to obesity or cancer.

Tannic acid modulates NFκB signaling pathway and skin inflammation in NC/Nga mice through PPARγ expression.

PubMed

Karuppagounder, Vengadeshprabhu; Arumugam, Somasundaram; Thandavarayan, Rajarajan Amirthalingam; Pitchaimani, Vigneshwaran; Sreedhar, Remya; Afrin, Rejina; Harima, Meilei; Suzuki, Hiroshi; Nomoto, Mayumi; Miyashita, Shizuka; Suzuki, Kenji; Nakamura, Masahiko; Ueno, Kazuyuki; Watanabe, Kenichi

2015-12-01

Polyphenolic compound tannic acid, which is mainly found in grapes and green tea, is a potent antioxidant with anticarcinogenic activities. In this present study, we hypothesized that tannic acid could inhibit nuclear factor (NF)κB signaling and inflammation in atopic dermatitis (AD) NC/Nga mice. We have analyzed the effects of tannic acid on dermatitis severity, histopathology and expression of inflammatory signaling proteins in house dust mite extract induced AD mouse skin. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)γ, interleukin (IL)-4) were measured by enzyme-linked immunosorbent assay. Treatment with tannic acid ameliorated the development of AD-like clinical symptoms and effectively inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells in the AD mouse skin. Serum levels of IFNγ and IL-4 were significantly down-regulated by tannic acid. Furthermore, tannic acid treatment inhibited DfE induced tumor necrosis factor (TNF)α, high mobility group protein (HMG)B1, receptor for advanced glycation end products (RAGE), extracellular signal-regulated kinase (ERK)1/2, NFκB, cyclooxygenase (COX)2, IL-1β and increased the protein expression of peroxisome proliferator-activated receptor (PPAR)γ. Taken together, our results demonstrate that, DfE induced skin inflammation might be mediated through NFκB signaling and tannic acid may be a potential therapeutic agent for AD, which may possibly act via induction of PPARγ protein. Copyright © 2015 Elsevier Ltd. All rights reserved.

Emerging roles of protein kinase CK2 in abscisic acid signaling.

PubMed

Vilela, Belmiro; Pagès, Montserrat; Riera, Marta

2015-01-01

The phytohormone abscisic acid (ABA) regulates many aspects of plant growth and development as well as responses to multiple stresses. Post-translational modifications such as phosphorylation or ubiquitination have pivotal roles in the regulation of ABA signaling. In addition to the positive regulator sucrose non-fermenting-1 related protein kinase 2 (SnRK2), the relevance of the role of other protein kinases, such as CK2, has been recently highlighted. We have recently established that CK2 phosphorylates the maize ortholog of open stomata 1 OST1, ZmOST1, suggesting a role of CK2 phosphorylation in the control of ZmOST1 protein degradation (Vilela et al., 2015). CK2 is a pleiotropic enzyme involved in multiple developmental and stress-responsive pathways. This review summarizes recent advances that taken together suggest a prominent role of protein kinase CK2 in ABA signaling and related processes.

A chloroplast retrograde signal, 3’-phosphoadenosine 5’-phosphate, acts as a secondary messenger in abscisic acid signaling in stomatal closure and germination

PubMed Central

Pornsiriwong, Wannarat; Estavillo, Gonzalo M; Chan, Kai Xun; Tee, Estee E; Ganguly, Diep; Crisp, Peter A; Phua, Su Yin; Zhao, Chenchen; Qiu, Jiaen; Park, Jiyoung; Yong, Miing Tiem; Nisar, Nazia; Yadav, Arun Kumar; Schwessinger, Benjamin; Rathjen, John; Cazzonelli, Christopher I; Wilson, Philippa B; Gilliham, Matthew; Chen, Zhong-Hua; Pogson, Barry J

2017-01-01

Organelle-nuclear retrograde signaling regulates gene expression, but its roles in specialized cells and integration with hormonal signaling remain enigmatic. Here we show that the SAL1-PAP (3′-phosphoadenosine 5′- phosphate) retrograde pathway interacts with abscisic acid (ABA) signaling to regulate stomatal closure and seed germination in Arabidopsis. Genetically or exogenously manipulating PAP bypasses the canonical signaling components ABA Insensitive 1 (ABI1) and Open Stomata 1 (OST1); priming an alternative pathway that restores ABA-responsive gene expression, ROS bursts, ion channel function, stomatal closure and drought tolerance in ost1-2. PAP also inhibits wild type and abi1-1 seed germination by enhancing ABA sensitivity. PAP-XRN signaling interacts with ABA, ROS and Ca2+; up-regulating multiple ABA signaling components, including lowly-expressed Calcium Dependent Protein Kinases (CDPKs) capable of activating the anion channel SLAC1. Thus, PAP exhibits many secondary messenger attributes and exemplifies how retrograde signals can have broader roles in hormone signaling, allowing chloroplasts to fine-tune physiological responses. DOI: http://dx.doi.org/10.7554/eLife.23361.001 PMID:28323614

Phospholipase D and phosphatidic acid in plant defence response: from protein-protein and lipid-protein interactions to hormone signalling.

PubMed

Zhao, Jian

2015-04-01

Phospholipase Ds (PLDs) and PLD-derived phosphatidic acids (PAs) play vital roles in plant hormonal and environmental responses and various cellular dynamics. Recent studies have further expanded the functions of PLDs and PAs into plant-microbe interaction. The molecular diversities and redundant functions make PLD-PA an important signalling complex regulating lipid metabolism, cytoskeleton dynamics, vesicle trafficking, and hormonal signalling in plant defence through protein-protein and protein-lipid interactions or hormone signalling. Different PLD-PA signalling complexes and their targets have emerged as fast-growing research topics for understanding their numerous but not yet established roles in modifying pathogen perception, signal transduction, and downstream defence responses. Meanwhile, advanced lipidomics tools have allowed researchers to reveal further the mechanisms of PLD-PA signalling complexes in regulating lipid metabolism and signalling, and their impacts on jasmonic acid/oxylipins, salicylic acid, and other hormone signalling pathways that essentially mediate plant defence responses. This review attempts to summarize the progress made in spatial and temporal PLD/PA signalling as well as PLD/PA-mediated modification of plant defence. It presents an in-depth discussion on the functions and potential mechanisms of PLD-PA complexes in regulating actin filament/microtubule cytoskeleton, vesicle trafficking, and hormonal signalling, and in influencing lipid metabolism-derived metabolites as critical signalling components in plant defence responses. The discussion puts PLD-PA in a broader context in order to guide future research. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

SIGNALLING THROUGH RETINOIC ACID RECEPTORS IN CARDIAC DEVELOPMENT: DOING THE RIGHT THINGS AT THE RIGHT TIMES

PubMed Central

Xavier-Neto, José; Costa, Ângela M. Sousa; Figueira, Ana Carolina M.; Caiaffa, Carlo Donato; do Amaral, Fabio Neves; Peres, Lara Maldanis Cerqueira; da Silva, Bárbara Santos Pires; Santos, Luana Nunes; Moise, Alexander R.; Castillo, Hozana Andrade

2015-01-01

Retinoic acid (RA) is a terpenoid that is synthesized from Vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinic and experimental data provide uncontested evidence for the pleiotropic roles of RA signalling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signalling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signalling is exquisitely regulated according to specific phases of cardiac development and that RA signalling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signalling by RA receptors (RARs) in early phases of heart development. PMID:25134739

Abscisic Acid and abiotic stress signaling.

PubMed

Tuteja, Narendra

2007-05-01

Abiotic stress is severe environmental stress, which impairs crop production on irrigated land worldwide. Overall, the susceptibility or tolerance to the stress in plants is a coordinated action of multiple stress responsive genes, which also cross-talk with other components of stress signal transduction pathways. Plant responses to abiotic stress can be determined by the severity of the stress and by the metabolic status of the plant. Abscisic acid (ABA) is a phytohormone critical for plant growth and development and plays an important role in integrating various stress signals and controlling downstream stress responses. Plants have to adjust ABA levels constantly in responce to changing physiological and environmental conditions. To date, the mechanisms for fine-tuning of ABA levels remain elusive. The mechanisms by which plants respond to stress include both ABA-dependent and ABA-independent processes. Various transcription factors such as DREB2A/2B, AREB1, RD22BP1 and MYC/MYB are known to regulate the ABA-responsive gene expression through interacting with their corrosponding cis-acting elements such as DRE/CRT, ABRE and MYCRS/MYBRS, respectively. Understanding these mechanisms is important to improve stress tolerance in crops plants. This article first describes the general pathway for plant stress response followed by roles of ABA and transcription factors in stress tolerance including the regulation of ABA biosynthesis.

Abscisic Acid and Abiotic Stress Signaling

PubMed Central

2007-01-01

Abiotic stress is severe environmental stress, which impairs crop production on irrigated land worldwide. Overall, the susceptibility or tolerance to the stress in plants is a coordinated action of multiple stress responsive genes, which also cross-talk with other components of stress signal transduction pathways. Plant responses to abiotic stress can be determined by the severity of the stress and by the metabolic status of the plant. Abscisic acid (ABA) is a phytohormone critical for plant growth and development and plays an important role in integrating various stress signals and controlling downstream stress responses. Plants have to adjust ABA levels constantly in responce to changing physiological and environmental conditions. To date, the mechanisms for fine-tuning of ABA levels remain elusive. The mechanisms by which plants respond to stress include both ABA-dependent and ABA-independent processes. Various transcription factors such as DREB2A/2B, AREB1, RD22BP1 and MYC/MYB are known to regulate the ABA-responsive gene expression through interacting with their corrosponding cis-acting elements such as DRE/CRT, ABRE and MYCRS/MYBRS, respectively. Understanding these mechanisms is important to improve stress tolerance in crops plants. This article first describes the general pathway for plant stress response followed by roles of ABA and transcription factors in stress tolerance including the regulation of ABA biosynthesis. PMID:19516981

Arabidopsis thaliana cdd1 mutant uncouples the constitutive activation of salicylic acid signalling from growth defects.

PubMed

Swain, Swadhin; Roy, Shweta; Shah, Jyoti; Van Wees, Saskia; Pieterse, Corné M; Nandi, Ashis K

2011-12-01

Arabidopsis genotypes with a hyperactive salicylic acid-mediated signalling pathway exhibit enhanced disease resistance, which is often coupled with growth and developmental defects, such as dwarfing and spontaneous necrotic lesions on the leaves, resulting in reduced biomass yield. In this article, we report a novel recessive mutant of Arabidopsis, cdd1 (constitutive defence without defect in growth and development1), that exhibits enhanced disease resistance associated with constitutive salicylic acid signalling, but without any observable pleiotropic phenotype. Both NPR1 (NON-EXPRESSOR OF PATHOGENESIS-RELATED GENES1)-dependent and NPR1-independent salicylic acid-regulated defence pathways are hyperactivated in cdd1 mutant plants, conferring enhanced resistance against bacterial pathogens. However, a functional NPR1 allele is required for the cdd1-conferred heightened resistance against the oomycete pathogen Hyaloperonospora arabidopsidis. Salicylic acid accumulates at elevated levels in cdd1 and cdd1 npr1 mutant plants and is necessary for cdd1-mediated PR1 expression and disease resistance phenotypes. In addition, we provide data which indicate that the cdd1 mutation negatively regulates the npr1 mutation-induced hyperactivation of ethylene/jasmonic acid signalling. © 2011 The Authors. Molecular Plant Pathology © 2011 BSPP and Blackwell Publishing Ltd.

Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation

PubMed Central

Koyama, Takashi; Mirth, Christen K.

2016-01-01

In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size. PMID:26928023

MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

PubMed Central

Seo, Minji; Lee, Seong-Ok; Kim, Ji-Hoon; Hong, Yujin; Kim, Seongchan; Kim, Yeumin; Min, Dal-Hee; Kong, Young-Yun; Shin, Jinwook; Ahn, Kwangseog

2016-01-01

The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA- and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling. Depletion of BTN3A1 inhibits the cytoplasmic nucleic acid- or virus-triggered activation of IFN-β production. In the resting state, BTN3A1 is constitutively associated with TBK1. Stimulation with nucleic acids induces the redistribution of the BTN3A1–TBK1 complex to the perinuclear region, where BTN3A1 mediates the interaction between TBK1 and IRF3, leading to the phosphorylation of IRF3. Furthermore, we show that microtubule-associated protein 4 (MAP4) controls the dynein-dependent transport of BTN3A1 in response to nucleic acid stimulation, thereby identifying MAP4 as an upstream regulator of BTN3A1. Thus, the depletion of either MAP4 or BTN3A1 impairs cytosolic DNA- or RNA-mediated type I IFN responses. Our findings demonstrate a critical role for MAP4 and BTN3A1 in the spatiotemporal regulation of TBK1, a central player in the intracellular nucleic acid-sensing pathways involved in antiviral signaling. PMID:27911820

Predicting Essential Components of Signal Transduction Networks: A Dynamic Model of Guard Cell Abscisic Acid Signaling

PubMed Central

Li, Song; Assmann, Sarah M; Albert, Réka

2006-01-01

Plants both lose water and take in carbon dioxide through microscopic stomatal pores, each of which is regulated by a surrounding pair of guard cells. During drought, the plant hormone abscisic acid (ABA) inhibits stomatal opening and promotes stomatal closure, thereby promoting water conservation. Dozens of cellular components have been identified to function in ABA regulation of guard cell volume and thus of stomatal aperture, but a dynamic description is still not available for this complex process. Here we synthesize experimental results into a consistent guard cell signal transduction network for ABA-induced stomatal closure, and develop a dynamic model of this process. Our model captures the regulation of more than 40 identified network components, and accords well with previous experimental results at both the pathway and whole-cell physiological level. By simulating gene disruptions and pharmacological interventions we find that the network is robust against a significant fraction of possible perturbations. Our analysis reveals the novel predictions that the disruption of membrane depolarizability, anion efflux, actin cytoskeleton reorganization, cytosolic pH increase, the phosphatidic acid pathway, or K+ efflux through slowly activating K+ channels at the plasma membrane lead to the strongest reduction in ABA responsiveness. Initial experimental analysis assessing ABA-induced stomatal closure in the presence of cytosolic pH clamp imposed by the weak acid butyrate is consistent with model prediction. Simulations of stomatal response as derived from our model provide an efficient tool for the identification of candidate manipulations that have the best chance of conferring increased drought stress tolerance and for the prioritization of future wet bench analyses. Our method can be readily applied to other biological signaling networks to identify key regulatory components in systems where quantitative information is limited. PMID:16968132

The regulator of G-protein signaling proteins involved in sugar and abscisic acid signaling in Arabidopsis seed germination.

PubMed

Chen, Yun; Ji, Fangfang; Xie, Hong; Liang, Jiansheng; Zhang, Jianhua

2006-01-01

The regulator of G-protein signaling (RGS) proteins, recently identified in Arabidopsis (Arabidopsis thaliana; named as AtRGS1), has a predicted seven-transmembrane structure as well as an RGS box with GTPase-accelerating activity and thus desensitizes the G-protein-mediated signaling. The roles of AtRGS1 proteins in Arabidopsis seed germination and their possible interactions with sugars and abscisic acid (ABA) were investigated in this study. Using seeds that carry a null mutation in the genes encoding RGS protein (AtRGS1) and the alpha-subunit (AtGPA1) of the G protein in Arabidopsis (named rgs1-2 and gpa1-3, respectively), our genetic evidence proved the involvement of the AtRGS1 protein in the modulation of seed germination. In contrast to wild-type Columbia-0 and gpa1-3, stratification was found not to be required and the after-ripening process had no effect on the rgs1-2 seed germination. In addition, rgs1-2 seed germination was insensitive to glucose (Glc) and sucrose. The insensitivities of rgs1-2 to Glc and sucrose were not due to a possible osmotic stress because the germination of rgs1-2 mutant seeds showed the same response as those of gpa1-3 mutants and wild type when treated with the same concentrations of mannitol and sorbitol. The gpa1-3 seed germination was hypersensitive while rgs1-2 was less sensitive to exogenous ABA. The different responses to ABA largely diminished and the inhibitory effects on seed germination by exogenous ABA and Glc were markedly alleviated when endogenous ABA biosynthesis was inhibited. Hypersensitive responses of seed germination to both Glc and ABA were also observed in the overexpressor of AtRGS1. Analysis of the active endogenous ABA levels and the expression of NCED3 and ABA2 genes showed that Glc significantly stimulated the ABA biosynthesis and increased the expression of NCED3 and ABA2 genes in germinating Columbia seeds, but not in rgs1-2 mutant seeds. These data suggest that AtRGS1 proteins are involved in the

Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus.

PubMed

Wolfrum, C; Borrmann, C M; Borchers, T; Spener, F

2001-02-27

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of lipid homeostasis in hepatocytes and target for fatty acids and hypolipidemic drugs. How these signaling molecules reach the nuclear receptor is not known; however, similarities in ligand specificity suggest the liver fatty acid binding protein (L-FABP) as a possible candidate. In localization studies using laser-scanning microscopy, we show that L-FABP and PPARalpha colocalize in the nucleus of mouse primary hepatocytes. Furthermore, we demonstrate by pull-down assay and immunocoprecipitation that L-FABP interacts directly with PPARalpha. In a cell biological approach with the aid of a mammalian two-hybrid system, we provide evidence that L-FABP interacts with PPARalpha and PPARgamma but not with PPARbeta and retinoid X receptor-alpha by protein-protein contacts. In addition, we demonstrate that the observed interaction of both proteins is independent of ligand binding. Final and quantitative proof for L-FABP mediation was obtained in transactivation assays upon incubation of transiently and stably transfected HepG2 cells with saturated, monounsaturated, and polyunsaturated fatty acids as well as with hypolipidemic drugs. With all ligands applied, we observed strict correlation of PPARalpha and PPARgamma transactivation with intracellular concentrations of L-FABP. This correlation constitutes a nucleus-directed signaling by fatty acids and hypolipidemic drugs where L-FABP acts as a cytosolic gateway for these PPARalpha and PPARgamma agonists. Thus, L-FABP and the respective PPARs could serve as targets for nutrients and drugs to affect expression of PPAR-sensitive genes.

The SAL-PAP Chloroplast Retrograde Pathway Contributes to Plant Immunity by Regulating Glucosinolate Pathway and Phytohormone Signaling.

PubMed

Ishiga, Yasuhiro; Watanabe, Mutsumi; Ishiga, Takako; Tohge, Takayuki; Matsuura, Takakazu; Ikeda, Yoko; Hoefgen, Rainer; Fernie, Alisdair R; Mysore, Kirankumar S

2017-10-01

Chloroplasts have a crucial role in plant immunity against pathogens. Increasing evidence suggests that phytopathogens target chloroplast homeostasis as a pathogenicity mechanism. In order to regulate the performance of chloroplasts under stress conditions, chloroplasts produce retrograde signals to alter nuclear gene expression. Many signals for the chloroplast retrograde pathway have been identified, including chlorophyll intermediates, reactive oxygen species, and metabolic retrograde signals. Although there is a reasonably good understanding of chloroplast retrograde signaling in plant immunity, some signals are not well-understood. In order to understand the role of chloroplast retrograde signaling in plant immunity, we investigated Arabidopsis chloroplast retrograde signaling mutants in response to pathogen inoculation. sal1 mutants (fry1-2 and alx8) responsible for the SAL1-PAP retrograde signaling pathway showed enhanced disease symptoms not only to the hemibiotrophic pathogen Pseudomonas syringae pv. tomato DC3000 but, also, to the necrotrophic pathogen Pectobacterium carotovorum subsp. carotovorum EC1. Glucosinolate profiles demonstrated the reduced accumulation of aliphatic glucosinolates in the fry1-2 and alx8 mutants compared with the wild-type Col-0 in response to DC3000 infection. In addition, quantification of multiple phytohormones and analyses of their gene expression profiles revealed that both the salicylic acid (SA)- and jasmonic acid (JA)-mediated signaling pathways were down-regulated in the fry1-2 and alx8 mutants. These results suggest that the SAL1-PAP chloroplast retrograde pathway is involved in plant immunity by regulating the SA- and JA-mediated signaling pathways.

Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling.

PubMed

Xu, Enjun; Brosché, Mikael

2014-06-04

Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling.

Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling

PubMed Central

2014-01-01

Background Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. Results In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Conclusions Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling. PMID:24898702

Wnt signaling regulates pancreatic β cell proliferation

PubMed Central

Rulifson, Ingrid C.; Karnik, Satyajit K.; Heiser, Patrick W.; ten Berge, Derk; Chen, Hainan; Gu, Xueying; Taketo, Makoto M.; Nusse, Roel; Hebrok, Matthias; Kim, Seung K.

2007-01-01

There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt signaling regulates pancreatic islet proliferation and differentiation. Here we provide evidence that Wnt signaling stimulates islet β cell proliferation. The addition of purified Wnt3a protein to cultured β cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of β cell cycle progression, and led to increased β cell proliferation in vitro. Conditional pancreatic β cell expression of activated β-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to β cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional β cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by β cells, resulting in reduced neonatal β cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet β cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function. PMID:17404238

Regulation of protein synthesis by amino acids in muscle of neonates

PubMed Central

Suryawan, Agus; Davis, Teresa A.

2011-01-01

The marked increase in skeletal muscle mass during the neonatal period is largely due to a high rate of postprandial protein synthesis that is modulated by an enhanced sensitivity to insulin and amino acids. The amino acid signaling pathway leading to the stimulation of protein synthesis has not been fully elucidated. Among the amino acids, leucine is considered to be a principal anabolic agent that regulates protein synthesis. mTORC1, which controls protein synthesis, has been implicated as a target for leucine. Until recently, there have been few studies exploring the role of amino acids in enhancing muscle protein synthesis in vivo. In this review, we discuss amino acid-induced protein synthesis in muscle in the neonate, focusing on current knowledge of the role of amino acids in the activation of mTORC1 leading to mRNA translation. The role of the amino acid transporters, SNAT2, LAT1, and PAT, in the modulation of mTORC1 activation and the role of amino acids in the activation of putative regulators of mTORC1, i.e., raptor, Rheb, MAP4K3, Vps34, and Rag GTPases, are discussed. PMID:21196241

Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis.

PubMed

Cañete, Ana; Cano, Elena; Muñoz-Chápuli, Ramón; Carmona, Rita

2017-02-20

Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.

Negative regulation of RIG-I-mediated antiviral signaling by TRK-fused gene (TFG) protein

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

Lee, Na-Rae; Shin, Han-Bo; Kim, Hye-In

2013-07-19

Highlights: •TRK-fused gene product (TFG) interacts with TRIM25 upon viral infection. •TFG negatively regulates RIG-I mediated antiviral signaling. •TFG depletion leads to enhanced viral replication. •TFG act downstream of MAVS. -- Abstract: RIG-I (retinoic acid inducible gene I)-mediated antiviral signaling serves as the first line of defense against viral infection. Upon detection of viral RNA, RIG-I undergoes TRIM25 (tripartite motif protein 25)-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that TRK-fused gene (TFG) protein, previously identified as a TRIM25-interacting protein, binds TRIM25 upon virus infection and negatively regulates RIG-I-mediated type-I IFN signaling. RIG-I-mediatedmore » IFN production and nuclear factor (NF)-κB signaling pathways were upregulated by the suppression of TFG expression. Furthermore, vesicular stomatitis virus (VSV) replication was significantly inhibited by small inhibitory hairpin RNA (shRNA)-mediated knockdown of TFG, supporting the suppressive role of TFG in RIG-I-mediated antiviral signaling. Interestingly, suppression of TFG expression increased not only RIG-I-mediated signaling but also MAVS (mitochondrial antiviral signaling protein)-induced signaling, suggesting that TFG plays a pivotal role in negative regulation of RNA-sensing, RIG-I-like receptor (RLR) family signaling pathways.« less

Integration of the tricarboxylic acid (TCA) cycle with cAMP signaling and Sfl2 pathways in the regulation of CO2 sensing and hyphal development in Candida albicans

PubMed Central

Tao, Li; Zhang, Yulong; Fan, Shuru; Nobile, Clarissa J.; Guan, Guobo; Huang, Guanghua

2017-01-01

Morphological transitions and metabolic regulation are critical for the human fungal pathogen Candida albicans to adapt to the changing host environment. In this study, we generated a library of central metabolic pathway mutants in the tricarboxylic acid (TCA) cycle, and investigated the functional consequences of these gene deletions on C. albicans biology. Inactivation of the TCA cycle impairs the ability of C. albicans to utilize non-fermentable carbon sources and dramatically attenuates cell growth rates under several culture conditions. By integrating the Ras1-cAMP signaling pathway and the heat shock factor-type transcription regulator Sfl2, we found that the TCA cycle plays fundamental roles in the regulation of CO2 sensing and hyphal development. The TCA cycle and cAMP signaling pathways coordinately regulate hyphal growth through the molecular linkers ATP and CO2. Inactivation of the TCA cycle leads to lowered intracellular ATP and cAMP levels and thus affects the activation of the Ras1-regulated cAMP signaling pathway. In turn, the Ras1-cAMP signaling pathway controls the TCA cycle through both Efg1- and Sfl2-mediated transcriptional regulation in response to elevated CO2 levels. The protein kinase A (PKA) catalytic subunit Tpk1, but not Tpk2, may play a major role in this regulation. Sfl2 specifically binds to several TCA cycle and hypha-associated genes under high CO2 conditions. Global transcriptional profiling experiments indicate that Sfl2 is indeed required for the gene expression changes occurring in response to these elevated CO2 levels. Our study reveals the regulatory role of the TCA cycle in CO2 sensing and hyphal development and establishes a novel link between the TCA cycle and Ras1-cAMP signaling pathways. PMID:28787458

The systems biology of uric acid transporters: the role of remote sensing and signaling.

PubMed

Nigam, Sanjay K; Bhatnagar, Vibha

2018-07-01

Uric acid homeostasis in the body is mediated by a number of SLC and ABC transporters in the kidney and intestine, including several multispecific 'drug' transporters (e.g., OAT1, OAT3, and ABCG2). Optimization of uric acid levels can be viewed as a 'systems biology' problem. Here, we consider uric acid transporters from a systems physiology perspective using the framework of the 'Remote Sensing and Signaling Hypothesis.' This hypothesis explains how SLC and ABC 'drug' and other transporters mediate interorgan and interorganismal communication (e.g., gut microbiome and host) via small molecules (e.g., metabolites, antioxidants signaling molecules) through transporters expressed in tissues lining body fluid compartments (e.g., blood, urine, cerebrospinal fluid). The list of uric acid transporters includes: SLC2A9, ABCG2, URAT1 (SLC22A12), OAT1 (SLC22A6), OAT3 (SLC22A8), OAT4 (SLC22A11), OAT10 (SLC22A13), NPT1 (SLC17A1), NPT4 (SLC17A3), MRP2 (ABCC2), MRP4 (ABCC4). Normally, SLC2A9, - along with URAT1, OAT1 and OAT3, - appear to be the main transporters regulating renal urate handling, while ABCG2 appears to regulate intestinal transport. In chronic kidney disease (CKD), intestinal ABCG2 becomes much more important, suggesting remote organ communication between the injured kidney and the intestine. The remote sensing and signaling hypothesis provides a useful systems-level framework for understanding the complex interplay of uric acid transporters expressed in different tissues involved in optimizing uric acid levels under normal and diseased (e.g., CKD, gut microflora dysbiosis) conditions.

Lysophosphatidic Acid (LPA) Signaling in Human and Ruminant Reproductive Tract

PubMed Central

Wocławek-Potocka, Izabela; Rawińska, Paulina; Kowalczyk-Zieba, Ilona; Boruszewska, Dorota; Sinderewicz, Emilia; Waśniewski, Tomasz; Skarzynski, Dariusz Jan

2014-01-01

Lysophosphatidic acid (LPA) through activating its G protein-coupled receptors (LPAR 1–6) exerts diverse cellular effects that in turn influence several physiological processes including reproductive function of the female. Studies in various species of animals and also in humans have identified important roles for the receptor-mediated LPA signaling in multiple aspects of human and animal reproductive tract function. These aspects range from ovarian and uterine function, estrous cycle regulation, early embryo development, embryo implantation, decidualization to pregnancy maintenance and parturition. LPA signaling can also have pathological consequences, influencing aspects of endometriosis and reproductive tissue associated tumors. The review describes recent progress in LPA signaling research relevant to human and ruminant reproduction, pointing at the cow as a relevant model to study LPA influence on the human reproductive performance. PMID:24744506

Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation.

PubMed

Manteiga, Sara; Choi, Kyungoh; Jayaraman, Arul; Lee, Kyongbum

2013-01-01

Adipose tissue (AT) depots actively regulate whole body energy homeostasis by orchestrating complex communications with other physiological systems as well as within the tissue. Adipocytes readily respond to hormonal and nutritional inputs to store excess nutrients as intracellular lipids or mobilize the stored fat for utilization. Co-ordinated regulation of metabolic pathways balancing uptake, esterification, and hydrolysis of lipids is accomplished through positive and negative feedback interactions of regulatory hubs comprising several pleiotropic protein kinases and nuclear receptors. Metabolic regulation in adipocytes encompasses biogenesis and remodeling of uniquely large lipid droplets (LDs). The regulatory hubs also function as energy and nutrient sensors, and integrate metabolic regulation with intercellular signaling. Over-nutrition causes hypertrophic expansion of adipocytes, which, through incompletely understood mechanisms, initiates a cascade of metabolic and signaling events leading to tissue remodeling and immune cell recruitment. Macrophage activation and polarization toward a pro-inflammatory phenotype drives a self-reinforcing cycle of pro-inflammatory signals in the AT, establishing an inflammatory state. Sustained inflammation accelerates lipolysis and elevates free fatty acids in circulation, which robustly correlates with development of obesity-related diseases. The adipose regulatory network coupling metabolism, growth, and signaling of multiple cell types is exceedingly complex. While components of the regulatory network have been individually studied in exquisite detail, systems approaches have rarely been utilized to comprehensively assess the relative engagements of the components. Thus, need and opportunity exist to develop quantitative models of metabolic and signaling networks to achieve a more complete understanding of AT biology in both health and disease. Copyright © 2013 Wiley Periodicals, Inc.

All-trans retinoic acid regulates hepatic bile acid homeostasis

PubMed Central

Yang, Fan; He, Yuqi; Liu, Hui-Xin; Tsuei, Jessica; Jiang, Xiaoyue; Yang, Li; Wang, Zheng-Tao; Wan, Yu-Jui Yvonne

2014-01-01

Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract. PMID:25175738

Role of Hippo signaling in regulating immunity.

PubMed

Hong, Lixin; Li, Xun; Zhou, Dawang; Geng, Jing; Chen, Lanfen

2018-03-22

The Hippo signaling pathway has been established as a key regulator of organ size control, tumor suppression, and tissue regeneration in multiple organisms. Recently, emerging evidence has indicated that Hippo signaling might play an important role in regulating the immune system in both Drosophila and mammals. In particular, patients bearing a loss-of-function mutation of MST1 are reported to have an autosomal recessive primary immunodeficiency syndrome. MST1/2 kinases, the mammalian orthologs of Drosophila Hippo, may activate the non-canonical Hippo signaling pathway via MOB1A/B and/or NDR1/2 or cross-talk with other essential signaling pathways to regulate both innate and adaptive immunity. In this review, we present and discuss recent findings of cellular mechanisms/functions of Hippo signaling in the innate immunity in Drosophila and in mammals, T cell immunity, as well as the implications of Hippo signaling for tumor immunity.

Abscisic acid-activated SNRK2 protein kinases function in the gene-regulation pathway of ABA signal transduction by phosphorylating ABA response element-binding factors.

PubMed

Kobayashi, Yuhko; Murata, Michiharu; Minami, Hideyuki; Yamamoto, Shuhei; Kagaya, Yasuaki; Hobo, Tokunori; Yamamoto, Akiko; Hattori, Tsukaho

2005-12-01

The plant hormone abscisic acid (ABA) induces gene expression via the ABA-response element (ABRE) present in the promoters of ABA-regulated genes. A group of bZIP proteins have been identified as ABRE-binding factors (ABFs) that activate transcription through this cis element. A rice ABF, TRAB1, has been shown to be activated via ABA-dependent phosphorylation. While a large number of signalling factors have been identified that are involved in stomatal regulation by ABA, relatively less is known about the ABA-signalling pathway that leads to gene expression. We have shown recently that three members of the rice SnRK2 protein kinase family, SAPK8, SAPK9 and SAPK10, are activated by ABA signal as well as by hyperosmotic stress. Here we show that transient overexpression in cultured cell protoplasts of these ABA-activated SnRK2 protein kinases leads to the activation of an ABRE-regulated promoter, suggesting that these kinases are involved in the gene-regulation pathway of ABA signalling. We further show several lines of evidence that these ABA-activated SnRK2 protein kinases directly phosphorylate TRAB1 in response to ABA. Kinetic analysis of SAPK10 activation and TRAB1 phosphorylation indicated that the latter immediately followed the former. TRAB1 was found to be phosphorylated not only in response to ABA, but also in response to hyperosmotic stress, which was interpreted as the consequence of phosphorylation of TRAB1 by hyperosmotically activated SAPKs. Physical interaction between TRAB1 and SAPK10 in vivo was demonstrated by a co-immunoprecipitation experiment. Finally, TRAB1 was phosphorylated in vitro by the ABA-activated SnRK2 protein kinases at Ser102, which is phosphorylated in vivo in response to ABA and is critical for the activation function.

Plant phospholipase C family: Regulation and functional role in lipid signaling.

PubMed

Singh, Amarjeet; Bhatnagar, Nikita; Pandey, Amita; Pandey, Girdhar K

2015-08-01

Phospholipase C (PLC), a major membrane phospholipid hydrolyzing enzyme generates signaling messengers such as diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) in animals, and their phosphorylated forms such as phosphatidic acid (PA) and inositol hexakisphosphate (IP6) are thought to regulate various cellular processes in plants. Based on substrate specificity, plant PLC family is sub-divided into phosphatidylinositol-PLC (PI-PLC) and phosphatidylcholine-PLC (PC-PLC) groups. The activity of plant PLCs is regulated by various factors and the major ones include, Ca(2+) concentration, phospholipid substrate, post-translational modifications and interacting proteins. Most of the PLC members have been localized at the plasma membrane, suited for their function of membrane lipid hydrolysis. Several PLC members have been implicated in various cellular processes and signaling networks, triggered in response to a number of environmental cues and developmental events in different plant species, which makes them potential candidates for genetically engineering the crop plants for stress tolerance and enhancing the crop productivity. In this review article, we are focusing mainly on the plant PLC signaling and regulation, potential cellular and physiological role in different abiotic and biotic stresses, nutrient deficiency, growth and development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fatty acid regulation of hepatic lipid metabolism

PubMed Central

Jump, Donald B.

2012-01-01

Purpose of review To discuss transcriptional mechanisms regulating hepatic lipid metabolism. Recent findings Humans who are obese or have diabetes (NIDDM) or metabolic syndrome (MetS) have low blood and tissue levels of C20–22 polyunsaturated fatty acids (PUFAs). Although the impact of low C20–22 PUFAs on disease progression in humans is not fully understood, studies with mice have provided clues suggesting that impaired PUFA metabolism may contribute to the severity of risk factors associated with NIDDM and MetS. High fat diets promote hyperglycemia, insulin resistance and fatty liver in C57BL/6J mice, an effect that correlates with suppressed expression of enzymes involved in PUFA synthesis and decreased hepatic C20–22 PUFA content. A/J mice, in contrast, are resistant to diet-induced obesity and diabetes; these mice have elevated expression of hepatic enzymes involved in PUFA synthesis and C20–22 PUFA content. Moreover, loss-of-function and gain-of-function studies have identified fatty acid elongase (Elovl5), a key enzyme involved in PUFA synthesis, as a regulator of hepatic lipid and carbohydrate metabolism. Elovl5 activity regulates hepatic C20–22 PUFA content, signaling pathways (Akt and PP2A) and transcription factors (SREBP-1, PPARα, FoxO1 and PGC1α) that control fatty acid synthesis and gluconeogenesis. Summary These studies may help define novel strategies to control fatty liver and hyperglycemia associated with NIDDM and MetS. PMID:21178610

L-Cysteine-induced up-regulation of the low-density lipoprotein receptor is mediated via a transforming growth factor-alpha signalling pathway.

PubMed

Tanaka, Yuma; Shimada, Masaya; Nagaoka, Satoshi

2014-02-14

Sulphur-containing amino acids regulate plasma cholesterol levels in animals and humans. However, their mechanism of action remains unclear. Low-density lipoprotein receptor (LDLR) plays an important role in cholesterol metabolism. We therefore investigated the effects of sulphur-containing amino acids on the expression of LDLR in hepatocytes. HepG2 cells were cultured in Dulbecco's Modified Eagle's Medium with or without sulphur-containing amino acids and cysteine-containing compounds. We found that L-cysteine increased LDLR mRNA and enhanced LDLR gene promoter activity through the extracellular-signal-related kinase and p38 mitogen-activated protein kinase signalling pathways in HepG2 cells. Moreover, we observed that L-cysteine stimulated the release of transforming growth factor-alpha (TGF-α) and that TGF-α increased the LDLR mRNA levels. This study provides a report of the L-cysteine mediated up-regulation of the LDLR expression via TGF-α signalling pathway. Our findings provide insights into cholesterol homeostasis and amino acid signalling. Copyright © 2014 Elsevier Inc. All rights reserved.

ENHANCED DISEASE SUSCEPTIBILITY 1 and SALICYLIC ACID act redundantly to regulate resistance gene-mediated signaling

USDA-ARS?s Scientific Manuscript database

Resistance (R) protein–associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non–race-specific disease resistance 1 (NDR1), ...

Regulation of mTORC1 by PI3K signaling.

PubMed

Dibble, Christian C; Cantley, Lewis C

2015-09-01

The class I phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1 [composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8(mLST8), 40-kDa proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR)] depends on the Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb) GTPase and requires signals from amino acids, glucose, oxygen, energy (ATP), and growth factors (including cytokines and hormones such as insulin). Here we discuss the signal transduction mechanisms through which growth factor-responsive PI3K signaling activates mTORC1. We focus on how PI3K-dependent activation of Akt and spatial regulation of the tuberous sclerosis complex (TSC) complex (TSC complex) [composed of TSC1, TSC2, and Tre2-Bub2-Cdc16-1 domain family member 7 (TBC1D7)] switches on Rheb at the lysosome, where mTORC1 is activated. Integration of PI3K- and amino acid-dependent signals upstream of mTORC1 at the lysosome is detailed in a working model. A coherent understanding of the PI3K-mTORC1 network is imperative as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

Caffeic acid phenethyl ester attenuates pathological cardiac hypertrophy by regulation of MEK/ERK signaling pathway in vivo and vitro.

PubMed

Ren, Jie; Zhang, Nan; Liao, Haihan; Chen, Si; Xu, Ling; Li, Jing; Yang, Zheng; Deng, Wei; Tang, Qizhu

2017-07-15

To explore the effects of caffeic acid phenethyl ester (CAPE) on cardiac hypertrophy induced by pressure overload. Male wild-type C57 mice, aged 8-10weeks, were used for aortic banding (AB) to induce cardiac hypertrophy. CAPE or (resveratrol) RS was administered from the 3rd day after AB surgery for 6weeks. Echocardiography and hemodynamic analysis were performed to estimate cardiac function. Mice hearts were collected for H&E and PSR staining. Western blot analysis and quantitative PCR were performed for to investigate molecular mechanism. We further confirmed our findings in H9c2 cardiac fibroblasts treated with PE or CAPE. CAPE protected against cardiac hypertrophy induced by pressure overload, as evidenced by inhibition of cardiac hypertrophy and improvement in mouse cardiac function. The effect of CAPE on cardiac hypertrophy was mediated via inhibition of the MEK/ERK and TGFβ-Smad signaling pathways. We also demonstrated that CAPE protected H9c2 cells from PE-induced hypertrophy in vitro via a similar molecular mechanism as seen in the mouse heart. Finally, CAPE seemed to be as effective as RS for treatment of pressure overload induced mouse cardiac hypertrophy. Our results suggest that CAPE may play an important role in the regulation of cardiac hypertrophy induced by pressure overload via negative regulation of the MEK/ERK and TGFβ/Smad signaling pathways. These results indicate that CAPE could potentially be used for treatment of cardiac hypertrophy. Copyright © 2017 Elsevier Inc. All rights reserved.

FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways.

PubMed

Devanna, Paolo; Middelbeek, Jeroen; Vernes, Sonja C

2014-01-01

FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.

FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways

PubMed Central

Devanna, Paolo; Middelbeek, Jeroen; Vernes, Sonja C.

2014-01-01

FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells. PMID:25309332

Comparative proteomic analyses reveal that the regulators of G-protein signaling proteins regulate amino acid metabolism of the rice blast fungus Magnaporthe oryzae.

PubMed

Zhang, Haifeng; Ma, Hongyu; Xie, Xin; Ji, Jun; Dong, Yanhan; Du, Yan; Tang, Wei; Zheng, Xiaobo; Wang, Ping; Zhang, Zhengguang

2014-11-01

The rice blast fungus Magnaporthe oryzae encodes eight regulators of G-protein (GTP-binding protein) signaling (RGS) proteins MoRgs1-MoRgs8 that orchestrate the growth, asexual/sexual production, appressorium differentiation, and pathogenicity. To address the mechanisms by which MoRgs proteins function, we conducted a 2DE proteome study and identified 82 differentially expressed proteins by comparing five ∆Morgs mutants with wild-type Guy11 strain. We found that the abundances of eight amino acid (AA) biosynthesis or degradation associated proteins were markedly altered in five ∆Morgs mutants, indicating one of the main collective roles for the MoRgs proteins is to influence AA metabolism. We showed that MoRgs proteins have distinct roles in AA metabolism and nutrient responses from growth assays. In addition, we characterized MoLys20 (Lys is lysine), a homocitrate synthase, whose abundance was significantly decreased in the ∆Morgs mutants. The ∆Molys20 mutant is auxotrophic for lys and exogenous lys could partially rescue its auxotrophic defects. Deletion of MoLYS20 resulted in defects in conidiation and infection, as well as pathogenicity on rice. Overall, our results indicate that one of the critical roles for MoRgs proteins is to regulate AA metabolism, and that MoLys20 may be directly or indirectly regulated by MoRgs and participated in lys biosynthesis, thereby affecting fungal development and pathogenicity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Arabidopsis WRKY6 Transcription Factor Acts as a Positive Regulator of Abscisic Acid Signaling during Seed Germination and Early Seedling Development

PubMed Central

Wu, Wei-Hua; Chen, Yi-Fang

2016-01-01

The phytohormone abscisic acid (ABA) plays important roles during seed germination and early seedling development. Here, we characterized the function of the Arabidopsis WRKY6 transcription factor in ABA signaling. The transcript of WRKY6 was repressed during seed germination and early seedling development, and induced by exogenous ABA. The wrky6-1 and wrky6-2 mutants were ABA insensitive, whereas WRKY6-overexpressing lines showed ABA-hypersensitive phenotypes during seed germination and early seedling development. The expression of RAV1 was suppressed in the WRKY6-overexpressing lines and elevated in the wrky6 mutants, and the expression of ABI3, ABI4, and ABI5, which was directly down-regulated by RAV1, was enhanced in the WRKY6-overexpressing lines and repressed in the wrky6 mutants. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that WRKY6 could bind to the RAV1 promoter in vitro and in vivo. Overexpression of RAV1 in WRKY6-overexpressing lines abolished their ABA-hypersensitive phenotypes, and the rav1 wrky6-2 double mutant showed an ABA-hypersensitive phenotype, similar to rav1 mutant. Together, the results demonstrated that the Arabidopsis WRKY6 transcription factor played important roles in ABA signaling by directly down-regulating RAV1 expression. PMID:26829043

ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) regulates jasmonic acid and abscisic acid biosynthesis and signaling through binding to a novel cis-element.

PubMed

Chen, Hsing-Yu; Hsieh, En-Jung; Cheng, Mei-Chun; Chen, Chien-Yu; Hwang, Shih-Ying; Lin, Tsan-Piao

2016-07-01

ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) of Arabidopsis thaliana is an AP2/ERF domain transcription factor that regulates jasmonate (JA) biosynthesis and is induced by methyl JA treatment. The regulatory mechanism of ORA47 remains unclear. ORA47 is shown to bind to the cis-element (NC/GT)CGNCCA, which is referred to as the O-box, in the promoter of ABI2. We proposed that ORA47 acts as a connection between ABA INSENSITIVE1 (ABI1) and ABI2 and mediates an ABI1-ORA47-ABI2 positive feedback loop. PORA47:ORA47-GFP transgenic plants were used in a chromatin immunoprecipitation (ChIP) assay to show that ORA47 participates in the biosynthesis and/or signaling pathways of nine phytohormones. Specifically, many abscisic acid (ABA) and JA biosynthesis and signaling genes were direct targets of ORA47 under stress conditions. The JA content of the P35S:ORA47-GR lines was highly induced under wounding and moderately induced under water stress relative to that of the wild-type plants. The wounding treatment moderately increased ABA accumulation in the transgenic lines, whereas the water stress treatment repressed the ABA content. ORA47 is proposed to play a role in the biosynthesis of JA and ABA and in regulating the biosynthesis and/or signaling of a suite of phytohormone genes when plants are subjected to wounding and water stress. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.

PubMed

Zhou, Nan; Yao, Yu; Ye, Hongxing; Zhu, Wei; Chen, Liang; Mao, Ying

2016-04-15

Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. © 2015 UICC.

Negative regulation of RIG-I-mediated antiviral signaling by TRK-fused gene (TFG) protein.

PubMed

Lee, Na-Rae; Shin, Han-Bo; Kim, Hye-In; Choi, Myung-Soo; Inn, Kyung-Soo

2013-07-19

RIG-I (retinoic acid inducible gene I)-mediated antiviral signaling serves as the first line of defense against viral infection. Upon detection of viral RNA, RIG-I undergoes TRIM25 (tripartite motif protein 25)-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that TRK-fused gene (TFG) protein, previously identified as a TRIM25-interacting protein, binds TRIM25 upon virus infection and negatively regulates RIG-I-mediated type-I IFN signaling. RIG-I-mediated IFN production and nuclear factor (NF)-κB signaling pathways were upregulated by the suppression of TFG expression. Furthermore, vesicular stomatitis virus (VSV) replication was significantly inhibited by small inhibitory hairpin RNA (shRNA)-mediated knockdown of TFG, supporting the suppressive role of TFG in RIG-I-mediated antiviral signaling. Interestingly, suppression of TFG expression increased not only RIG-I-mediated signaling but also MAVS (mitochondrial antiviral signaling protein)-induced signaling, suggesting that TFG plays a pivotal role in negative regulation of RNA-sensing, RIG-I-like receptor (RLR) family signaling pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

The Regulator of G-Protein Signaling Proteins Involved in Sugar and Abscisic Acid Signaling in Arabidopsis Seed Germination1

PubMed Central

Chen, Yun; Ji, Fangfang; Xie, Hong; Liang, Jiansheng; Zhang, Jianhua

2006-01-01

The regulator of G-protein signaling (RGS) proteins, recently identified in Arabidopsis (Arabidopsis thaliana; named as AtRGS1), has a predicted seven-transmembrane structure as well as an RGS box with GTPase-accelerating activity and thus desensitizes the G-protein-mediated signaling. The roles of AtRGS1 proteins in Arabidopsis seed germination and their possible interactions with sugars and abscisic acid (ABA) were investigated in this study. Using seeds that carry a null mutation in the genes encoding RGS protein (AtRGS1) and the α-subunit (AtGPA1) of the G protein in Arabidopsis (named rgs1-2 and gpa1-3, respectively), our genetic evidence proved the involvement of the AtRGS1 protein in the modulation of seed germination. In contrast to wild-type Columbia-0 and gpa1-3, stratification was found not to be required and the after-ripening process had no effect on the rgs1-2 seed germination. In addition, rgs1-2 seed germination was insensitive to glucose (Glc) and sucrose. The insensitivities of rgs1-2 to Glc and sucrose were not due to a possible osmotic stress because the germination of rgs1-2 mutant seeds showed the same response as those of gpa1-3 mutants and wild type when treated with the same concentrations of mannitol and sorbitol. The gpa1-3 seed germination was hypersensitive while rgs1-2 was less sensitive to exogenous ABA. The different responses to ABA largely diminished and the inhibitory effects on seed germination by exogenous ABA and Glc were markedly alleviated when endogenous ABA biosynthesis was inhibited. Hypersensitive responses of seed germination to both Glc and ABA were also observed in the overexpressor of AtRGS1. Analysis of the active endogenous ABA levels and the expression of NCED3 and ABA2 genes showed that Glc significantly stimulated the ABA biosynthesis and increased the expression of NCED3 and ABA2 genes in germinating Columbia seeds, but not in rgs1-2 mutant seeds. These data suggest that AtRGS1 proteins are involved in the

Phosphatidic acid binding inhibits RGS1 activity to affect specific signaling pathways in Arabidopsis.

PubMed

Roy Choudhury, Swarup; Pandey, Sona

2017-05-01

Modulation of the active versus inactive forms of the Gα protein is critical for the signaling processes mediated by the heterotrimeric G-protein complex. We have recently established that in Arabidopsis, the regulator of G-protein signaling (RGS1) protein and a lipid-hydrolyzing enzyme, phospholipase Dα1 (PLDα1), both act as GTPase-activity accelerating proteins (GAPs) for the Gα protein to attenuate its activity. RGS1 and PLDα1 interact with each other, and RGS1 inhibits the activity of PLDα1 during regulation of a subset of responses. In this study, we present evidence that this regulation is bidirectional. Phosphatidic acid (PA), a second messenger typically derived from the lipid-hydrolyzing activity of PLDα1, is a molecular target of RGS1. PA binds and inhibits the GAP activity of RGS1. A conserved lysine residue in RGS1 (Lys 259 ) is directly involved in RGS1-PA binding. Introduction of this RGS1 protein variant in the rgs1 mutant background makes plants hypersensitive to a subset of abscisic acid-mediated responses. Our data point to the existence of negative feedback loops between these two regulatory proteins that precisely modulate the level of active Gα, consequently generating a highly controlled signal-response output. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Modularized Smad-regulated TGFβ signaling pathway.

PubMed

Li, Yongfeng; Wang, Minli; Carra, Claudio; Cucinotta, Francis A

2012-12-01

The transforming Growth Factor β (TGFβ) signaling pathway is a prominent regulatory signaling pathway controlling various important cellular processes. TGFβ signaling can be induced by several factors including ionizing radiation. The pathway is regulated in a negative feedback loop through promoting the nuclear import of the regulatory Smads and a subsequent expression of inhibitory Smad7, that forms ubiquitin ligase with Smurf2, targeting active TGFβ receptors for degradation. In this work, we proposed a mathematical model to study the Smad-regulated TGFβ signaling pathway. By modularization, we are able to analyze mathematically each component subsystem and recover the nonlinear dynamics of the entire network system. Meanwhile the excitability, a common feature observed in the biological systems, in the TGFβ signaling pathway is discussed and supported as well by numerical simulation, indicating the robustness of the model. Published by Elsevier Inc.

Feedback regulation of TGF-β signaling.

PubMed

Yan, Xiaohua; Xiong, Xiangyang; Chen, Ye-Guang

2018-01-01

Transforming growth factor beta (TGF-β) is a multi-functional polypeptide that plays a critical role in regulating a broad range of cellular functions and physiological processes. Signaling is initiated when TGF-β ligands bind to two types of cell membrane receptors with intrinsic Ser/Thr kinase activity and transmitted by the intracellular Smad proteins, which act as transcription factors to regulate gene expression in the nucleus. Although it is relatively simple and straight-forward, this TGF-β/Smad pathway is regulated by various feedback loops at different levels, including the ligand, the receptor, Smads and transcription, and is thus fine-tuned in terms of signaling robustness, duration, specificity, and plasticity. The precise control gives rise to versatile and context-dependent pathophysiological functions. In this review, we firstly give an overview of TGF-β signaling, and then discuss how each step of TGF-β signaling is finely controlled by distinct modes of feedback mechanisms, involving both protein regulators and miRNAs. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Solanum lycopersicum IAA15 functions in the 2,4-dichlorophenoxyacetic acid herbicide mechanism of action by mediating abscisic acid signalling.

PubMed

Xu, Tao; Wang, Yanling; Liu, Xin; Gao, Song; Qi, Mingfang; Li, Tianlai

2015-07-01

2,4-Dichlorophenoxyacetic acid (2,4-D), an important plant growth regulator, is the herbicide most commonly used worldwide to control weeds. However, broad-leaf fruits and vegetables are extremely sensitive to herbicides, which can cause damage and result in lost crops when applied in a manner inconsistent with the directions. Despite detailed knowledge of the mechanism of 2,4-D, the regulation of auxin signalling is still unclear. For example, although the major mediators of auxin signalling, including auxin/indole acetic acid (AUX/IAA) proteins and auxin response factors (ARFs), are known to mediate auxinic herbicides, the underlying mechanisms are still unclear. In this study, the effects of 2,4-D on AUX/IAA gene expression in tomato were investigated, and the two most notably up-regulated genes, SlIAA15 and SlIAA29, were selected for further study. Western blotting revealed the substantial accumulation of both SlIAA15 and SlIAA29, and the expression levels of the corresponding genes were increased following abscisic acid (ABA) and ethylene treatment. Overexpressing SlIAA15, but not SlIAA29, induced a 2,4-D herbicide damage phenotype. The 35S::SlIAA15 line exhibited a strong reduction in leaf stomatal density and altered expression of some R2R3 MYB genes that are putatively involved in the regulation of stomatal differentiation. Further study revealed that root elongation in 35S::SlIAA15 was sensitive to ABA treatment, and was most probably due to the altered expression of an ABA signal transduction gene. In addition, the altered auxin sensitivities of SlIAA15 transformants were also explored. These results suggested that SlIAA15 plays an important role in determining the effects of the herbicide 2,4-D. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Stress Marker Signatures in Lesion Mimic Single and Double Mutants Identify a Crucial Leaf Age-Dependent Salicylic Acid Related Defense Signal.

PubMed

Kaurilind, Eve; Brosché, Mikael

2017-01-01

Plants are exposed to abiotic and biotic stress conditions throughout their lifespans that activates various defense programs. Programmed cell death (PCD) is an extreme defense strategy the plant uses to manage unfavorable environments as well as during developmentally induced senescence. Here we investigated the role of leaf age on the regulation of defense gene expression in Arabidopsis thaliana. Two lesion mimic mutants with misregulated cell death, catalase2 (cat2) and defense no death1 (dnd1) were used together with several double mutants to dissect signaling pathways regulating defense gene expression associated with cell death and leaf age. PCD marker genes showed leaf age dependent expression, with the highest expression in old leaves. The salicylic acid (SA) biosynthesis mutant salicylic acid induction deficient2 (sid2) had reduced expression of PCD marker genes in the cat2 sid2 double mutant demonstrating the importance of SA biosynthesis in regulation of defense gene expression. While the auxin- and jasmonic acid (JA)- insensitive auxin resistant1 (axr1) double mutant cat2 axr1 also led to decreased expression of PCD markers; the expression of several marker genes for SA signaling (ISOCHORISMATE SYNTHASE 1, PR1 and PR2) were additionally decreased in cat2 axr1 compared to cat2. The reduced expression of these SA markers genes in cat2 axr1 implicates AXR1 as a regulator of SA signaling in addition to its known role in auxin and JA signaling. Overall, the current study reinforces the important role of SA signaling in regulation of leaf age-related transcript signatures.

Hypothalamic mTOR signaling regulates food intake.

PubMed

Cota, Daniela; Proulx, Karine; Smith, Kathi A Blake; Kozma, Sara C; Thomas, George; Woods, Stephen C; Seeley, Randy J

2006-05-12

The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.

Acid mediates a prolonged antinociception via substance P signaling in acid-induced chronic widespread pain.

PubMed

Chen, Wei-Nan; Chen, Chih-Cheng

2014-05-21

Substance P is an important neuropeptide released from nociceptors to mediate pain signals. We recently revealed antinociceptive signaling by substance P in acid-sensing ion channel 3 (ASIC3)-expressing muscle nociceptors in a mouse model of acid-induced chronic widespread pain. However, methods to specifically trigger the substance P antinociception were still lacking. Here we show that acid could induce antinociceptive signaling via substance P release in muscle. We prevented the intramuscular acid-induced hyperalgesia by pharmacological inhibition of ASIC3 and transient receptor potential V1 (TRPV1). The antinociceptive effect of non-ASIC3, non-TRPV1 acid signaling lasted for 2 days. The non-ASIC3, non-TRPV1 acid antinociception was largely abolished in mice lacking substance P. Moreover, pretreatment with substance P in muscle mimicked the acid antinociceptive effect and prevented the hyperalgesia induced by next-day acid injection. Acid could mediate a prolonged antinociceptive signaling via the release of substance P from muscle afferent neurons in a non-ASIC3, non-TRPV1 manner.

Monitoring Phosphatidic Acid Signaling in Breast Cancer Cells Using Genetically Encoded Biosensors.

PubMed

Lu, Maryia; Tay, Li Wei Rachel; He, Jingquan; Du, Guangwei

2016-01-01

Phospholipids are important signaling molecules that regulate cell proliferation, death, migration, and metabolism. Many phospholipid signaling cascades are altered in breast cancer. To understand the functions of phospholipid signaling molecules, genetically encoded phospholipid biosensors have been developed to monitor their spatiotemporal dynamics. Compared to other phospholipids, much less is known about the subcellular production and cellular functions of phosphatidic acid (PA), partially due to the lack of a specific and sensitive PA biosensor in the past. This chapter describes the use of a newly developed PA biosensor, PASS, in two applications: regular fluorescent microscopy and fluorescence lifetime imaging microscopy-Förster/fluorescence resonance energy transfer (FLIM-FRET). These protocols can be also used with other phospholipid biosensors.

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

PubMed Central

Tape, Christopher J.; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Lauffenburger, Douglas A.; Jørgensen, Claus

2016-01-01

Summary Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Video Abstract PMID:27087446

Gibberellic Acid-Stimulated Arabidopsis6 Serves as an Integrator of Gibberellin, Abscisic Acid, and Glucose Signaling during Seed Germination in Arabidopsis.

PubMed

Zhong, Chunmei; Xu, Hao; Ye, Siting; Wang, Shiyi; Li, Lingfei; Zhang, Shengchun; Wang, Xiaojing

2015-11-01

The DELLA protein REPRESSOR OF ga1-3-LIKE2 (RGL2) plays an important role in seed germination under different conditions through a number of transcription factors. However, the functions of the structural genes associated with RGL2-regulated germination are less defined. Here, we report the role of an Arabidopsis (Arabidopsis thaliana) cell wall-localized protein, Gibberellic Acid-Stimulated Arabidopsis6 (AtGASA6), in functionally linking RGL2 and a cell wall loosening expansin protein (Arabidopsis expansin A1 [AtEXPA1]), resulting in the control of embryonic axis elongation and seed germination. AtGASA6-overexpressing seeds showed precocious germination, whereas transfer DNA and RNA interference mutant seeds displayed delayed seed germination under abscisic acid, paclobutrazol, and glucose (Glc) stress conditions. The differences in germination rates resulted from corresponding variation in cell elongation in the hypocotyl-radicle transition region of the embryonic axis. AtGASA6 was down-regulated by RGL2, GLUCOSE INSENSITIVE2, and ABSCISIC ACID-INSENSITIVE5 genes, and loss of AtGASA6 expression in the gasa6 mutant reversed the insensitivity shown by the rgl2 mutant to paclobutrazol and the gin2 mutant to Glc-induced stress, suggesting that it is involved in regulating both the gibberellin and Glc signaling pathways. Furthermore, it was found that the promotion of seed germination and length of embryonic axis by AtGASA6 resulted from a promotion of cell elongation at the embryonic axis mediated by AtEXPA1. Taken together, the data indicate that AtGASA6 links RGL2 and AtEXPA1 functions and plays a role as an integrator of gibberellin, abscisic acid, and Glc signaling, resulting in the regulation of seed germination through a promotion of cell elongation. © 2015 American Society of Plant Biologists. All Rights Reserved.

Acid sphingomyelinase mediates human CD4+ T-cell signaling: potential roles in T-cell responses and diseases

PubMed Central

Bai, Aiping; Guo, Yuan

2017-01-01

Acid sphingomyelinase (ASM) is a lipid hydrolase. By generating ceramide, ASM had been reported to have an important role in regulating immune cell functions inclusive of macrophages, NK cells, and CD8+ T cells, whereas the role of ASM bioactivity in regulation of human CD4+ T-cell functions remained uncertain. Recent studies have provided novel findings in this field. Upon stimulation of CD3 and/or CD28, ASM-dependent ceramide signaling mediates intracellular downstream signal cascades of CD3 and CD28, and regulates CD4+ T-cell activation and proliferation. Meanwhile, CD39 and CD161 have direct interactions with ASM, which mediates downstream signals inclusive of STAT3 and mTOR and thus defines human Th17 cells. Intriguingly, ASM mediates Th1 responses, but negatively regulates Treg functions. In this review, we summarized the pivotal roles of ASM in regulation of human CD4+ T-cell activation and responses. ASM/sphingolipid signaling may be a novel target for the therapy of human autoimmune diseases. PMID:28749465

Proteolytic degradation of regulator of G protein signaling 2 facilitates temporal regulation of Gq/11 signaling and vascular contraction.

PubMed

Kanai, Stanley M; Edwards, Alethia J; Rurik, Joel G; Osei-Owusu, Patrick; Blumer, Kendall J

2017-11-24

Regulator of G protein signaling 2 (RGS2) controls signaling by receptors coupled to the G q/11 class heterotrimeric G proteins. RGS2 deficiency causes several phenotypes in mice and occurs in several diseases, including hypertension in which a proteolytically unstable RGS2 mutant has been reported. However, the mechanisms and functions of RGS2 proteolysis remain poorly understood. Here we addressed these questions by identifying degradation signals in RGS2, and studying dynamic regulation of G q/11 -evoked Ca 2+ signaling and vascular contraction. We identified a novel bipartite degradation signal in the N-terminal domain of RGS2. Mutations disrupting this signal blunted proteolytic degradation downstream of E3 ubiquitin ligase binding to RGS2. Analysis of RGS2 mutants proteolyzed at various rates and the effects of proteasome inhibition indicated that proteolytic degradation controls agonist efficacy by setting RGS2 protein expression levels, and affecting the rate at which cells regain agonist responsiveness as synthesis of RGS2 stops. Analyzing contraction of mesenteric resistance arteries supported the biological relevance of this mechanism. Because RGS2 mRNA expression often is strikingly and transiently up-regulated and then down-regulated upon cell stimulation, our findings indicate that proteolytic degradation tightly couples RGS2 transcription, protein levels, and function. Together these mechanisms provide tight temporal control of G q/11 -coupled receptor signaling in the cardiovascular, immune, and nervous systems. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Amino acids--a life between metabolism and signaling.

PubMed

Häusler, Rainer E; Ludewig, Frank; Krueger, Stephan

2014-12-01

Amino acids serve as constituents of proteins, precursors for anabolism, and, in some cases, as signaling molecules in mammalians and plants. This review is focused on new insights, or speculations, on signaling functions of serine, γ-aminobutyric acid (GABA) and phenylalanine-derived phenylpropanoids. Serine acts as signal in brain tissue and mammalian cancer cells. In plants, de novo serine biosynthesis is also highly active in fast growing tissues such as meristems, suggesting a similar role of serine as in mammalians. GABA functions as inhibitory neurotransmitter in the brain. In plants, GABA is also abundant and seems to be involved in sexual reproduction, cell elongation, patterning and cell identity. The aromatic amino acids phenylalanine, tyrosine, and tryptophan are precursors for the production of secondary plant products. Besides their pharmaceutical value, lignans, neolignans and hydroxycinnamic acid amides (HCAA) deriving from phenylpropanoid metabolism and, in the case of HCAA, also from arginine have been shown to fulfill signaling functions or are involved in the response to biotic and abiotic stress. Although some basics on phenylpropanoid-derived signaling have been described, little is known on recognition- or signal transduction mechanisms. In general, mutant- and transgenic approaches will be helpful to elucidate the mechanistic basis of metabolite signaling. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Regulation of B cell functions by the sialic acid-binding receptors siglec-G and CD22.

PubMed

Jellusova, Julia; Nitschke, Lars

2011-01-01

B cell antigen receptor (BCR) engagement can lead to many different physiologic outcomes. To achieve an appropriate response, the BCR signal is interpreted in the context of other stimuli and several additional receptors on the B cell surface participate in the modulation of the signal. Two members of the Siglec (sialic acid-binding immunoglobulin-like lectin) family, CD22 and Siglec-G have been shown to inhibit the BCR signal. Recent findings indicate that the ability of these two receptors to bind sialic acids might be important to induce tolerance to self-antigens. Sialylated glycans are usually absent on microbes but abundant in higher vertebrates and might therefore provide an important tolerogenic signal. Since the expression of the specific ligands for Siglec-G and CD22 is tightly regulated and since Siglecs are not only able to bind their ligands in trans but also on the same cell surface this might provide additional mechanisms to control the BCR signal. Although both Siglec-G and CD22 are expressed on B cells and are able to inhibit BCR mediated signaling, they also show unique biological functions. While CD22 is the dominant regulator of calcium signaling on conventional B2 cells and also seems to play a role on marginal zone B cells, Siglec-G exerts its function mainly on B1 cells and influences their lifespan and antibody production. Both Siglec-G and CD22 have also recently been linked to toll-like receptor signaling and may provide a link in the regulation of the adaptive and innate immune response of B cells.

Evolution of Abscisic Acid Synthesis and Signaling Mechanisms

PubMed Central

Hauser, Felix; Waadt, Rainer; Schroeder, Julian I.

2011-01-01

The plant hormone abscisic acid (ABA) mediates seed dormancy, controls seedling development and triggers tolerance to abiotic stresses, including drought. Core ABA signaling components consist of a recently identified group of ABA receptor proteins of the PYRABACTIN RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family that act as negative regulators of members of the PROTEIN PHOSPHATASE 2C (PP2C) family. Inhibition of PP2C activity enables activation of SNF1-RELATED KINASE 2 (SnRK2) protein kinases, which target downstream components, including transcription factors, ion channels and NADPH oxidases. These and other components form a complex ABA signaling network. Here, an in depth analysis of the evolution of components in this ABA signaling network shows that (i) PYR/RCAR ABA receptor and ABF-type transcription factor families arose during land colonization of plants and are not found in algae and other species, (ii) ABA biosynthesis enzymes have evolved to plant- and fungal-specific forms, leading to different ABA synthesis pathways, (iii) existing stress signaling components, including PP2C phosphatases and SnRK kinases, were adapted for novel roles in this plant-specific network to respond to water limitation. In addition, evolutionarily conserved secondary structures in the PYR/RCAR ABA receptor family are visualized. PMID:21549957

Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression.

PubMed

Zhang, Baochun; Crankshaw, Will; Nesemeier, Ryan; Patel, Jay; Nweze, Ikenna; Lakshmanan, Jaganathan; Harbrecht, Brian G

2015-02-01

Induced nitric oxide synthase (iNOS) is induced in hepatocytes by shock and inflammatory stimuli. Excessive NO from iNOS mediates shock-induced hepatic injury and death, so understanding the regulation of iNOS will help elucidate the pathophysiology of septic shock. In vitro, cytokines induce iNOS expression through activation of signaling pathways including mitogen-activated protein kinases and nuclear factor κB. Cytokines also induce calcium (Ca(2+)) mobilization and activate calcium-mediated intracellular signaling pathways, typically through activation of calmodulin-dependent kinases (CaMK). Calcium regulates NO production in macrophages but the role of calcium and calcium-mediated signaling in hepatocyte iNOS expression has not been defined. Primary rat hepatocytes were isolated, cultured, and induced to produce NO with proinflammatory cytokines. Calcium mobilization and Ca(2+)-mediated signaling were altered with ionophore, Ca(2+) channel blockers, and inhibitors of CaMK. The Ca(2+) ionophore A23187 suppressed cytokine-stimulated NO production, whereas Ethylene glycol tetraacetic acid and nifedipine increased NO production, iNOS messenger RNA, and iNOS protein expression. Inhibition of CaMK with KN93 and CBD increased NO production but the calcineurin inhibitor FK 506 decreased iNOS expression. These data demonstrate that calcium-mediated signaling regulates hepatocyte iNOS expression and does so through a mechanism independent of calcineurin. Changes in intracellular calcium levels may regulate iNOS expression during hepatic inflammation induced by proinflammatory cytokines. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of DreI as an Antiviral Factor Regulated by RLR Signaling Pathway

PubMed Central

Li, Shun; Sun, Fan; Zhang, Yi-Bing; Gui, Jian-Fang; Zhang, Qi-Ya

2012-01-01

Background Retinoic acid-inducible gene I (RIG-I)–like receptors (RLRs) had been demonstrated to prime interferon (IFN) response against viral infection via the conserved RLR signaling in fish, and a novel fish-specific gene, the grass carp reovirus (GCRV)-induced gene 2 (Gig2), had been suggested to play important role in host antiviral response. Methodology/Principal Findings In this study, we cloned and characterized zebrafish Gig2 homolog (named Danio rerio Gig2-I, DreI), and revealed its antiviral role and expressional regulation signaling pathway. RT-PCR, Western blot and promoter activity assay indicate that DreI can be induced by poly I:C, spring viremia of carp virus (SVCV) and recombinant IFN (rIFN), showing that DreI is a typical ISG. Using the pivotal signaling molecules of RLR pathway, including RIG-I, MDA5 and IRF3 from crucian carp, it is found that DreI expression is regulated by RLR cascade and IRF3 plays an important role in this regulation. Furthermore, promoter mutation assay confirms that the IFN-stimulated regulatory elements (ISRE) in the 5′ flanking region of DreI is essential for its induction. Finally, overexpression of DreI leads to establish a strong antiviral state against SVCV and Rana grylio virus (RGV) infection in EPC (Epithelioma papulosum cyprinid) cells. Conclusions/Significance These data indicate that DreI is an antiviral protein, which is regulated by RLR signaling pathway. PMID:22412872

Release of GTP Exchange Factor Mediated Down-Regulation of Abscisic Acid Signal Transduction through ABA-Induced Rapid Degradation of RopGEFs

PubMed Central

Waadt, Rainer; Schroeder, Julian I.

2016-01-01

The phytohormone abscisic acid (ABA) is critical to plant development and stress responses. Abiotic stress triggers an ABA signal transduction cascade, which is comprised of the core components PYL/RCAR ABA receptors, PP2C-type protein phosphatases, and protein kinases. Small GTPases of the ROP/RAC family act as negative regulators of ABA signal transduction. However, the mechanisms by which ABA controls the behavior of ROP/RACs have remained unclear. Here, we show that an Arabidopsis guanine nucleotide exchange factor protein RopGEF1 is rapidly sequestered to intracellular particles in response to ABA. GFP-RopGEF1 is sequestered via the endosome-prevacuolar compartment pathway and is degraded. RopGEF1 directly interacts with several clade A PP2C protein phosphatases, including ABI1. Interestingly, RopGEF1 undergoes constitutive degradation in pp2c quadruple abi1/abi2/hab1/pp2ca mutant plants, revealing that active PP2C protein phosphatases protect and stabilize RopGEF1 from ABA-mediated degradation. Interestingly, ABA-mediated degradation of RopGEF1 also plays an important role in ABA-mediated inhibition of lateral root growth. The presented findings point to a PP2C-RopGEF-ROP/RAC control loop model that is proposed to aid in shutting off ABA signal transduction, to counteract leaky ABA signal transduction caused by “monomeric” PYL/RCAR ABA receptors in the absence of stress, and facilitate signaling in response to ABA. PMID:27192441

INTRACELLULAR SIGNALING BY BILE ACIDS

PubMed Central

Anwer, Mohammed Sawkat

2014-01-01

Bile acids, synthesized from cholesterol, are known to produce beneficial as well as toxic effects in the liver. The beneficial effects include choleresis, immunomodulation, cell survival, while the toxic effects include cholestasis, apoptosis and cellular toxicity. It is believed that bile acids produce many of these effects by activating intracellular signaling pathways. However, it has been a challenge to relate intracellular signaling to specific and at times opposing effects of bile acids. It is becoming evident that bile acids produce different effects by activating different isoforms of phosphoinositide 3-kinase (PI3K), Protein kinase Cs (PKCs), and mitogen activated protein kinases (MAPK). Thus, the apoptotic effect of bile acids may be mediated via PI3K-110γ, while cytoprotection induce by cAMP-GEF pathway involves activation of PI3K-p110α/β isoforms. Atypical PKCζ may mediate beneficial effects and nPKCε may mediate toxic effects, while cPKCα and nPKCδ may be involved in both beneficial and toxic effects of bile acids. The opposing effects of nPKCδ activation may depend on nPKCδ phosphorylation site(s). Activation of ERK1/2 and JNK1/2 pathway appears to mediate beneficial and toxic effects, respectively, of bile acids. Activation of p38α MAPK and p38β MAPK may mediate choleretic and cholestatic effects, respectively, of bile acids. Future studies clarifying the isoform specific effects on bile formation should allow us to define potential therapeutic targets in the treatment of cholestatic disorders. PMID:25378891

3,4-dihydroxyphenyl acetic acid and (+)-epoxydon isolated from marine algae-derived microorganisms induce down regulation of epidermal growth factor activated mitogenic signaling cascade in Hela cells.

PubMed

Jo, Mi Jeong; Bae, Seong Ja; Son, Byeng Wha; Kim, Chi Yeon; Kim, Gun Do

2013-05-25

Epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinase (RTK) family. Epidermal growth factor induces its dimerization and stimulates phosphorylation of intracellular tyrosine residues. Phosphorylation of EGFR is studied for cancer therapy because EGFR regulates many cellular processes including cell proliferation, differentiation, and survival. Hence, down-regulation of EGFR kinase activity results in inhibition of signaling cascades amenable for proliferation and progression of cell cycle. In the study, we purified 3,4-dihydroxyphenyl acetic acid and (+)-epoxydon from Aspergillus sp. isolated from marine brown alga Ishige okamurae and Phoma herbarum isolated from marine red alga Hypnea saidana respectively and determined its anti-tumor activities against HeLa human cervical cancer cells. Two compounds suppressed EGFR activity in vitro with IC50 values for 3,4-dihydroxyphenyl acetic acid and (+)-epoxydon were 2.8 and 0.6 μg/mL respectively and reduced the viable numbers of HeLa cells. Immunoblotting analysis exhibited that the compounds induced inhibition of cell growth by causing downregulation of the mitogenic signaling cascade, inactivation of p90RSK, and release of cytochrome c from mitochondria. Results suggest that decreased expression of active EGFR and EGFR-related downstream molecules by treatment with the compounds may results in the inhibition of cell growth and inducement of apoptosis.

Expression of Stipa purpurea SpCIPK26 in Arabidopsis thaliana Enhances Salt and Drought Tolerance and Regulates Abscisic Acid Signaling

PubMed Central

Zhou, Yanli; Sun, Xudong; Yang, Yunqiang; Li, Xiong; Cheng, Ying; Yang, Yongping

2016-01-01

Stipa purpurea (S. purpurea) is the dominant plant species in the alpine steppe of the Qinghai-Tibet Plateau, China. It is highly resistant to cold and drought conditions. However, the underlying mechanisms regulating the stress tolerance are unknown. In this study, a CIPK gene from S. purpurea (SpCIPK26) was isolated. The SpCIPK26 coding region consisted of 1392 bp that encoded 464 amino acids. The protein has a highly conserved catalytic structure and regulatory domain. The expression of SpCIPK26 was induced by drought and salt stress. SpCIPK26 overexpression in Arabidopsis thaliana (A. thaliana) plants provided increased tolerance to drought and salt stress in an abscisic acid (ABA)-dependent manner. Compared with wild-type A. thaliana plants, SpCIPK26-overexpressing plants had higher survival rates, water potentials, and photosynthetic efficiency (Fv/Fm), as well as lower levels of reactive oxygen species (ROS) following exposure to drought and salt stress. Gene expression analyses indicated stress-inducible genes (RD29A, RD29B, and ABF2) and a ROS-scavenger gene (CAT1) were upregulated in SpCIPK26-overexpressing plants after stress treatments. All of these marker genes are associated with ABA-responsive cis-acting elements. Additionally, the similarities in the gene expression patterns following ABA, mannitol, and NaCl treatments suggest SpCIPK26 has an important role during plant responses to drought and salt stress and in regulating ABA signaling. PMID:27338368

HPS4/SABRE regulates plant responses to phosphate starvation through antagonistic interaction with ethylene signalling

PubMed Central

Yu, Hailan; Luo, Nan; Sun, Lichao; Liu, Dong

2012-01-01

The phytohormone ethylene plays important roles in regulating plant responses to phosphate (Pi) starvation. To date, however, no molecular components have been identified that interact with ethylene signalling in regulating such responses. In this work, an Arabidopsis mutant, hps4, was characterized that exhibits enhanced responses to Pi starvation, including increased inhibition of primary root growth, enhanced expression of Pi starvation-induced genes, and overproduction of root-associated acid phosphatases. Molecular cloning indicated that hps4 is a new allele of SABRE, which was previously identified as an important regulator of cell expansion in Arabidopsis. HPS4/SABRE antagonistically interacts with ethylene signalling to regulate plant responses to Pi starvation. Furthermore, it is shown that Pi-starved hps4 mutants accumulate more auxin in their root tips than the wild type, which may explain the increased inhibition of their primary root growth when grown under Pi deficiency. PMID:22615140

Mitochondria dysfunctions under Fe and S deficiency: is citric acid involved in the regulation of adaptive responses?

PubMed

Vigani, Gianpiero; Pii, Youry; Celletti, Silvia; Maver, Mauro; Mimmo, Tanja; Cesco, Stefano; Astolfi, Stefania

2018-05-01

Within the last years, extensive information has been accumulated on the reciprocal influence between S and Fe nutrition at both physiological and molecular level in several plant species, but the mechanisms regulating S and Fe sensing and signaling are not fully understood. Fe and S interact for the building of Fe-S clusters, and mitochondria is one of the cellular compartments where Fe-S cluster assembly takes place. Therefore, it would be expected that mitochondria might play a central role in the regulation of Fe and S interaction. The Fe deficiency-induced alteration in the synthesis of mitochondria-derived carboxylic acids, such as citric acid, and the evidence that such molecules have already been identified as important players of metabolite signaling in several organisms, further support this hypothesis. Tomato plants were grown under single or combined Fe and S deficiency with the aim of verifying whether mitochondria activities played a role in Fe/S interaction. Both Fe and S deficiencies determined similar alteration of respiratory chain activity: a general decrease of Fe-S containing complexes as well as an increase of alternative NAD(P)H activities was observed in both Fe and S deficient-plants. However, the content of Krebs cycle-related organic acids in roots was substantially different in response to treatments, being the accumulation of citric acid always increased, while the others (i.e. succinic, malic, fumaric acids) always decreased. Interestingly, citric acid levels significantly correlated with the expression of some Fe and S deficiency induced genes. Our results contribute to existing knowledge on the complexity of the S/Fe interaction, suggesting a model in which endogenous alteration of citric acid content in plant tissues might act as signal molecule for the regulation of some nuclear-encoded and nutrient-responsive genes and also provide a basis for further study of the mechanism underlying S and Fe sensing and signalling. Copyright �

Aldolase positively regulates of the canonical Wnt signaling pathway

PubMed Central

2014-01-01

The Wnt signaling pathway is an evolutionary conserved system, having pivotal roles during animal development. When over-activated, this signaling pathway is involved in cancer initiation and progression. The canonical Wnt pathway regulates the stability of β-catenin primarily by a destruction complex containing a number of different proteins, including Glycogen synthase kinase 3β (GSK-3β) and Axin, that promote proteasomal degradation of β-catenin. As this signaling cascade is modified by various proteins, novel screens aimed at identifying new Wnt signaling regulators were conducted in our laboratory. One of the different genes that were identified as Wnt signaling activators was Aldolase C (ALDOC). Here we report that ALDOC, Aldolase A (ALDOA) and Aldolase B (ALDOB) activate Wnt signaling in a GSK-3β-dependent mechanism, by disrupting the GSK-3β-Axin interaction and targeting Axin to the dishevelled (Dvl)-induced signalosomes that positively regulate the Wnt pathway thus placing the Aldolase proteins as novel Wnt signaling regulators. PMID:24993527

Neuropilins are positive regulators of Hedgehog signal transduction

PubMed Central

Hillman, R. Tyler; Feng, Brian Y.; Ni, Jun; Woo, Wei-Meng; Milenkovic, Ljiljana; Hayden Gephart, Melanie G.; Teruel, Mary N.; Oro, Anthony E.; Chen, James K.; Scott, Matthew P.

2011-01-01

The Hedgehog (Hh) pathway is essential for vertebrate embryogenesis, and excessive Hh target gene activation can cause cancer in humans. Here we show that Neuropilin 1 (Nrp1) and Nrp2, transmembrane proteins with roles in axon guidance and vascular endothelial growth factor (VEGF) signaling, are important positive regulators of Hh signal transduction. Nrps are expressed at times and locations of active Hh signal transduction during mouse development. Using cell lines lacking key Hh pathway components, we show that Nrps mediate Hh transduction between activated Smoothened (Smo) protein and the negative regulator Suppressor of Fused (SuFu). Nrp1 transcription is induced by Hh signaling, and Nrp1 overexpression increases maximal Hh target gene activation, indicating the existence of a positive feedback circuit. The regulation of Hh signal transduction by Nrps is conserved between mammals and bony fish, as we show that morpholinos targeting the Nrp zebrafish ortholog nrp1a produce a specific and highly penetrant Hh pathway loss-of-function phenotype. These findings enhance our knowledge of Hh pathway regulation and provide evidence for a conserved nexus between Nrps and this important developmental signaling system. PMID:22051878

HRS1 acts as a negative regulator of abscisic acid signaling to promote timely germination of Arabidopsis seeds.

PubMed

Wu, Chongming; Feng, Juanjuan; Wang, Ran; Liu, Hong; Yang, Huixia; Rodriguez, Pedro L; Qin, Huanju; Liu, Xin; Wang, Daowen

2012-01-01

In this work, we conducted functional analysis of Arabidopsis HRS1 gene in order to provide new insights into the mechanisms governing seed germination. Compared with wild type (WT) control, HRS1 knockout mutant (hrs1-1) exhibited significant germination delays on either normal medium or those supplemented with abscisic acid (ABA) or sodium chloride (NaCl), with the magnitude of the delay being substantially larger on the latter media. The hypersensitivity of hrs1-1 germination to ABA and NaCl required ABI3, ABI4 and ABI5, and was aggravated in the double mutant hrs1-1abi1-2 and triple mutant hrs1-1hab1-1abi1-2, indicating that HRS1 acts as a negative regulator of ABA signaling during seed germination. Consistent with this notion, HRS1 expression was found in the embryo axis, and was regulated both temporally and spatially, during seed germination. Further analysis showed that the delay of hrs1-1 germination under normal conditions was associated with reduction in the elongation of the cells located in the lower hypocotyl (LH) and transition zone (TZ) of embryo axis. Interestingly, the germination rate of hrs1-1 was more severely reduced by the inhibitor of cell elongation, and more significantly decreased by the suppressors of plasmalemma H(+)-ATPase activity, than that of WT control. The plasmalemma H(+)-ATPase activity in the germinating seeds of hrs1-1 was substantially lower than that exhibited by WT control, and fusicoccin, an activator of this pump, corrected the transient germination delay of hrs1-1. Together, our data suggest that HRS1 may be needed for suppressing ABA signaling in germinating embryo axis, which promotes the timely germination of Arabidopsis seeds probably by facilitating the proper function of plasmalemma H(+)-ATPase and the efficient elongation of LH and TZ cells.

HRS1 Acts as a Negative Regulator of Abscisic Acid Signaling to Promote Timely Germination of Arabidopsis Seeds

PubMed Central

Wang, Ran; Liu, Hong; Yang, Huixia; Rodriguez, Pedro L.; Qin, Huanju; Liu, Xin; Wang, Daowen

2012-01-01

In this work, we conducted functional analysis of Arabidopsis HRS1 gene in order to provide new insights into the mechanisms governing seed germination. Compared with wild type (WT) control, HRS1 knockout mutant (hrs1-1) exhibited significant germination delays on either normal medium or those supplemented with abscisic acid (ABA) or sodium chloride (NaCl), with the magnitude of the delay being substantially larger on the latter media. The hypersensitivity of hrs1-1 germination to ABA and NaCl required ABI3, ABI4 and ABI5, and was aggravated in the double mutant hrs1-1abi1-2 and triple mutant hrs1-1hab1-1abi1-2, indicating that HRS1 acts as a negative regulator of ABA signaling during seed germination. Consistent with this notion, HRS1 expression was found in the embryo axis, and was regulated both temporally and spatially, during seed germination. Further analysis showed that the delay of hrs1-1 germination under normal conditions was associated with reduction in the elongation of the cells located in the lower hypocotyl (LH) and transition zone (TZ) of embryo axis. Interestingly, the germination rate of hrs1-1 was more severely reduced by the inhibitor of cell elongation, and more significantly decreased by the suppressors of plasmalemma H+-ATPase activity, than that of WT control. The plasmalemma H+-ATPase activity in the germinating seeds of hrs1-1 was substantially lower than that exhibited by WT control, and fusicoccin, an activator of this pump, corrected the transient germination delay of hrs1-1. Together, our data suggest that HRS1 may be needed for suppressing ABA signaling in germinating embryo axis, which promotes the timely germination of Arabidopsis seeds probably by facilitating the proper function of plasmalemma H+-ATPase and the efficient elongation of LH and TZ cells. PMID:22545134

CIRCADIAN REGULATION METABOLIC SIGNALING MECHANISMS OF HUMAN BREAST CANCER GROWTH BY THE NOCTURNAL MELATONIN SIGNAL AND THE CONSEQUENCES OF ITS DISRUPTION BY LIGHT AT NIGHT

PubMed Central

Blask, David E.; Hill, Steven M.; Dauchy, Robert T.; Xiang, Shulin; Yuan, Lin; Duplessis, Tamika; Mao, Lulu; Dauchy, Erin; Sauer, Leonard A.

2011-01-01

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light-at-night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT1 melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT1-induced activation of Gαi2 signaling and reduction of cAMP levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT1-mediated suppression of cAMP leading to blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN. PMID:21605163

N,N-dimethyl hexadecylamine and related amines regulate root morphogenesis via jasmonic acid signaling in Arabidopsis thaliana.

PubMed

Raya-González, Javier; Velázquez-Becerra, Crisanto; Barrera-Ortiz, Salvador; López-Bucio, José; Valencia-Cantero, Eduardo

2017-05-01

Plant growth-promoting rhizobacteria are natural inhabitants of roots, colonize diverse monocot and dicot species, and affect several functional traits such as root architecture, adaptation to adverse environments, and protect plants from pathogens. N,N-dimethyl-hexadecylamine (C16-DMA) is a rhizobacterial amino lipid that modulates the postembryonic development of several plants, likely as part of volatile blends. In this work, we evaluated the bioactivity of C16-DMA and other related N,N-dimethyl-amines with varied length and found that inhibition of primary root growth was related to the length of the acyl chain. C16-DMA inhibited primary root growth affecting cell division and elongation, while promoting lateral root formation and root hair growth and density in Arabidopsis thaliana (Arabidopsis) wild-type (WT) seedlings. Interestingly, C16-DMA induced the expression of the jasmonic acid (JA)-responsive gene marker pLOX2:uidA, while JA-related mutants jar1, coi1-1, and myc2 affected on JA biosynthesis and perception, respectively, are compromised in C16-DMA responses. Comparison of auxin-regulated gene expression, root architectural changes in WT, and auxin-related mutants aux1-7, tir1/afb2/afb3, and arf7-1/arf19-1 to C16-DMA shows that the C16-DMA effects occur independently of auxin signaling. Together, these results reveal a novel class of aminolipids modulating root organogenesis via crosstalk with the JA signaling pathway.

Structural Basis for Ligand Regulation of the Fatty Acid-binding Protein 5, Peroxisome Proliferator-activated Receptor β/δ (FABP5-PPARβ/δ) Signaling Pathway*

PubMed Central

Armstrong, Eric H.; Goswami, Devrishi; Griffin, Patrick R.; Noy, Noa; Ortlund, Eric A.

2014-01-01

Fatty acid-binding proteins (FABPs) are a widely expressed group of calycins that play a well established role in solubilizing cellular fatty acids. Recent studies, however, have recast FABPs as active participants in vital lipid-signaling pathways. FABP5, like its family members, displays a promiscuous ligand binding profile, capable of interacting with numerous long chain fatty acids of varying degrees of saturation. Certain “activating” fatty acids induce the protein's cytoplasmic to nuclear translocation, stimulating PPARβ/δ transactivation; however, the rules that govern this process remain unknown. Using a range of structural and biochemical techniques, we show that both linoleic and arachidonic acid elicit FABP5's translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap of the protein. Furthermore, we show that more saturated, nonactivating fatty acids inhibit nuclear localization signal formation by destabilizing this activation loop, thus implicating FABP5 specifically in cis-bonded, polyunsaturated fatty acid signaling. PMID:24692551

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish

PubMed Central

Swartz, Mary E.; McCarthy, Neil; Norrie, Jacqueline L.; Eberhart, Johann K.

2016-01-01

The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. PMID:27122171

Plant elicitor peptides are conserved signals regulating direct and indirect antiherbivore defense

PubMed Central

Huffaker, Alisa; Pearce, Gregory; Veyrat, Nathalie; Erb, Matthias; Turlings, Ted C. J.; Sartor, Ryan; Shen, Zhouxin; Briggs, Steven P.; Vaughan, Martha M.; Alborn, Hans T.; Teal, Peter E. A.; Schmelz, Eric A.

2013-01-01

Insect-induced defenses occur in nearly all plants and are regulated by conserved signaling pathways. As the first described plant peptide signal, systemin regulates antiherbivore defenses in the Solanaceae, but in other plant families, peptides with analogous activity have remained elusive. In the current study, we demonstrate that a member of the maize (Zea mays) plant elicitor peptide (Pep) family, ZmPep3, regulates responses against herbivores. Consistent with being a signal, expression of the ZmPROPEP3 precursor gene is rapidly induced by Spodoptera exigua oral secretions. At concentrations starting at 5 pmol per leaf, ZmPep3 stimulates production of jasmonic acid, ethylene, and increased expression of genes encoding proteins associated with herbivory defense. These include proteinase inhibitors and biosynthetic enzymes for production of volatile terpenes and benzoxazinoids. In accordance with gene expression data, plants treated with ZmPep3 emit volatiles similar to those from plants subjected to herbivory. ZmPep3-treated plants also exhibit induced accumulation of the benzoxazinoid phytoalexin 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one glucoside. Direct and indirect defenses induced by ZmPep3 contribute to resistance against S. exigua through significant reduction of larval growth and attraction of Cotesia marginiventris parasitoids. ZmPep3 activity is specific to Poaceous species; however, peptides derived from PROPEP orthologs identified in Solanaceous and Fabaceous plants also induce herbivory-associated volatiles in their respective species. These studies demonstrate that Peps are conserved signals across diverse plant families regulating antiherbivore defenses and are likely to be the missing functional homologs of systemin outside of the Solanaceae. PMID:23509266

Regulation, Signaling, and Physiological Functions of G-Proteins.

PubMed

Syrovatkina, Viktoriya; Alegre, Kamela O; Dey, Raja; Huang, Xin-Yun

2016-09-25

Heterotrimeric guanine-nucleotide-binding regulatory proteins (G-proteins) mainly relay the information from G-protein-coupled receptors (GPCRs) on the plasma membrane to the inside of cells to regulate various biochemical functions. Depending on the targeted cell types, tissues, and organs, these signals modulate diverse physiological functions. The basic schemes of heterotrimeric G-proteins have been outlined. In this review, we briefly summarize what is known about the regulation, signaling, and physiological functions of G-proteins. We then focus on a few less explored areas such as the regulation of G-proteins by non-GPCRs and the physiological functions of G-proteins that cannot be easily explained by the known G-protein signaling pathways. There are new signaling pathways and physiological functions for G-proteins to be discovered and further interrogated. With the advancements in structural and computational biological techniques, we are closer to having a better understanding of how G-proteins are regulated and of the specificity of G-protein interactions with their regulators. Copyright © 2016 Elsevier Ltd. All rights reserved.

Regulation of B Cell Functions by the Sialic Acid-Binding Receptors Siglec-G and CD22

PubMed Central

Jellusova, Julia; Nitschke, Lars

2011-01-01

B cell antigen receptor (BCR) engagement can lead to many different physiologic outcomes. To achieve an appropriate response, the BCR signal is interpreted in the context of other stimuli and several additional receptors on the B cell surface participate in the modulation of the signal. Two members of the Siglec (sialic acid-binding immunoglobulin-like lectin) family, CD22 and Siglec-G have been shown to inhibit the BCR signal. Recent findings indicate that the ability of these two receptors to bind sialic acids might be important to induce tolerance to self-antigens. Sialylated glycans are usually absent on microbes but abundant in higher vertebrates and might therefore provide an important tolerogenic signal. Since the expression of the specific ligands for Siglec-G and CD22 is tightly regulated and since Siglecs are not only able to bind their ligands in trans but also on the same cell surface this might provide additional mechanisms to control the BCR signal. Although both Siglec-G and CD22 are expressed on B cells and are able to inhibit BCR mediated signaling, they also show unique biological functions. While CD22 is the dominant regulator of calcium signaling on conventional B2 cells and also seems to play a role on marginal zone B cells, Siglec-G exerts its function mainly on B1 cells and influences their lifespan and antibody production. Both Siglec-G and CD22 have also recently been linked to toll-like receptor signaling and may provide a link in the regulation of the adaptive and innate immune response of B cells. PMID:22566885

Modulation of organic acids and sugar content in tomato fruits by an abscisic acid-regulated transcription factor.

PubMed

Bastías, Adriana; López-Climent, María; Valcárcel, Mercedes; Rosello, Salvador; Gómez-Cadenas, Aurelio; Casaretto, José A

2011-03-01

Growing evidence suggests that the phytohormone abscisic acid (ABA) plays a role in fruit development. ABA signaling components of developmental programs and responses to stress conditions include the group of basic leucine zipper transcriptional activators known as ABA-response element binding factors (AREBs/ABFs). AREB transcription factors mediate ABA-regulated gene expression involved in desiccation tolerance and are expressed mainly in seeds and in vegetative tissues under stress; however, they are also expressed in some fruits such as tomato. In order to get an insight into the role of ABA signaling in fruit development, the expression of two AREB-like factors were investigated during different developmental stages. In addition, tomato transgenic lines that overexpress and downregulate one AREB-like transcription factor, SlAREB1, were used to determine its effect on the levels of some metabolites determining fruit quality. Higher levels of citric acid, malic acid, glutamic acid, glucose and fructose were observed in SlAREB1-overexpressing lines compared with those in antisense suppression lines in red mature fruit pericarp. The higher hexose concentration correlated with increased expression of genes encoding a vacuolar invertase (EC 3.2.1.26) and a sucrose synthase (EC 2.4.1.13). No significant changes were found in ethylene content which agrees with the normal ripening phenotype observed in transgenic fruits. These results suggest that an AREB-mediated ABA signal affects the metabolism of these compounds during the fruit developmental program. Copyright © Physiologia Plantarum 2010.

Redox-dependent regulation of epidermal growth factor receptor signaling.

PubMed

Heppner, David E; van der Vliet, Albert

2016-08-01

Tyrosine phosphorylation-dependent cell signaling represents a unique feature of multicellular organisms, and is important in regulation of cell differentiation and specialized cell functions. Multicellular organisms also contain a diverse family of NADPH oxidases (NOXs) that have been closely linked with tyrosine kinase-based cell signaling and regulate tyrosine phosphorylation via reversible oxidation of cysteine residues that are highly conserved within many proteins involved in this signaling pathway. An example of redox-regulated tyrosine kinase signaling involves the epidermal growth factor receptor (EGFR), a widely studied receptor system with diverse functions in normal cell biology as well as pathologies associated with oxidative stress such as cancer. The purpose of this Graphical Redox Review is to highlight recently emerged concepts with respect to NOX-dependent regulation of this important signaling pathway. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Oleic acid levels regulated by glycerolipid metabolism modulate defense gene expression in Arabidopsis

PubMed Central

Kachroo, Aardra; Venugopal, Srivathsa C.; Lapchyk, Ludmila; Falcone, Deane; Hildebrand, David; Kachroo, Pradeep

2004-01-01

Stearoyl-acyl-carrier-protein-desaturase-mediated conversion of stearic acid (18:0) to oleic acid (18:1) is a key step, which regulates levels of unsaturated fatty acids in cells. We previously showed that stearoyl-acyl-carrier-protein-desaturase mutants ssi2/fab2 carrying a loss-of-function mutation in the plastidial glycerol-3-phosphate (G3P) acyltransferase (act1) have elevated 18:1 levels and are restored in their altered defense signaling. Because G3P is required for the acylation of 18:1 by G3P acyltransferase, it was predicted that reduction of G3P levels should increase 18:1 levels and thereby revert ssi2-triggered phenotypes. Here we show that a mutation in G3P dehydrogenase restores both salicylic acid- and jasmonic acid-mediated phenotypes of ssi2 plants. The G3P dehydrogenase gene was identified by map-based cloning of the ssi2 suppressor mutant rdc8 (gly1-3) and confirmed by epistatic analysis of ssi2 with gly1-1. Restoration of ssi2-triggered phenotypes by the gly1-3 mutation was age-dependent and correlated with the levels of 18:1. Regeneration of G3P pools by glycerol application in ssi2 and ssi2 gly1-3 plants caused a marked reduction in the 18:1 levels, which rendered these plants hypersensitive to glycerol. This hypersensitivity in ssi2 was rescued by the act1 mutation. Furthermore, overexpression of the ACT1 gene resulted in enhanced sensitivity to glycerol. Glycerol application also lowered the 18:1 content in SSI2 plants and converted these into ssi2-mimics. Our results show that 18:1 levels in plastids are regulated by means of acylation with G3P, and a balance between G3P and 18:1 is critical for the regulation of salicylic acid- and jasmonic acid-mediated signaling pathways. PMID:15044700

Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway

PubMed Central

Liu, Yunxia; Dong, Weibing; Shao, Jing; Wang, Yibin; Zhou, Meiyi; Sun, Haipeng

2017-01-01

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation. PMID:29118722

Branched-Chain Amino Acid Negatively Regulates KLF15 Expression via PI3K-AKT Pathway.

PubMed

Liu, Yunxia; Dong, Weibing; Shao, Jing; Wang, Yibin; Zhou, Meiyi; Sun, Haipeng

2017-01-01

Recent studies have linked branched-chain amino acid (BCAA) with numerous metabolic diseases. However, the molecular basis of BCAA's roles in metabolic regulation remains to be established. KLF15 (Krüppel-like factor 15) is a transcription factor and master regulator of glycemic, lipid, and amino acids metabolism. In the present study, we found high concentrations of BCAA suppressed KLF15 expression while BCAA starvation induced KLF15 expression, suggesting KLF15 expression is negatively controlled by BCAA.Interestingly, BCAA starvation induced PI3K-AKT signaling. KLF15 induction by BCAA starvation was blocked by PI3K and AKT inhibitors, indicating the activation of PI3K-AKT signaling pathway mediated the KLF15 induction. BCAA regulated KLF15 expression at transcriptional level but not post-transcriptional level. However, BCAA starvation failed to increase the KLF15-promoter-driven luciferase expression, suggesting KLF15 promoter activity was not directly controlled by BCAA. Finally, fasting reduced BCAA abundance in mice and KLF15 expression was dramatically induced in muscle and white adipose tissue, but not in liver. Together, these data demonstrated BCAA negatively regulated KLF15 expression, suggesting a novel molecular mechanism underlying BCAA's multiple functions in metabolic regulation.

Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription

PubMed Central

Kang, Jian; Kusnadi, Eric P.; Ogden, Allison J.; Hicks, Rodney J.; Bammert, Lukas; Kutay, Ulrike; Hung, Sandy; Sanij, Elaine; Hannan, Ross D.; Hannan, Katherine M.; Pearson, Richard B.

2016-01-01

Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer. PMID:27385002

Gibberellic Acid-Stimulated Arabidopsis6 Serves as an Integrator of Gibberellin, Abscisic Acid, and Glucose Signaling during Seed Germination in Arabidopsis1[OPEN

PubMed Central

Zhong, Chunmei; Xu, Hao; Ye, Siting; Wang, Shiyi; Li, Lingfei; Zhang, Shengchun; Wang, Xiaojing

2015-01-01

The DELLA protein REPRESSOR OF ga1-3-LIKE2 (RGL2) plays an important role in seed germination under different conditions through a number of transcription factors. However, the functions of the structural genes associated with RGL2-regulated germination are less defined. Here, we report the role of an Arabidopsis (Arabidopsis thaliana) cell wall-localized protein, Gibberellic Acid-Stimulated Arabidopsis6 (AtGASA6), in functionally linking RGL2 and a cell wall loosening expansin protein (Arabidopsis expansin A1 [AtEXPA1]), resulting in the control of embryonic axis elongation and seed germination. AtGASA6-overexpressing seeds showed precocious germination, whereas transfer DNA and RNA interference mutant seeds displayed delayed seed germination under abscisic acid, paclobutrazol, and glucose (Glc) stress conditions. The differences in germination rates resulted from corresponding variation in cell elongation in the hypocotyl-radicle transition region of the embryonic axis. AtGASA6 was down-regulated by RGL2, GLUCOSE INSENSITIVE2, and ABSCISIC ACID-INSENSITIVE5 genes, and loss of AtGASA6 expression in the gasa6 mutant reversed the insensitivity shown by the rgl2 mutant to paclobutrazol and the gin2 mutant to Glc-induced stress, suggesting that it is involved in regulating both the gibberellin and Glc signaling pathways. Furthermore, it was found that the promotion of seed germination and length of embryonic axis by AtGASA6 resulted from a promotion of cell elongation at the embryonic axis mediated by AtEXPA1. Taken together, the data indicate that AtGASA6 links RGL2 and AtEXPA1 functions and plays a role as an integrator of gibberellin, abscisic acid, and Glc signaling, resulting in the regulation of seed germination through a promotion of cell elongation. PMID:26400990

Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells.

PubMed

Rosario, Fredrick J; Kanai, Yoshikatsu; Powell, Theresa L; Jansson, Thomas

2013-02-01

Abnormal fetal growth increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Emerging evidence suggests that changes in placental amino acid transport directly contribute to altered fetal growth. However, the molecular mechanisms regulating placental amino acid transport are largely unknown. Here we combined small interfering (si) RNA-mediated silencing approaches with protein expression/localization and functional studies in cultured primary human trophoblast cells to test the hypothesis that mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate amino acid transporters by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal System A and System L amino acid transport activity but had no effect on growth factor-stimulated amino acid uptake. Simultaneous inhibition of mTORC1 and 2 completely inhibited both basal and growth factor-stimulated amino acid transport activity. In contrast, mTOR inhibition had no effect on serotonin transport. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of specific System A (SNAT2, SLC38A2) and System L (LAT1, SLC7A5) transporter isoforms without affecting global protein expression. In conclusion, mTORC1 and mTORC2 regulate human trophoblast amino acid transporters by modulating the cell surface abundance of specific transporter isoforms. This is the first report showing regulation of amino acid transport by mTORC2. Because placental mTOR activity and amino acid transport are decreased in human intrauterine growth restriction our data are consistent with the possibility that dysregulation of placental mTOR plays an important role in the development of abnormal fetal growth.

Arachidonic Acid: An Evolutionarily Conserved Signaling Molecule Modulates Plant Stress Signaling Networks[C][W

PubMed Central

Savchenko, Tatyana; Walley, Justin W.; Chehab, E. Wassim; Xiao, Yanmei; Kaspi, Roy; Pye, Matthew F.; Mohamed, Maged E.; Lazarus, Colin M.; Bostock, Richard M.; Dehesh, Katayoon

2010-01-01

Fatty acid structure affects cellular activities through changes in membrane lipid composition and the generation of a diversity of bioactive derivatives. Eicosapolyenoic acids are released into plants upon infection by oomycete pathogens, suggesting they may elicit plant defenses. We exploited transgenic Arabidopsis thaliana plants (designated EP) producing eicosadienoic, eicosatrienoic, and arachidonic acid (AA), aimed at mimicking pathogen release of these compounds. We also examined their effect on biotic stress resistance by challenging EP plants with fungal, oomycete, and bacterial pathogens and an insect pest. EP plants exhibited enhanced resistance to all biotic challenges, except they were more susceptible to bacteria than the wild type. Levels of jasmonic acid (JA) were elevated and levels of salicylic acid (SA) were reduced in EP plants. Altered expression of JA and SA pathway genes in EP plants shows that eicosapolyenoic acids effectively modulate stress-responsive transcriptional networks. Exogenous application of various fatty acids to wild-type and JA-deficient mutants confirmed AA as the signaling molecule. Moreover, AA treatment elicited heightened expression of general stress-responsive genes. Importantly, tomato (Solanum lycopersicum) leaves treated with AA exhibited reduced susceptibility to Botrytis cinerea infection, confirming AA signaling in other plants. These studies support the role of AA, an ancient metazoan signaling molecule, in eliciting plant stress and defense signaling networks. PMID:20935246

Shifting from priming of salicylic acid- to jasmonic acid-regulated defences by Trichoderma protects tomato against the root knot nematode Meloidogyne incognita.

PubMed

Martínez-Medina, Ainhoa; Fernandez, Ivan; Lok, Gerrit B; Pozo, María J; Pieterse, Corné M J; Van Wees, Saskia C M

2017-02-01

Beneficial root endophytes such as Trichoderma spp. can reduce infections by parasitic nematodes through triggering host defences. Little is currently known about the complex hormone signalling underlying the induction of resistance. In this study, we investigated whether Trichoderma modulates the hormone signalling network in the host to induce resistance to nematodes. We investigated the role and the timing of the jasmonic acid (JA)- and salicylic acid (SA)-regulated defensive pathways in Trichoderma-induced resistance to the root knot nematode Meloidogyne incognita. A split-root system of tomato (Solanum lycopersicum) was used to study local and systemic induced defences by analysing nematode performance, defence gene expression, responsiveness to exogenous hormone application, and dependence on SA and JA signalling of Trichoderma-induced resistance. Root colonization by Trichoderma impeded nematode performance both locally and systemically at multiple stages of the parasitism, that is, invasion, galling and reproduction. First, Trichoderma primed SA-regulated defences, which limited nematode root invasion. Then, Trichoderma enhanced JA-regulated defences, thereby antagonizing the deregulation of JA-dependent immunity by the nematodes, which compromised galling and fecundity. Our results show that Trichoderma primes SA- and JA-dependent defences in roots, and that the priming of responsiveness to these hormones upon nematode attack is plastic and adaptive to the parasitism stage. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Necrotrophic pathogens use the salicylic acid signaling pathway to promote disease development in tomato.

PubMed

Rahman, Taha Abd El; Oirdi, Mohamed El; Gonzalez-Lamothe, Rocio; Bouarab, Kamal

2012-12-01

Plants use different immune pathways to combat pathogens. The activation of the jasmonic acid (JA)-signaling pathway is required for resistance against necrotrophic pathogens; however, to combat biotrophic pathogens, the plants activate mainly the salicylic acid (SA)-signaling pathway. SA can antagonize JA signaling and vice versa. NPR1 (noninducible pathogenesis-related 1) is considered a master regulator of SA signaling. NPR1 interacts with TGA transcription factors, ultimately leading to the activation of SA-dependent responses. SA has been shown to promote disease development caused by the necrotrophic pathogen Botrytis cinerea through NPR1, by suppressing the expression of two JA-dependent defense genes, proteinase inhibitors I and II. We show here that the transcription factor TGA1.a contributes to disease development caused by B. cinerea in tomato by suppressing the expression of proteinase inhibitors I and II. Finally, we present evidence that the SA-signaling pathway contributes to disease development caused by another necrotrophic pathogen, Alternaria solani, in tomato. Disease development promoted by SA through NPR1 requires the TGA1.a transcription factor. These data highlight how necrotrophs manipulate the SAsignaling pathway to promote their disease in tomato.

Heat shock transcription factor 3 regulates plant immune response through modulation of salicylic acid accumulation and signaling in cassava.

PubMed

Wei, Yunxie; Liu, Guoyin; Chang, Yanli; He, Chaozu; Shi, Haitao

2018-04-16

As the terminal components of signal transduction, heat stress transcription factors (Hsfs) mediate the activation of multiple genes responsive to various stresses. However, the information and functional analysis are very limited in non-model plants, especially in cassava (Manihot esculenta), one of the most important crops in the tropical area. In this study, 32 MeHsfs were identified from cassava genome, the evolutionary tree, gene structures and motifs were also analyzed. Gene expression analysis found that MeHsfs were commonly regulated by Xanthomonas axonopodis pv manihotis (Xam). Among these MeHsfs, MeHsf3 was specifically located in the cell nucleus and had transcriptional activated activity on HSEs. Through transient expression in Nicotiana benthamiana leaves and virus-induced gene silencing (VIGS) in cassava, we identified the essential role of MeHsf3 in plant disease resistance, by regulating the transcripts of Enhanced Disease Susceptibility 1 (EDS1) and pathogen-related gene 4 (PR4). Notably, as regulators of defense susceptibility, MeEDS1 and MePR4 were identified as direct targets of MeHsf3. Moreover, the disease sensitivity of MeHsf3- and MeEDS1-silenced plants could be restored by exogenous salicylic acid (SA) treatment. Taken together, this study highlights the involvement of MeHsf3 in defense resistance through the transcription activation on MeEDS1 and MePR4. This article is protected by copyright. All rights reserved. © 2018 BSPP and John Wiley & Sons Ltd.

ISOLATION AND CHARACTERIZATION OF AXOLOTL NPDC-1 AND ITS EFFECTS ON RETINOIC ACID RECEPTOR SIGNALING

PubMed Central

Theodosiou, Maria; Monaghan, James R; Spencer, Michael L; Voss, S Randal; Noonan, Daniel J

2009-01-01

Retinoic acid, a key morphogen in early vertebrate development and tissue regeneration, mediates its effects through the binding of receptors that act as ligand-induced transcription factors. These binding events function to recruit an array of transcription co-regulatory proteins to specific gene promoters. One such co-regulatory protein, neuronal proliferation and differentiation control-1 (NPDC-1), is broadly expressed during mammalian development and functions as an in vitro repressor of retinoic acid receptor (RAR)-mediated transcription. To obtain comparative and developmental insights about NPDC-1 function, we cloned the axolotl (Ambystoma mexicanum) orthologue and measured transcript abundances among tissues sampled during the embryonic and juvenile phases of development, and also during spinal cord regeneration. Structurally, the axolotl orthologue of NPDC-1 retained sequence identity to mammalian sequences in all functional domains. Functionally, we observed that axolotl NPDC-1 mRNA expression peaked late in embryogenesis, with highest levels of expression occurring during the time of limb development, a process regulated by retinoic acid signaling. Also similar to what has been observed in mammals, axolotl NPDC-1 directly interacts with axolotl RAR, modulates axolotl RAR DNA binding, and represses cell proliferation and axolotl RAR-mediated gene transcription. These data justify axolotl as a model to further investigate NPDC-1 and its role in regulating retinoic acid signaling. PMID:17331771

Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway.

PubMed

Armstrong, Eric H; Goswami, Devrishi; Griffin, Patrick R; Noy, Noa; Ortlund, Eric A

2014-05-23

Fatty acid-binding proteins (FABPs) are a widely expressed group of calycins that play a well established role in solubilizing cellular fatty acids. Recent studies, however, have recast FABPs as active participants in vital lipid-signaling pathways. FABP5, like its family members, displays a promiscuous ligand binding profile, capable of interacting with numerous long chain fatty acids of varying degrees of saturation. Certain "activating" fatty acids induce the protein's cytoplasmic to nuclear translocation, stimulating PPARβ/δ transactivation; however, the rules that govern this process remain unknown. Using a range of structural and biochemical techniques, we show that both linoleic and arachidonic acid elicit FABP5's translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap of the protein. Furthermore, we show that more saturated, nonactivating fatty acids inhibit nuclear localization signal formation by destabilizing this activation loop, thus implicating FABP5 specifically in cis-bonded, polyunsaturated fatty acid signaling. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive ActivityS⃞

PubMed Central

Zhao, Pingwei; Sharir, Haleli; Kapur, Ankur; Cowan, Alan; Geller, Ellen B.; Adler, Martin W.; Seltzman, Herbert H.; Reggio, Patricia H.; Heynen-Genel, Susanne; Sauer, Michelle; Chung, Thomas D.Y.; Bai, Yushi; Chen, Wei; Caron, Marc G.; Barak, Larry S.

2010-01-01

Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drugs and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics oxantel pamoate and pyrantel pamoate; the psychoactive compounds hydroxyzine pamoate (Vistaril) and imipramine pamoate (Tofranil-PM); and the peptide hormones triptorelin pamoate (Trelstar) and octreotide pamoate (OncoLar). We have found that pamoic acid induces a Gi/o-linked, GPR35-mediated increase in the phosphorylation of extracellular signal-regulated kinase 1/2, recruitment of β-arrestin2 to GPR35, and internalization of GPR35. In mice, it attenuates visceral pain perception, indicating an antinociceptive effect, possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID2745687). Pamoic acid and potent antagonists such as CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35-associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent. PMID:20826425

The putative glutamate receptor 1.1 (AtGLR1.1) in Arabidopsis thaliana regulates abscisic acid biosynthesis and signaling to control development and water loss.

PubMed

Kang, Jiman; Mehta, Sohum; Turano, Frank J

2004-10-01

The involvement of the putative glutamate receptor 1.1 (AtGLR1.1) gene in the regulation of abscisic acid (ABA) biosynthesis and signaling was investigated in Arabidopsis. Seeds from AtGLR1.1-deficient (antiAtGLR1.1) lines had increased sensitivity to exogenous ABA with regard to the effect of the hormone on the inhibition of seed germination and root growth. Seed germination, which was inhibited by an animal ionotropic glutamate receptor antagonist, 6,7-dinitroquinoxaline-2,3-[1H,4H]-dione, was restored by co-incubation with an inhibitor of ABA biosynthesis, fluridone. These results confirm that germination in antiAtGLR1.1 lines was inhibited by increased ABA. When antiAtGLR1.1 and WT seeds were co-incubated in fluridone and exogenous ABA, the antiAtGLR1.1 seeds were more sensitive to ABA. In addition, the antiAtGLR1.1 lines exhibited altered expression of ABA biosynthetic (ABA) and signaling (ABI) genes, when compared with WT. Combining the physiological and molecular results suggest that ABA biosynthesis and signaling in antiAtGLR1.1 lines are altered. ABA levels in leaves of antiAtGLR1.1 lines are higher than those in WT. In addition, the antiAtGLR1.1 lines had reduced stomatal apertures, and exhibited enhanced drought tolerance due to deceased water loss compared with WT lines. The results from these experiments imply that ABA biosynthesis and signaling can be regulated through AtGLR1.1 to trigger pre- and post-germination arrest and changes in whole plant responses to water stress. Combined with our earlier results, these findings suggest that AtGLR1.1 integrates and regulates the different aspects of C, N and water balance that are required for normal plant growth and development.

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish.

PubMed

Lovely, C Ben; Swartz, Mary E; McCarthy, Neil; Norrie, Jacqueline L; Eberhart, Johann K

2016-06-01

The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. © 2016. Published by The Company of Biologists Ltd.

ASM-3 Acid Sphingomyelinase Functions as a Positive Regulator of the DAF-2/AGE-1 Signaling Pathway and Serves as a Novel Anti-Aging Target

PubMed Central

Kim, Yongsoon; Sun, Hong

2012-01-01

In C. elegans, the highly conserved DAF-2/insulin/insulin-like growth factor 1 receptor signaling (IIS) pathway regulates longevity, metabolism, reproduction and development. In mammals, acid sphingomyelinase (ASM) is an enzyme that hydrolyzes sphingomyelin to produce ceramide. ASM has been implicated in CD95 death receptor signaling under certain stress conditions. However, the involvement of ASM in growth factor receptor signaling under physiological conditions is not known. Here, we report that in vivo ASM functions as a positive regulator of the DAF-2/IIS pathway in C. elegans. We have shown that inactivation of asm-3 extends animal lifespan and promotes dauer arrest, an alternative developmental process. A significant cooperative effect on lifespan is observed between asm-3 deficiency and loss-of-function alleles of the age-1/PI 3-kinase, with the asm-3; age-1 double mutant animals having a mean lifespan 259% greater than that of the wild-type animals. The lifespan extension phenotypes caused by the loss of asm-3 are dependent on the functions of daf-16/FOXO and daf-18/PTEN. We have demonstrated that inactivation of asm-3 causes nuclear translocation of DAF-16::GFP protein, up-regulates endogenous DAF-16 protein levels and activates the downstream targeting genes of DAF-16. Together, our findings reveal a novel role of asm-3 in regulation of lifespan and diapause by modulating IIS pathway. Importantly, we have found that two drugs known to inhibit mammalian ASM activities, desipramine and clomipramine, markedly extend the lifespan of wild-type animals, in a manner similar to that achieved by genetic inactivation of the asm genes. Our studies illustrate a novel strategy of anti-aging by targeting ASM, which may potentially be extended to mammals. PMID:23049887

ASM-3 acid sphingomyelinase functions as a positive regulator of the DAF-2/AGE-1 signaling pathway and serves as a novel anti-aging target.

PubMed

Kim, Yongsoon; Sun, Hong

2012-01-01

In C. elegans, the highly conserved DAF-2/insulin/insulin-like growth factor 1 receptor signaling (IIS) pathway regulates longevity, metabolism, reproduction and development. In mammals, acid sphingomyelinase (ASM) is an enzyme that hydrolyzes sphingomyelin to produce ceramide. ASM has been implicated in CD95 death receptor signaling under certain stress conditions. However, the involvement of ASM in growth factor receptor signaling under physiological conditions is not known. Here, we report that in vivo ASM functions as a positive regulator of the DAF-2/IIS pathway in C. elegans. We have shown that inactivation of asm-3 extends animal lifespan and promotes dauer arrest, an alternative developmental process. A significant cooperative effect on lifespan is observed between asm-3 deficiency and loss-of-function alleles of the age-1/PI 3-kinase, with the asm-3; age-1 double mutant animals having a mean lifespan 259% greater than that of the wild-type animals. The lifespan extension phenotypes caused by the loss of asm-3 are dependent on the functions of daf-16/FOXO and daf-18/PTEN. We have demonstrated that inactivation of asm-3 causes nuclear translocation of DAF-16::GFP protein, up-regulates endogenous DAF-16 protein levels and activates the downstream targeting genes of DAF-16. Together, our findings reveal a novel role of asm-3 in regulation of lifespan and diapause by modulating IIS pathway. Importantly, we have found that two drugs known to inhibit mammalian ASM activities, desipramine and clomipramine, markedly extend the lifespan of wild-type animals, in a manner similar to that achieved by genetic inactivation of the asm genes. Our studies illustrate a novel strategy of anti-aging by targeting ASM, which may potentially be extended to mammals.

Inhibition of Melanogenesis by Gallic Acid: Possible Involvement of the PI3K/Akt, MEK/ERK and Wnt/β-Catenin Signaling Pathways in B16F10 Cells

PubMed Central

Su, Tzu-Rong; Lin, Jen-Jie; Tsai, Chi-Chu; Huang, Tsu-Kei; Yang, Zih-Yan; Wu, Ming-O; Zheng, Yu-Qing; Su, Ching-Chyuan; Wu, Yu-Jen

2013-01-01

Gallic acid is one of the major flavonoids found in plants. It acts as an antioxidant, and seems to have anti-inflammatory, anti-viral, and anti-cancer properties. In this study, we investigated the effects of gallic acid on melanogenesis, including the activation of melanogenesis signaling pathways. Gallic acid significantly inhibited both melanin synthesis and tyrosinase activity in a dose- and time-dependent manner, and decreased the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP1), and dopachrome tautomerase (Dct). In addition, gallic acid also acts by phosphorylating and activating melanogenesis inhibitory proteins such as Akt and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Using inhibitors against PI3K/Akt (LY294002) or MEK/ERK-specific (PD98059), the hypopigmentation effect was suppressed, and the gallic acid-initiated activation of MEK/ERK and PI3K/Akt was also revoked. Gallic acid also increased GSK3β and p-β-catenin expression but down-regulated p-GSK3β. Moreover, GSK3β-specific inhibitor (SB216763) restored gallic acid-induced melanin reduction. These results suggest that activation of the MEK/ERK, PI3K/Akt, and inhibition of Wnt/β-catenin signaling pathways is involved in the melanogenesis signaling cascade, and that activation by gallic acid reduces melanin synthesis via down-regulation of MITF and its downstream signaling pathway. In conclusion, gallic acid may be a potentially agent for the treatment of certain skin conditions. PMID:24129178

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA.

PubMed

Schmid, Tobias; Snoek, L Basten; Fröhli, Erika; van der Bent, M Leontien; Kammenga, Jan; Hajnal, Alex

2015-05-01

Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.

Dynein-mediated trafficking negatively regulates LET-23 EGFR signaling

PubMed Central

Skorobogata, Olga; Meng, Jassy; Gauthier, Kimberley; Rocheleau, Christian E.

2016-01-01

Epidermal growth factor receptor (EGFR) signaling is essential for animal development, and increased signaling underlies many human cancers. Identifying the genes and cellular processes that regulate EGFR signaling in vivo will help to elucidate how this pathway can become inappropriately activated. Caenorhabditis elegans vulva development provides an in vivo model to genetically dissect EGFR signaling. Here we identified a mutation in dhc-1, the heavy chain of the cytoplasmic dynein minus end–directed microtubule motor, in a genetic screen for regulators of EGFR signaling. Despite the many cellular functions of dynein, DHC-1 is a strong negative regulator of EGFR signaling during vulva induction. DHC-1 is required in the signal-receiving cell and genetically functions upstream or in parallel to LET-23 EGFR. LET-23 EGFR accumulates in cytoplasmic foci in dhc-1 mutants, consistent with mammalian cell studies in which dynein is shown to regulate late endosome trafficking of EGFR with the Rab7 GTPase. However, we found different distributions of LET-23 EGFR foci in rab-7 versus dhc-1 mutants, suggesting that dynein functions at an earlier step of LET-23 EGFR trafficking to the lysosome than RAB-7. Our results demonstrate an in vivo role for dynein in limiting LET-23 EGFR signaling via endosomal trafficking. PMID:27654944

Mesodermal retinoic acid signaling regulates endothelial cell coalescence in caudal pharyngeal arch artery vasculogenesis

PubMed Central

Li, Peng; Pashmforoush, Mohammad; Sucov, Henry M.

2011-01-01

Disruption of retinoic acid signaling causes a variety of pharyngeal arch artery and great vessel defects, as well as malformations in many other tissues, including those derived from the pharyngeal endoderm. Previous studies implied that arch artery defects in the context of defective RA signaling occur secondary to pharyngeal pouch segmentation defects, although this model has never been experimentally verified. In this study, we examined arch artery morphogenesis during mouse development, and the role of RA in this process. We show in normal embryos that the arch arteries form by vasculogenic differentiation of pharyngeal mesoderm. Using various genetic backgrounds and tissue-specific mutation approaches, we segregate pharyngeal arch artery and pharyngeal pouch defects in RA receptor mutants, and show that RA signal transduction only in pharyngeal mesoderm is required for arch artery formation. RA does not control pharyngeal mesodermal differentiation to endothelium, but instead promotes the aggregation of endothelial cells into nascent vessels. Expression of VE-cadherin was substantially reduced in RAR mutants, and this deficiency may underlie the arch artery defects. The consequences of disrupted mesodermal and endodermal RA signaling were restricted to the 4th and 6th arch arteries and to the 4th pharyngeal pouch, respectively, suggesting that different regulatory mechanisms control the formation of the more anterior arch arteries and pouches. PMID:22040871

Cell Signaling Pathways that Regulate Ag Presentation

PubMed Central

Brutkiewicz, Randy R.

2016-01-01

Cell signaling pathways regulate much in the life of a cell: from shuttling cargo through intracellular compartments and onto the cell surface, how it should respond to stress, protecting itself from harm (environmental insults or infections), to ultimately, death by apoptosis. These signaling pathways are important for various aspects of the immune response as well. However, not much is known in terms of the participation of cell signaling pathways in Ag presentation--a necessary first step in the activation of innate and adaptive T cells. In this brief review, I will discuss the known signaling molecules (and pathways) that regulate how Ags are presented to T cells and the mechanism(s) if identified. Studies in this area have important implications in vaccine development and new treatment paradigms against infectious diseases, autoimmunity and cancer. PMID:27824592

The Transcription Factor ABI4 Is Required for the Ascorbic Acid–Dependent Regulation of Growth and Regulation of Jasmonate-Dependent Defense Signaling Pathways in Arabidopsis[C][W

PubMed Central

Kerchev, Pavel I.; Pellny, Till K.; Vivancos, Pedro Diaz; Kiddle, Guy; Hedden, Peter; Driscoll, Simon; Vanacker, Hélène; Verrier, Paul; Hancock, Robert D.; Foyer, Christine H.

2011-01-01

Cellular redox homeostasis is a hub for signal integration. Interactions between redox metabolism and the ABSCISIC ACID-INSENSITIVE-4 (ABI4) transcription factor were characterized in the Arabidopsis thaliana vitamin c defective1 (vtc1) and vtc2 mutants, which are defective in ascorbic acid synthesis and show a slow growth phenotype together with enhanced abscisic acid (ABA) levels relative to the wild type (Columbia-0). The 75% decrease in the leaf ascorbate pool in the vtc2 mutants was not sufficient to adversely affect GA metabolism. The transcriptome signatures of the abi4, vtc1, and vtc2 mutants showed significant overlap, with a large number of transcription factors or signaling components similarly repressed or induced. Moreover, lincomycin-dependent changes in LIGHT HARVESTING CHLOROPHYLL A/B BINDING PROTEIN 1.1 expression were comparable in these mutants, suggesting overlapping participation in chloroplast to nucleus signaling. The slow growth phenotype of vtc2 was absent in the abi4 vtc2 double mutant, as was the sugar-insensitive phenotype of the abi4 mutant. Octadecanoid derivative-responsive AP2/ERF-domain transcription factor 47 (ORA47) and AP3 (an ABI5 binding factor) transcripts were enhanced in vtc2 but repressed in abi4 vtc2, suggesting that ABI4 and ascorbate modulate growth and defense gene expression through jasmonate signaling. We conclude that low ascorbate triggers ABA- and jasmonate-dependent signaling pathways that together regulate growth through ABI4. Moreover, cellular redox homeostasis exerts a strong influence on sugar-dependent growth regulation. PMID:21926335

LPA3-mediated lysophosphatidic acid signalling in implantation and embryo spacing

PubMed Central

Ye, Xiaoqin; Hama, Kotaro; Contos, James J.A.; Anliker, Brigitte; Inoue, Aska; Skinner, Michael K.; Suzuki, Hiroshi; Amano, Tomokazu; Kennedy, Grace; Arai, Hiroyuki; Aoki, Junken; Chun, Jerold

2005-01-01

Every successful pregnancy requires proper embryo implantation. Low implantation rate is a major problem during infertility treatments using assisted reproductive technologies (ART) 1. Here we report a new molecular influence on implantation through the lysophosphatidic acid (LPA) receptor LPA3 2–4. Targeted deletion of LPA3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos, and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase-2 (COX-2) 5, was down-regulated in LPA3-deficient uteri during preimplantation. Down regulation of COX-2 led to reduced levels of prostaglandins that are critical for implantation 1. Exogenous administration of the prostaglandins PGE2 and cPGI into LPA3-deficient females rescued delayed implantation but did not rescue defects in embryo spacing. These data identify LPA3 receptor-mediated signalling as a new influence on implantation and further indicate linkage between LPA signalling and prostaglandin biosynthesis. PMID:15875025

Parathyroid hormone-dependent signaling pathways regulating genes in bone cells

NASA Technical Reports Server (NTRS)

Swarthout, John T.; D'Alonzo, Richard C.; Selvamurugan, Nagarajan; Partridge, Nicola C.

2002-01-01

Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific

Histone methyltransferase G9a modulates hepatic insulin signaling via regulating HMGA1.

PubMed

Xue, Weili; Huang, Jin; Chen, Hong; Zhang, Yu; Zhu, Xiuqin; Li, Jianshuang; Zhang, Wenquan; Yuan, Yangmian; Wang, Yan; Zheng, Ling; Huang, Kun

2018-02-01

Hepatic insulin sensitivity is critical for glucose homeostasis, and insulin resistance is a fundamental syndrome found in various metabolic disorders, including obesity and type 2 diabetes. Despite considerable studies on the mechanisms of hepatic insulin resistance, the link between epigenetic regulation and the development of insulin resistance remains elusive. Here, we reported that G9a/EHMT2, a histone methyltransferase, was markedly decreased in the liver of db/db mice and high-fat diet (HFD)-fed mice. In cultured hepatic cells, G9a knockdown resulted in downregulation of insulin receptor, p-AKT and p-GSK3β; while upon upregulation, G9a prevented the palmitic acid- or glucosamine-induced insulin resistance by preserving the normal level of insulin receptor and integrity of insulin signaling. Further mechanistic study suggested that G9a regulated the expression level of high mobility group AT-hook 1 (HMGA1), a key regulator responsible for the transcription of insulin receptor (INSR) gene. Overexpression of HMGA1 normalized the impaired insulin signaling in G9a knockdown hepatic cells. Importantly, in db/db mice, restoring the expression level of G9a not only upregulated HMGA1 level and improved the impaired hepatic insulin signaling, but also alleviated hyperglycemia and hyperinsulinemia. Together, our results revealed a novel role for G9a in modulating insulin signaling, at least in part, depending on its regulatory function on HMGA1. Copyright © 2017 Elsevier B.V. All rights reserved.

Salicylic acid regulates basal resistance to Fusarium head blight in wheat.

PubMed

Makandar, Ragiba; Nalam, Vamsi J; Lee, Hyeonju; Trick, Harold N; Dong, Yanhong; Shah, Jyoti

2012-03-01

Fusarium head blight (FHB) is a destructive disease of cereal crops such as wheat and barley. Previously, expression in wheat of the Arabidopsis NPR1 gene (AtNPR1), which encodes a key regulator of salicylic acid (SA) signaling, was shown to reduce severity of FHB caused by Fusarium graminearum. It was hypothesized that SA signaling contributes to wheat defense against F. graminearum. Here, we show that increased accumulation of SA in fungus-infected spikes correlated with elevated expression of the SA-inducible pathogenesis-related 1 (PR1) gene and FHB resistance. In addition, FHB severity and mycotoxin accumulation were curtailed in wheat plants treated with SA and in AtNPR1 wheat, which is hyper-responsive to SA. In support of a critical role for SA in basal resistance to FHB, disease severity was higher in wheat expressing the NahG-encoded salicylate hydroxylase, which metabolizes SA. The FHB-promoting effect of NahG was overcome by application of benzo (1,2,3), thiadiazole-7 carbothioic acid S-methyl ester, a synthetic functional analog of SA, thus confirming an important role for SA signaling in basal resistance to FHB. We further demonstrate that jasmonate signaling has a dichotomous role in wheat interaction with F. graminearum, constraining activation of SA signaling during early stages of infection and promoting resistance during the later stages of infection.

POSH regulates Hippo signaling through ubiquitin-mediated expanded degradation.

PubMed

Ma, Xianjue; Guo, Xiaowei; Richardson, Helena E; Xu, Tian; Xue, Lei

2018-02-27

The Hippo signaling pathway is a master regulator of organ growth, tissue homeostasis, and tumorigenesis. The activity of the Hippo pathway is controlled by various upstream components, including Expanded (Ex), but the precise molecular mechanism of how Ex is regulated remains poorly understood. Here we identify Plenty of SH3s (POSH), an E3 ubiquitin ligase, as a key component of Hippo signaling in Drosophila POSH overexpression synergizes with loss of Kibra to induce overgrowth and up-regulation of Hippo pathway target genes. Furthermore, knockdown of POSH impedes dextran sulfate sodium-induced Yorkie-dependent intestinal stem cell renewal, suggesting a physiological role of POSH in modulating Hippo signaling. Mechanistically, POSH binds to the C-terminal of Ex and is essential for the Crumbs-induced ubiquitination and degradation of Ex. Our findings establish POSH as a crucial regulator that integrates the signal from the cell surface to negatively regulate Ex-mediated Hippo activation in Drosophila .

Abscisic acid perception and signaling: structural mechanisms and applications

PubMed Central

Ng, Ley Moy; Melcher, Karsten; Teh, Bin Tean; Xu, H Eric

2014-01-01

Adverse environmental conditions are a threat to agricultural yield and therefore exert a global effect on livelihood, health and the economy. Abscisic acid (ABA) is a vital plant hormone that regulates abiotic stress tolerance, thereby allowing plants to cope with environmental stresses. Previously, attempts to develop a complete understanding of the mechanisms underlying ABA signaling have been hindered by difficulties in the identification of bona fide ABA receptors. The discovery of the PYR/PYL/RCAR family of ABA receptors therefore represented a major milestone in the effort to overcome these roadblocks; since then, many structural and functional studies have provided detailed insights into processes ranging from ABA perception to the activation of ABA-responsive gene transcription. This understanding of the mechanisms of ABA perception and signaling has served as the basis for recent, preliminary developments in the genetic engineering of stress-resistant crops as well as in the design of new synthetic ABA agonists, which hold great promise for the agricultural enhancement of stress tolerance. PMID:24786231

The Kidney and Acid-Base Regulation

ERIC Educational Resources Information Center

Koeppen, Bruce M.

2009-01-01

Since the topic of the role of the kidneys in the regulation of acid base balance was last reviewed from a teaching perspective (Koeppen BM. Renal regulation of acid-base balance. Adv Physiol Educ 20: 132-141, 1998), our understanding of the specific membrane transporters involved in H+, HCO , and NH transport, and especially how these…

Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) expression is regulated by multiple neural differentiation signals

PubMed Central

Jaworski, Diane M.; Pérez-Martínez, Leonor

2010-01-01

Neuronal differentiation requires exquisitely timed cell cycle arrest for progenitors to acquire an appropriate neuronal cell fate and is achieved by communication between soluble signals, such as growth factors and extracellular matrix molecules. Here we report that the expression of TIMP-2, a matrix metalloproteinase inhibitor, is up-regulated by signals that control proliferation (bFGF and EGF) and differentiation (retinoic acid and NGF) in neural progenitor and neuroblastoma cell lines. TIMP-2 expression coincides with the appearance of neurofilament-positive neurons, indicating that TIMP-2 may play a role in neurogenesis. The up-regulation of TIMP-2 expression by proliferative signals suggests a role in the transition from proliferation to neuronal differentiation. Live labeling experiments demonstrate TIMP-2 expression only on α3 integrin-positive cells. Thus, TIMP-2 function may be mediated via interaction with integrin receptor(s). We propose that TIMP-2 represents a component of the neurogenic signaling cascade induced by mitogenic stimuli that may withdraw progenitor cells from the cell cycle permitting their terminal neuronal differentiation. PMID:16805810

Chitosan oligosaccharide induces resistance to Tobacco mosaic virus in Arabidopsis via the salicylic acid-mediated signalling pathway

PubMed Central

Jia, Xiaochen; Meng, Qingshan; Zeng, Haihong; Wang, Wenxia; Yin, Heng

2016-01-01

Chitosan is one of the most abundant carbohydrate biopolymers in the world, and chitosan oligosaccharide (COS), which is prepared from chitosan, is a plant immunity regulator. The present study aimed to validate the effect of COS on inducing resistance to tobacco mosaic virus (TMV) in Arabidopsis and to investigate the potential defence-related signalling pathways involved. Optimal conditions for the induction of TMV resistance in Arabidopsis were COS pretreatment at 50 mg/L for 1 day prior to inoculation with TMV. Multilevel indices, including phenotype data, and TMV coat protein expression, revealed that COS induced TMV resistance in wild-type and jasmonic acid pathway- deficient (jar1) Arabidopsis plants, but not in salicylic acid pathway deficient (NahG) Arabidopsis plants. Quantitative-PCR and analysis of phytohormone levels confirmed that COS pretreatment enhanced the expression of the defence-related gene PR1, which is a marker of salicylic acid signalling pathway, and increased the amount of salicylic acid in WT and jar1, but not in NahG plants. Taken together, these results confirm that COS induces TMV resistance in Arabidopsis via activation of the salicylic acid signalling pathway. PMID:27189192

Chitosan oligosaccharide induces resistance to Tobacco mosaic virus in Arabidopsis via the salicylic acid-mediated signalling pathway.

PubMed

Jia, Xiaochen; Meng, Qingshan; Zeng, Haihong; Wang, Wenxia; Yin, Heng

2016-05-18

Chitosan is one of the most abundant carbohydrate biopolymers in the world, and chitosan oligosaccharide (COS), which is prepared from chitosan, is a plant immunity regulator. The present study aimed to validate the effect of COS on inducing resistance to tobacco mosaic virus (TMV) in Arabidopsis and to investigate the potential defence-related signalling pathways involved. Optimal conditions for the induction of TMV resistance in Arabidopsis were COS pretreatment at 50 mg/L for 1 day prior to inoculation with TMV. Multilevel indices, including phenotype data, and TMV coat protein expression, revealed that COS induced TMV resistance in wild-type and jasmonic acid pathway- deficient (jar1) Arabidopsis plants, but not in salicylic acid pathway deficient (NahG) Arabidopsis plants. Quantitative-PCR and analysis of phytohormone levels confirmed that COS pretreatment enhanced the expression of the defence-related gene PR1, which is a marker of salicylic acid signalling pathway, and increased the amount of salicylic acid in WT and jar1, but not in NahG plants. Taken together, these results confirm that COS induces TMV resistance in Arabidopsis via activation of the salicylic acid signalling pathway.

Impressic acid from Acanthopanax koreanum, possesses matrix metalloproteinase-13 down-regulating capacity and protects cartilage destruction.

PubMed

Lim, Hyun; Min, Dong Suk; Yun, Han Eul; Kim, Kil Tae; Sun, Ya Nan; Dat, Le Duc; Kim, Young Ho; Kim, Hyun Pyo

2017-09-14

Acanthopanax koreanum (Araliaceae) has been used in traditional medicine for enhancing vitality, rheumatism, and bone-related pains. But its activity on cartilage protection has not been known yet. Matrix metalloproteinase (MMP)-13 has an important role in degrading cartilage materials under pathologic conditions such as arthritis. The present study was designed to find the inhibitory activity of impressic acid on MMP-13 expression and cartilage protective action. 70% ethanol extract of Acanthopanax koreanum leaves and impressic acid, a major constituent isolated from the same plant materials, were examined on MMP-13 down-regulating capacity in IL-1β-treated human chondrocyte cell line (SW1353) and rabbit cartilage explants. In IL-1β-treated SW1353 cells, impressic acid significantly and concentration-dependently inhibited MMP-13 expression at 0.5-10μM. Impressic acid was found to be able to inhibit MMP-13 expression by blocking the phosphorylation of signal transducer and activator of transcription-1/-2 (STAT-1/-2) and activation of c-Jun and c-Fos among the cellular signaling pathways involved. Further, impressic acid was found to inhibit the expression of MMP-13 mRNA (47.7% inhibition at 10μM), glycosaminoglycan release (42.2% reduction at 10μM) and proteoglycan loss in IL-1-treated rabbit cartilage explants culture. In addition, a total of 21 lupane-type triterpenoids structurally-related to impressic acid were isolated from the same plant materials and their suppressive activities against MMP-13 expression were also examined. Among these derivatives, compounds 2, 3, 16, and 18 clearly down-regulated MMP-13 expression. However, impressic acid was more potent than these derivatives in down-regulating MMP-13 expression. Impressic acid, its related triterpenoids, and A. koreanum extract have potential as therapeutic agents to prevent cartilage degradation by inhibiting matrix protein degradation. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Multiple Signals Regulate PLC beta 3 in Human Myometrial Cells

PubMed Central

Zhong, Miao; Murtazina, Dilyara A.; Phillips, Jennifer; Ku, Chun-Ying; Sanborn, Barbara M.

2008-01-01

Summary The regulation of PLCB3-Serine1105 phosphorylation by both negative feedback and negative crosstalk facilitates the integration of multiple signaling pathways in myometrial cells. Phospholipase CB3 (PLCB3) Serine1105, a substrate for multiple protein kinases, represents a potential point of convergence of several signaling pathways in the myometrium. To explore this hypothesis, the regulation of PLCB3-Serine1105 phosphorylation (P-S1105) was studied in immortalized and primary human myometrial cells. CPT-cAMP and calcitonin gene-related peptide (CALCA) transiently increased P-S1105. Relaxin also stimulated P-S1105; this effect was partially blocked by the protein kinase A (PRKA) inhibitor Rp-8-CPT-cAMPS. Oxytocin, which stimulates Gαq-mediated pathways, also rapidly increased P-S1105, as did PGF2α and ATP. Oxytocin-stimulated phosphorylation was blocked by the protein kinase C (PRKC) inhibitor Go6976 and by pretreatment overnight with a phorbol ester. Cypermethrin, a PP2B phosphatase inhibitor, but not okadaic acid, a PP1/PP2A inhibitor, prolonged the effect of CALCA on P-S1105, whereas the reverse was the case for the oxytocin-stimulated increase in P-S1105. PLCB3 was the predominant PLC isoform expressed in the myometrial cells and PLCB3 shRNA constructs significantly attenuated oxytocin-stimulated increases in intracellular calcium. Oxytocin-induced phosphatidylinositol (PI) turnover was inhibited by CPT-cAMP and okadaic acid but enhanced by pretreatment with Go6976. CPT-cAMP inhibited oxytocin-stimulated PI turnover in the presence of overexpressed PLCB3, but not overexpressed PLCB3-S1105A. These data demonstrate that both negative crosstalk from the cAMP/PRKA pathway and a negative feedback loop in the oxytocin/G protein/PLCB pathway involving PRKC operate in myometrial cells and suggest that different protein phosphatases predominate in mediating P-S1105 dephosphorylation in these pathways. The integration of multiple signal components at the level

Bile acid-FXRα pathways regulate male sexual maturation in mice

PubMed Central

Vega, Aurélie; Sédes, Lauriane; Rouaisnel, Betty; de Haze, Angélique; Baron, Silvère; Schoonjans, Kristina; Caira, Françoise; Volle, David H.

2016-01-01

The bile acid receptor Farnesol-X-Receptor alpha (FRXα) is a member of the nuclear receptor superfamily. FRXα is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. In adult, short term treatment (12 hours) with FRXα agonist inhibits the expression of steroidogenic genes via the induction of the Small heterodimer partner (SHP). However the consequences of FRXα activation on testicular pathophysiology have never been evaluated. We demonstrate here that mice fed a diet supplemented with bile acid during pubertal age show increased incidence of infertility. This is associated with altered differentiation and increase apoptosis of germ cells due to lower testosterone levels. At the molecular level, next to the repression of basal steroidogenesis via the induction expression of Shp and Dax-1, two repressors of steroidogenesis, the main action of the BA-FRXα signaling is through lowering the Leydig cell sensitivity to the hypothalamo-pituitary axis, the main regulator of testicular endocrine function. In conclusion, BA-FRXα signaling is a critical actor during sexual maturation. PMID:26848619

NFκB signaling regulates embryonic and adult neurogenesis

PubMed Central

ZHANG, Yonggang; HU, Wenhui

2013-01-01

Both embryonic and adult neurogenesis involves the self-renewal/proliferation, survival, migration and lineage differentiation of neural stem/progenitor cells. Such dynamic process is tightly regulated by intrinsic and extrinsic factors and complex signaling pathways. Misregulated neurogenesis contributes much to a large range of neurodevelopmental defects and neurodegenerative diseases. The signaling of NFκB regulates many genes important in inflammation, immunity, cell survival and neural plasticity. During neurogenesis, NFκB signaling mediates the effect of numerous niche factors such as cytokines, chemokines, growth factors, extracellular matrix molecules, but also crosstalks with other signaling pathways such as Notch, Shh, Wnt/β-catenin. This review summarizes current progress on the NFκB signaling in all aspects of neurogenesis, focusing on the novel role of NFκB signaling in initiating early neural differentiation of neural stem cells and embryonic stem cells. PMID:24324484

Regulation of the Electric Charge in Phosphatidic Acid Domains

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

Wang, Wenjie; Anderson, Nathaniel A.; Travesset, Alex

Although a minor component of the lipidome, phosphatidic acid (PA) plays a crucial role in nearly all signaling pathways involving cell membranes, in part because of its variable electrical charge in response to environmental conditions. To investigate how charge is regulated in domains of PA, we applied surface-sensitive X-ray reflectivity and fluorescence near-totalreflection techniques to determine the binding of divalent ions (Ca2+ at various pH values) to 1,2-dimyristoyl-sn-glycero-3-phosphate (DMPA) and to the simpler lipid dihexadecyl phosphate (DHDP) spread as monolayers at the air/water interface. We found that the protonation state of PA is controlled not only by the pKa andmore » local pH but also by the strong affinity to PA driven by electrostatic correlations from divalent ions and the cooperative effect of the two dissociable protons, which dramatically enhance the surface charge. A precise theoretical model is presented providing a general framework to predict the protonation state of PA. Implications for recent experiments on charge regulation by hydrogen bonding and the role of pH in PA signaling are discussed in detail.« less

Lipoic acid metabolism and mitochondrial redox regulation.

PubMed

Solmonson, Ashley D; DeBerardinis, Ralph J

2017-11-30

Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multi-enzyme complexes.  Many of these dehydrogenases are regulated by reactive oxygen species, mediated through the disulfide bond of the prosthetic lipoyl moiety.  Collectively, its functions explain why lipoic acid is required for cell growth, mitochondrial activity and coordination of fuel metabolism. Lipoic acid is an essential cofactor for mitochondrial metabolism and is synthesized de novo using intermediates from mitochondrial fatty acid synthesis type II, S-adenosylmethionine and iron-sulfur clusters. This cofactor is required for catalysis by multiple mitochondrial 2-ketoacid dehydrogenase complexes, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase. Lipoic acid also plays a critical role in stabilizing and regulating these multi-enzyme complexes.  Many of these dehydrogenases are regulated by reactive oxygen species, mediated through the disulfide bond of the prosthetic lipoyl moiety.  Collectively, its functions explain why lipoic acid is required for cell growth, mitochondrial activity and coordination of fuel metabolism. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

HONSU, a protein phosphatase 2C, regulates seed dormancy by inhibiting ABA signaling in Arabidopsis.

PubMed

Kim, Woohyun; Lee, Yeon; Park, Jeongmoo; Lee, Nayoung; Choi, Giltsu

2013-04-01

Seed dormancy, a seed status that prohibits germination even in the presence of inductive germination signals, is a poorly understood process. To identify molecular components that regulate seed dormancy, we screened T-DNA insertion lines and identified a mutant designated honsu (hon). HON loss-of-function mutants display deep seed dormancy, whereas HON-overexpressing lines display shallow seed dormancy. HON encodes a seed-specific group A phosphatase 2C (PP2C) and is one of the major negative regulators of seed dormancy among group A PP2Cs. Like other PP2C family members, HON interacts with PYR1/RCAR11 in the presence of ABA. Our analysis indicates that HON inhibits ABA signaling and activates gibberellic acid signaling, and both of these conditions must be satisfied to promote the release of seed dormancy. However, HON mRNA levels are increased in mutants displaying deep seed dormancy or under conditions that deepen seed dormancy, and decreased in mutants displaying shallow seed dormancy or under conditions that promote the release of seed dormancy. Taken together, our results indicate that the expression of HON mRNA is homeostatically regulated by seed dormancy.

Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins.

PubMed

Chen, Buxin; Siderovski, David P; Neubig, Richard R; Lawson, Mark A; Trejo, Joann

2014-01-17

The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of "regulator of G protein signaling" (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 (420)AKKAA(424) mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gαq association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins.

The NF-YC–RGL2 module integrates GA and ABA signalling to regulate seed germination in Arabidopsis

PubMed Central

Liu, Xu; Hu, Pengwei; Huang, Mingkun; Tang, Yang; Li, Yuge; Li, Ling; Hou, Xingliang

2016-01-01

The antagonistic crosstalk between gibberellic acid (GA) and abscisic acid (ABA) plays a pivotal role in the modulation of seed germination. However, the molecular mechanism of such phytohormone interaction remains largely elusive. Here we show that three Arabidopsis NUCLEAR FACTOR-Y C (NF-YC) homologues NF-YC3, NF-YC4 and NF-YC9 redundantly modulate GA- and ABA-mediated seed germination. These NF-YCs interact with the DELLA protein RGL2, a key repressor of GA signalling. The NF-YC–RGL2 module targets ABI5, a gene encoding a core component of ABA signalling, via specific CCAAT elements and collectively regulates a set of GA- and ABA-responsive genes, thus controlling germination. These results suggest that the NF-YC–RGL2–ABI5 module integrates GA and ABA signalling pathways during seed germination. PMID:27624486

GID1 modulates stomatal response and submergence tolerance involving abscisic acid and gibberellic acid signaling in rice.

PubMed

Du, Hao; Chang, Yu; Huang, Fei; Xiong, Lizhong

2015-11-01

Plant responses to abiotic stresses are coordinated by arrays of growth and developmental programs. Gibberellic acid (GA) and abscisic acid (ABA) play critical roles in the developmental programs and environmental responses, respectively, through complex signaling and metabolism networks. However, crosstalk between the two phytohormones in stress responses remains largely unknown. In this study, we report that GIBBERELLIN-INSENSITIVE DWARF 1 (GID1), a soluble receptor for GA, regulates stomatal development and patterning in rice (Oryza sativa L.). The gid1 mutant showed impaired biosynthesis of endogenous ABA under drought stress conditions, but it exhibited enhanced sensitivity to exogenous ABA. Scanning electron microscope and infrared thermal image analysis indicated an increase in the stomatal conductance in the gid1 mutant under drought conditions. Interestingly, the gid1 mutant had increased levels of chlorophyll and carbohydrates under submergence conditions, and showed enhanced reactive oxygen species (ROS)-scavenging ability and submergence tolerance compared with the wild-type. Further analyses suggested that the function of GID1 in submergence responses is partially dependent on ABA, and GA signaling by GID1 is involved in submergence tolerance by modulating carbohydrate consumption. Taken together, these findings suggest GID1 plays distinct roles in stomatal response and submergence tolerance through both the ABA and GA signaling pathways in rice. © 2014 Institute of Botany, Chinese Academy of Sciences.

Fatty Acid Desaturases, Polyunsaturated Fatty Acid Regulation, and Biotechnological Advances

PubMed Central

Lee, Je Min; Lee, Hyungjae; Kang, SeokBeom; Park, Woo Jung

2016-01-01

Polyunsaturated fatty acids (PUFAs) are considered to be critical nutrients to regulate human health and development, and numerous fatty acid desaturases play key roles in synthesizing PUFAs. Given the lack of delta-12 and -15 desaturases and the low levels of conversion to PUFAs, humans must consume some omega-3 and omega-6 fatty acids in their diet. Many studies on fatty acid desaturases as well as PUFAs have shown that fatty acid desaturase genes are closely related to different human physiological conditions. Since the first front-end desaturases from cyanobacteria were cloned, numerous desaturase genes have been identified and animals and plants have been genetically engineered to produce PUFAs such as eicosapentaenoic acid and docosahexaenoic acid. Recently, a biotechnological approach has been used to develop clinical treatments for human physiological conditions, including cancers and neurogenetic disorders. Thus, understanding the functions and regulation of PUFAs associated with human health and development by using biotechnology may facilitate the engineering of more advanced PUFA production and provide new insights into the complexity of fatty acid metabolism. PMID:26742061

Regulation of the Hippo signaling pathway by ubiquitin modification.

PubMed

Kim, Youngeun; Jho, Eek-Hoon

2018-03-01

The Hippo signaling pathway plays an essential role in adult tissue homeostasis and organ size control. Abnormal regulation of Hippo signaling can be a cause for multiple types of human cancers. Since the awareness of the importance of the Hippo signaling in a wide range of biological fields has been continually grown, it is also understood that a thorough and well-rounded comprehension of the precise dynamics could provide fundamental insights for therapeutic applications. Several components in the Hippo signaling pathway are known to be targeted for proteasomal degradation via ubiquitination by E3 ligases. β-TrCP is a well-known E3 ligase of YAP/TAZ, which leads to the reduction of YAP/TAZ levels. The Hippo signaling pathway can also be inhibited by the E3 ligases (such as ITCH) which target LATS1/2 for degradation. Regulation via ubiquitination involves not only complex network of E3 ligases but also deubiquitinating enzymes (DUBs), which remove ubiquitin from its targets. Interestingly, non-degradative ubiquitin modifications are also known to play important roles in the regulation of Hippo signaling. Although there has been much advanced progress in the investigation of ubiquitin modifications acting as regulators of the Hippo signaling pathway, research done to date still remains inadequate due to the sheer complexity and diversity of the subject. Herein, we review and discuss recent developments that implicate ubiquitin-mediated regulatory mechanisms at multiple steps of the Hippo signaling pathway. [BMB Reports 2018; 51(3): 143-150].

Dynamic Redox Regulation of IL-4 Signaling.

PubMed

Dwivedi, Gaurav; Gran, Margaret A; Bagchi, Pritha; Kemp, Melissa L

2015-11-01

Quantifying the magnitude and dynamics of protein oxidation during cell signaling is technically challenging. Computational modeling provides tractable, quantitative methods to test hypotheses of redox mechanisms that may be simultaneously operative during signal transduction. The interleukin-4 (IL-4) pathway, which has previously been reported to induce reactive oxygen species and oxidation of PTP1B, may be controlled by several other putative mechanisms of redox regulation; widespread proteomic thiol oxidation observed via 2D redox differential gel electrophoresis upon IL-4 treatment suggests more than one redox-sensitive protein implicated in this pathway. Through computational modeling and a model selection strategy that relied on characteristic STAT6 phosphorylation dynamics of IL-4 signaling, we identified reversible protein tyrosine phosphatase (PTP) oxidation as the primary redox regulatory mechanism in the pathway. A systems-level model of IL-4 signaling was developed that integrates synchronous pan-PTP oxidation with ROS-independent mechanisms. The model quantitatively predicts the dynamics of IL-4 signaling over a broad range of new redox conditions, offers novel hypotheses about regulation of JAK/STAT signaling, and provides a framework for interrogating putative mechanisms involving receptor-initiated oxidation.

Dynamic Redox Regulation of IL-4 Signaling

PubMed Central

Dwivedi, Gaurav; Gran, Margaret A.; Bagchi, Pritha; Kemp, Melissa L.

2015-01-01

Quantifying the magnitude and dynamics of protein oxidation during cell signaling is technically challenging. Computational modeling provides tractable, quantitative methods to test hypotheses of redox mechanisms that may be simultaneously operative during signal transduction. The interleukin-4 (IL-4) pathway, which has previously been reported to induce reactive oxygen species and oxidation of PTP1B, may be controlled by several other putative mechanisms of redox regulation; widespread proteomic thiol oxidation observed via 2D redox differential gel electrophoresis upon IL-4 treatment suggests more than one redox-sensitive protein implicated in this pathway. Through computational modeling and a model selection strategy that relied on characteristic STAT6 phosphorylation dynamics of IL-4 signaling, we identified reversible protein tyrosine phosphatase (PTP) oxidation as the primary redox regulatory mechanism in the pathway. A systems-level model of IL-4 signaling was developed that integrates synchronous pan-PTP oxidation with ROS-independent mechanisms. The model quantitatively predicts the dynamics of IL-4 signaling over a broad range of new redox conditions, offers novel hypotheses about regulation of JAK/STAT signaling, and provides a framework for interrogating putative mechanisms involving receptor-initiated oxidation. PMID:26562652

Chelidonic acid evokes antidepressant-like effect through the up-regulation of BDNF in forced swimming test.

PubMed

Jeong, Hyun-Ja; Yang, Shi-Young; Kim, Hee-Yun; Kim, Na-Rae; Jang, Jae-Bum; Kim, Hyung-Min

2016-08-01

Depression is usually accompanied by neuro-inflammatory reactions. Chelidonic acid, in particular, has shown anti-inflammatory effects. The objective of this study was to evaluate the anti-depressant effects of chelidonic acid and to discuss the potential mechanisms of a forced swimming test. Chelidonic acid was administered orally once a day for 14 days. On the 14th day, chelidonic acid resulted in a significant decrease in immobility time during the forced swimming test without alteration of locomotor activity, in an open field test. Chelidonic acid also increased the number of nissl bodies in the hippocampus. Brain-derived neurotrophic factor expression and extracellular signal-regulated protein kinase phosphorylation in the hippocampus were up-regulated by the administration of chelidonic acid. Chelidonic acid administration significantly increased the mRNA expression of hippocampal estrogen receptor-β. The levels of hippocampal interleukin (IL)-1β, IL-6, and tumor necrosis factor-α were effectively attenuated by the administration of chelidonic acid. In addition, chelidonic acid significantly increased the levels of 5-hydroxytryptamine (serotonin), dopamine, and norepinephrine compared with those levels for the mice that were administered distilled water in the hippocampus. These results suggest that chelidonic acid might serve as a new therapeutic strategy for the regulation of depression associated with inflammation. © 2016 by the Society for Experimental Biology and Medicine.

Calcium signaling in taste cells: regulation required.

PubMed

Medler, Kathryn F

2010-11-01

Peripheral taste receptor cells depend on distinct calcium signals to generate appropriate cellular responses that relay taste information to the central nervous system. Some taste cells have conventional chemical synapses and rely on calcium influx through voltage-gated calcium channels. Other taste cells lack these synapses and depend on calcium release from stores to formulate an output signal through a hemichannel. Despite the importance of calcium signaling in taste cells, little is known about how these signals are regulated. This review summarizes recent studies that have identified 2 calcium clearance mechanisms expressed in taste cells, including mitochondrial calcium uptake and sodium/calcium exchangers (NCXs). These studies identified a unique constitutive calcium influx that contributes to maintaining appropriate calcium homeostasis in taste cells and the role of the mitochondria and exchangers in this process. The additional role of NCXs in the regulation of evoked calcium responses is also discussed. Clearly, calcium signaling is a dynamic process in taste cells and appears to be more complex than has previously been appreciated.

Caenorhabditis elegans TRPV Channels Function in a Modality-Specific Pathway to Regulate Response to Aberrant Sensory Signaling

PubMed Central

Ezak , Meredith J.; Hong , Elizabeth; Chaparro-Garcia , Angela; Ferkey , Denise M.

2010-01-01

Olfaction and some forms of taste (including bitter) are mediated by G protein-coupled signal transduction pathways. Olfactory and gustatory ligands bind to chemosensory G protein-coupled receptors (GPCRs) in specialized sensory cells to activate intracellular signal transduction cascades. G protein-coupled receptor kinases (GRKs) are negative regulators of signaling that specifically phosphorylate activated GPCRs to terminate signaling. Although loss of GRK function usually results in enhanced cellular signaling, Caenorhabditis elegans lacking GRK-2 function are not hypersensitive to chemosensory stimuli. Instead, grk-2 mutant animals do not chemotax toward attractive olfactory stimuli or avoid aversive tastes and smells. We show here that loss-of-function mutations in the transient receptor potential vanilloid (TRPV) channels OSM-9 and OCR-2 selectively restore grk-2 behavioral avoidance of bitter tastants, revealing modality-specific mechanisms for TRPV channel function in the regulation of C. elegans chemosensation. Additionally, a single amino acid point mutation in OCR-2 that disrupts TRPV channel-mediated gene expression, but does not decrease channel function in chemosensory primary signal transduction, also restores grk-2 bitter taste avoidance. Thus, loss of GRK-2 function may lead to changes in gene expression, via OSM-9/OCR-2, to selectively alter the levels of signaling components that transduce or regulate bitter taste responses. Our results suggest a novel mechanism and multiple modality-specific pathways that sensory cells employ in response to aberrant signal transduction. PMID:20176974

Signal-activated phospholipase regulation of leukocyte chemotaxis.

PubMed

Cathcart, Martha K

2009-04-01

Signal-activated phospholipases are a recent focus of the rapidly growing field of lipid signaling. The extent of their impact on the pathways regulating diverse cell functions is beginning to be appreciated. A critical step in inflammation is the attraction of leukocytes to injured or diseased tissue. Chemotaxis of leukocytes, a requisite process for monocyte and neutrophil extravasation from the blood into tissues, is a critical step for initiating and maintaining inflammation in both acute and chronic settings. Recent studies have identified new important and required roles for two signal-activated phospholipases A2 (PLA2) in regulating chemotaxis. The two intracellular phospholipases, cPLA2alpha (Group IVA) and iPLA2beta (Group VIA), act in parallel to provide distinct lipid mediators at different intracellular sites that are both required for leukocytes to migrate toward the chemokine monocyte chemoattractant protein-1. This review will summarize the separate roles of these phospholipases as well as what is currently known about the influence of two other classes of intracellular signal-activated phospholipases, phospholipase C and phospholipase D, in regulating chemotaxis in eukaryotic cells, but particularly in human monocytes. The contributions of these phospholipases to chemotaxis both in vitro and in vivo will be highlighted.

[Mechanism of Chlorogenic Acid in Apoptotic Regulation through Notch1 
Pathway in Non-small Cell Lung Carcinoma in Animal Level].

PubMed

Li, Wei; Liu, Xu; Zhang, Guoqian; Zhang, Linlin

2017-08-20

It has been proven that chlorogenic acids can produce anticancer effects by regulating cell cycle, inducing apoptosis, inhibiting cell growth, Notch signaling pathways are closely related to many human tumors. The aim of this study is to study the mechanism of chlorogenic acid on apoptosis of non-small lung cancer through Notch1 pathway in animal level, and hope to provide theory basis on clinical treatment and research aimed at targeting Notch1 signaling in non-small cell carcinoma (NSCLC). MTT assay was used to evaluate the A549 cell proliferation under the treatment of chlorogenic acid. The effect of chlorogenic acid on apoptotic and cell cycle were detected by flow cytometry. The animal model of A549 cell transplanted in nude was established, tumer size and weight were detected. The mRNA level of Notch1 signal pathway related facter were detected by RT-PCR; the expression of Notch1 signal pathway related facter in tumor tissue was detected by western blot. Chlorogenic acid inhibited the A549 cell proliferation. incresed cell apoptotic and cell percentagein G2/M (P<0.05), and in a dose-dependent manner. In animal model, tumer size and weight were lower than control group, the difference was statistically significant (P<0.05). The relative expression of mRNA of Notch1, VEGF, Delta4, HES1 and HEY1 were decreaced (P<0.05) in tumor tissue which treated with chlorogenic. The expression of Notch1 were decreaced, PTEN, p-PTEN, p-AKT were increced significantly in tumor tissue which treated with chlorogenic (P<0.05). Chlorogenic acid can regulate theapoptosis of non-small lung cancer through Notch pathway in animal level, which may be associated with the down-regulating the expression of VEGF and Delta4. Notch pathway may cross talk with PI3K/AKT pathway through PTEN in NSCLC.

Regulation of Hedgehog Signalling Inside and Outside the Cell

PubMed Central

Ramsbottom, Simon A.; Pownall, Mary E.

2016-01-01

The hedgehog (Hh) signalling pathway is conserved throughout metazoans and plays an important regulatory role in both embryonic development and adult homeostasis. Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The fatty nature of the Shh ligand means that it tends to associate tightly with the cell membrane, and yet it is known to act as a morphogen that diffuses to elicit pattern formation. Heparan sulfate proteoglycans (HSPGs) play a major role in the regulation of Hh distribution outside the cell. Inside the cell, the primary cilium provides an important hub for processing the Hh signal in vertebrates. This review will summarise the current understanding of how the Hh pathway is regulated from ligand production, release, and diffusion, through to signal reception and intracellular transduction. PMID:27547735

Micelle-assisted signaling of peracetic acid by the oxidation of pyreneboronic acid via monomer-excimer switching.

PubMed

Choi, Jiyoung; Lee, Hyo Jin; Cho, Min Jeoung; Chang, Suk-Kyu

2015-08-15

A simple fluorescent probe for the industrial oxidant peracetic acid (PAA) was investigated. PAA-assisted oxidative conversion of pyrene-1-boronic acid into 1-hydroxypyrene was used as the signaling tool. Pyreneboronic acid was found to display selective signaling behavior, being more responsive to PAA than to other commonly used practical oxidants such as H2O2 and HOCl. The changes in pyrene monomer fluorescence to excimer were used in the quantitative analysis of PAA. When using the surfactant hexadecyltrimethylammonium bromide as a micellar additive, the signaling of PAA was markedly enhanced. Selective fluorescence signaling of PAA by pyrene-1-boronic acid with a detection limit of 1.5×10(-6)M in aqueous environment was successfully achieved. Copyright © 2015 Elsevier B.V. All rights reserved.

Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/β-Catenin Pathway in Rat Brain Endothelial Cells Requires Cross-talk with Notch Signaling*

PubMed Central

Sneve, Mary; Haroldson, Thomas A.; Smith, Jeffrey P.

2016-01-01

The transport of monocarboxylate fuels such as lactate, pyruvate, and ketone bodies across brain endothelial cells is mediated by monocarboxylic acid transporter 1 (MCT1). Although the canonical Wnt/β-catenin pathway is required for rodent blood-brain barrier development and for the expression of associated nutrient transporters, the role of this pathway in the regulation of brain endothelial MCT1 is unknown. Here we report expression of nine members of the frizzled receptor family by the RBE4 rat brain endothelial cell line. Furthermore, activation of the canonical Wnt/β-catenin pathway in RBE4 cells via nuclear β-catenin signaling with LiCl does not alter brain endothelial Mct1 mRNA but increases the amount of MCT1 transporter protein. Plasma membrane biotinylation studies and confocal microscopic examination of mCherry-tagged MCT1 indicate that increased transporter results from reduced MCT1 trafficking from the plasma membrane via the endosomal/lysosomal pathway and is facilitated by decreased MCT1 ubiquitination following LiCl treatment. Inhibition of the Notch pathway by the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester negated the up-regulation of MCT1 by LiCl, demonstrating a cross-talk between the canonical Wnt/β-catenin and Notch pathways. Our results are important because they show, for the first time, the regulation of MCT1 in cerebrovascular endothelial cells by the multifunctional canonical Wnt/β-catenin and Notch signaling pathways. PMID:26872974

EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells.

PubMed

Demiroglu-Zergeroglu, Asuman; Candemir, Gulsife; Turhanlar, Ebru; Sagir, Fatma; Ayvali, Nurettin

2016-12-01

The unrestrained EGFR signalling contributes to malignant phenotype in a number of cancers including Malignant Mesotheliomas. Present study was designed to evaluate EGFR-dependent anti-proliferative and apoptotic effects of Gallic acid in transformed Mesothelial (MeT-5A) and Malignant Mesothelioma (SPC212) cells. Gallic acid reduced the viability of Malignant Mesothelioma cells in a concentration and time-dependent manner. However, viability of mesothelial cells reduced only at high concentration and longer time periods. Gallic acid restrained the activation of EGFR, ERK1/2 and AKT proteins and down regulated expression of Cyclin D and Bcl-2 genes, but upregulated the expression of p21 gene in EGF-induced SPC212 cells. GA-induced transitory G1 arrest and triggered mitochondrial and death receptor mediated apoptosis, which requires p38MAPK activation. The data provided here indicate that GA is able to inhibit EGFR dependent proliferation and survival signals and induces p38 pathway dependent apoptosis in Malignant Mesothelioma cells. On the basis of these experimental findings it is worthwhile to investigate further the biological activity of Gallic acid on other Mesothelioma cell lines harbouring aberrant EGFR signals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Negative regulation of BMP signaling by the ski oncoprotein.

PubMed

Luo, Kunxin

2003-01-01

The bone morphogenetic proteins (BMPs) play important roles in the regulation of multiple aspects of vertebrate development. BMPs signal through the cell surface receptors and downstream Smad molecules. Upon stimulation with BMP, Smad1, Smad5, and Smad8 are phosphorylated by the activated BMP receptors, form a complex with Smad4, and translocate into the nucleus, where they regulate the expression of BMP target genes. The activity of this signal pathway can be modulated both by extracellular factors that regulate the binding of BMPs to the receptor and by intracellular proteins that interact with the Smad proteins. We have shown that Ski is an important negative regulator of the Smad proteins. Ski can bind to the BMP-Smad protein complexes in response to BMP and repress their ability to activate BMP target genes through disruption of a functional Smad complex and through recruitment of transcriptional co-repressors. The antagonism of BMP signaling by Ski results in neural specification in Xenopus embryos and inhibition of osteoblast differentiation in mouse bone-marrow stromal progenitor cells. This ability to modulate BMP signaling by Ski may play an important role in the regulation of craniofacial, neuronal, and skeletal muscle development.

Analysis of Phosphatidic Acid Binding and Regulation of PIPKI In Vitro and in Intact Cells.

PubMed

Tay, L W R; Wang, Z; Du, G

2017-01-01

Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is a lipid second messenger that regulates a wide array of essential cellular events, such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, adhesion, and motility. To control the spatiotemporal production of PI(4,5)P2, the activity of type 1 phosphotidylinositol-4-phosphate-5-kinases (PIPKIs) is tightly regulated by small GTPases and another signaling lipid, phosphatidic acid (PA). It is of interest that PI(4,5)P2 is also a critical cofactor for the activation of the PA-generating enzyme, phospholipase D (PLD). It has been proposed that the reciprocal stimulation of PLD and PIPKI enzymes enables a rapid feedforward stimulation loop for the localized and acute generation of signaling lipids that are critical for the regulation of actin cytoskeletal reorganization and membrane trafficking. Here, we outline the methods for the expression and purification of PIPKIγ from bacteria, determination of direct PA binding, and activation of PIPKIγ using in vitro liposomes assays, and examination of actin cytoskeletal reorganization promoted by the PA-PIPKIγ signaling in intact cells using fluorescent microscopy. © 2017 Elsevier Inc. All rights reserved.

Seasonal Abscisic Acid Signal and a Basic Leucine Zipper Transcription Factor, DkbZIP5, Regulate Proanthocyanidin Biosynthesis in Persimmon Fruit1[C][W][OA

PubMed Central

Akagi, Takashi; Katayama-Ikegami, Ayako; Kobayashi, Shozo; Sato, Akihiko; Kono, Atsushi; Yonemori, Keizo

2012-01-01

Proanthocyanidins (PAs) are secondary metabolites that contribute to plant protection and crop quality. Persimmon (Diospyros kaki) has a unique characteristic of accumulating large amounts of PAs, particularly in its fruit. Normal astringent-type and mutant nonastringent-type fruits show different PA accumulation patterns depending on the seasonal expression patterns of DkMyb4, which is a Myb transcription factor (TF) regulating many PA pathway genes in persimmon. In this study, attempts were made to identify the factors involved in DkMyb4 expression and the resultant PA accumulation in persimmon fruit. Treatment with abscisic acid (ABA) and an ABA biosynthesis inhibitor resulted in differential changes in the expression patterns of DkMyb4 and PA biosynthesis in astringent-type and nonastringent-type fruits depending on the development stage. To obtain an ABA-signaling TF, we isolated a full-length basic leucine zipper (bZIP) TF, DkbZIP5, which is highly expressed in persimmon fruit. We also showed that ectopic DkbZIP5 overexpression in persimmon calluses induced the up-regulation of DkMyb4 and the resultant PA biosynthesis. In addition, a detailed molecular characterization using the electrophoretic mobility shift assay and transient reporter assay indicated that DkbZIP5 recognized ABA-responsive elements in the promoter region of DkMyb4 and acted as a direct regulator of DkMyb4 in an ABA-dependent manner. These results suggest that ABA signals may be involved in PA biosynthesis in persimmon fruit via DkMyb4 activation by DkbZIP5. PMID:22190340

Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development

PubMed Central

Lenti, Elisa; Farinello, Diego; Penkov, Dmitry; Castagnaro, Laura; Lavorgna, Giovanni; Wuputra, Kenly; Tjaden, Naomi E. Butler; Bernassola, Francesca; Caridi, Nicoletta; Wagner, Michael; Kozinc, Katja; Niederreither, Karen; Blasi, Francesco; Pasini, Diego; Trainor, Paul A.

2016-01-01

The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia. PMID:27214556

Fatty acid transport and transporters in muscle are critically regulated by Akt2.

PubMed

Jain, Swati S; Luiken, Joost J F P; Snook, Laelie A; Han, Xiao Xia; Holloway, Graham P; Glatz, Jan F C; Bonen, Arend

2015-09-14

Muscle contains various fatty acid transporters (CD36, FABPpm, FATP1, FATP4). Physiological stimuli (insulin, contraction) induce the translocation of all four transporters to the sarcolemma to enhance fatty acid uptake similarly to glucose uptake stimulation via glucose transporter-4 (GLUT4) translocation. Akt2 mediates insulin-induced, but not contraction-induced, GLUT4 translocation, but its role in muscle fatty acid transporter translocation is unknown. In muscle from Akt2-knockout mice, we observed that Akt2 is critically involved in both insulin-induced and contraction-induced fatty acid transport and translocation of fatty acid translocase/CD36 (CD36) and FATP1, but not of translocation of fatty acid-binding protein (FABPpm) and FATP4. Instead, Akt2 mediates intracellular retention of both latter transporters. Collectively, our observations reveal novel complexities in signaling mechanisms regulating the translocation of fatty acid transporters in muscle. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night.

PubMed

Blask, David E; Hill, Steven M; Dauchy, Robert T; Xiang, Shulin; Yuan, Lin; Duplessis, Tamika; Mao, Lulu; Dauchy, Erin; Sauer, Leonard A

2011-10-01

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT(1) -induced activation of G(αi2) signaling and reduction of 3',5'-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT(1) -mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN. © 2011

Defense to Sclerotinia sclerotiorum in oilseed rape is associated with the sequential activations of salicylic acid signaling and jasmonic acid signaling.

PubMed

Wang, Zheng; Tan, Xiaoli; Zhang, Zhiyan; Gu, Shoulai; Li, Guanying; Shi, Haifeng

2012-03-01

Signaling pathways mediated by salicylic acid (SA) and jasmonic acid (JA) are widely studied in various host-pathogen interactions. For oilseed rape (Brassica napus)-Sclerotinia sclerotiorum interaction, little information of the two signaling molecules has been described in detail. In this study, we showed that the level of SA and JA in B. napus leaves was increased with a distinct temporal profile, respectively, after S. sclerotiorum infection. The application of SA or methyl jasmonate enhanced the resistance to the pathogen. Furthermore, a set of SA and JA signaling marker genes were identified from B. napus and were used to monitor the signaling responses to S. sclerotiorum infection by examining the temporal expression profiles of these marker genes. The SA signaling was activated within 12h post inoculation (hpi) followed by the JA signaling which was activated around 24 hpi. In addition, SA-JA crosstalk genes were activated during this process. These results suggested that defense against S. sclerotiorum in oilseed rape is associated with a sequential activation of SA signaling and JA signaling, which provide important clues for designing strategies to curb diseases caused by S. sclerotioru. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Oleic acid-dependent modulation of Nitric oxide associated 1 protein levels regulates nitric oxide-mediated defense signaling in Arabidopsis

USDA-ARS?s Scientific Manuscript database

The conserved cellular metabolites nitric oxide (NO) and oleic acid (18:1) are well-known regulators of disease physiologies in diverse organism. We show that NO production in plants is regulated via 18:1. Reduction in 18:1 levels, via a genetic mutation in the 18:1-synthesizing gene SUPPRESSOR OF S...

Ursolic Acid Attenuates Diabetic Mesangial Cell Injury through the Up-Regulation of Autophagy via miRNA-21/PTEN/Akt/mTOR Suppression

PubMed Central

Lu, Xinxing; Fan, Qiuling; Xu, Li; Li, Lin; Yue, Yuan; Xu, Yanyan; Su, Yan; Zhang, Dongcheng; Wang, Lining

2015-01-01

Objective To investigate the effect of ursolic acid on autophagy mediated through the miRNA-21-targeted phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in rat mesangial cells cultured under high glucose (HG) conditions. Methods Rat glomerular mesangial cells were cultured under normal glucose, HG, HG with the PI3K inhibitor LY294002 or HG with ursolic acid conditions. Cell proliferation and hypertrophy were assayed using an MTT assay and the ratio of total protein to cell number, respectively. The miRNA-21 expression was detected using RT-qPCR. The expression of phosphatase and tensin homolog (PTEN)/AKT/mTOR signaling signatures, autophagy-associated protein and collagen I was detected by western blotting and RT-qPCR. Autophagosomes were observed using electron microscopy. Results Compared with mesangial cells cultured under normal glucose conditions, the cells exposed to HG showed up-regulated miRNA-21 expression, down-regulated PTEN protein and mRNA expression, up-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and down-regulated LC3II expression. Ursolic acid and LY294002 inhibited HG-induced mesangial cell hypertrophy and proliferation, down-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and up-regulated LC3II expression. However, LY294002 did not affect the expression of miRNA-21 and PTEN. Ursolic acid down-regulated miRNA-21 expression and up-regulated PTEN protein and mRNA expression. Conclusions Ursolic acid inhibits the glucose-induced up-regulation of mesangial cell miRNA-21 expression, up-regulates PTEN expression, inhibits the activation of PI3K/Akt/mTOR signaling pathway, and enhances autophagy to reduce the accumulation of the extracellular matrix and ameliorate cell hypertrophy and proliferation. PMID:25689721

Retinoic Acid Modulates Interferon-γ Production by Hepatic Natural Killer T Cells via Phosphatase 2A and the Extracellular Signal-Regulated Kinase Pathway

PubMed Central

Chang, Heng-Kwei

2015-01-01

Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune function, such as defending against infections and immune regulation. Although RA affects various types of immune cells, including antigen-presenting cells, B lymphocytes, and T lymphocytes, whether it affects natural killer T (NKT) cells remain unknown. In this study, we found that RA decreased interferon (IFN)-γ production by activated NKT cells through T-cell receptor (TCR) and CD28. We also found that RA reduced extracellular signal-regulated kinase (ERK) phosphorylation, but increased phosphatase 2A (PP2A) activity in TCR/CD28-stimulated NKT cells. The increased PP2A activity, at least partly, contributed to the reduction of ERK phosphorylation. Since inhibition of ERK activation decreases IFN-γ production by TCR/CD28-stimulated NKT cells, RA may downregulate IFN-γ production by TCR/CD28-stimulated NKT cells through the PP2A-ERK pathway. Our results demonstrated a novel function of RA in modulating the IFN-γ expression by activated NKT cells. PMID:25343668

Signaling, Gene Regulation and Cancer | Center for Cancer Research

Cancer.gov

Although there have been tremendous progress in cancer research and treatment, the mortality caused by this disease is still very high. Cancer is the leading cause of death worldwide and second leading cause of death in the United States of America. Signaling, Gene Regulation and Cancer covers topics including the role of various signaling pathways in development, regulation

Activation of p38 MAPK-regulated Bcl-xL signaling increases survival against zoledronic acid-induced apoptosis in osteoclast precursors.

PubMed

Tai, Ta-Wei; Su, Fong-Chin; Chen, Ching-Yu; Jou, I-Ming; Lin, Chiou-Feng

2014-10-01

The nitrogen-containing bisphosphonate zoledronic acid (ZA) induces apoptosis in osteoclasts and inhibits osteoclast-mediated bone resorption. It is widely used to treat osteoporosis. However, some patients are less responsive to ZA treatment, and the mechanisms of resistance are still unclear. Here, we identified that murine osteoclast precursors may develop resistance to ZA-induced apoptosis. These resistant cells survived the apoptotic effect of ZA following an increase in anti-apoptotic Bcl-xL. Pharmacologically inhibiting Bcl-xL facilitated ZA-induced apoptosis. Treatment with ZA activated p38 MAPK, increasing Bcl-xL expression and cell survival. Nuclear import of β-catenin regulated by p38 MAPK determined Bcl-xL mRNA expression and cell survival in response to ZA. ZA also inactivated glycogen synthase kinase (GSK)-3β, a negative upstream regulator of β-catenin, in a p38 MAPK-mediated manner. Synergistic pharmacological inhibition of p38 MAPK with ZA attenuated receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and facilitated ZA-induced apoptosis. These results demonstrate that elevated Bcl-xL expression mediated by p38 MAPK-regulated GSK-3β/β-catenin signaling is required for cell survival of ZA-induced apoptosis in both osteoclast precursors and osteoclasts. Finally, we demonstrated that inhibiting p38 MAPK-mediated pathway enhanced ZA effect on increasing the bone mineral density of ovariectomized mice. This result suggests that targeting these pathways may represent a potential therapeutic strategy. Copyright © 2014 Elsevier Inc. All rights reserved.

SEUSS and PIF4 Coordinately Regulate Light and Temperature Signaling Pathways to Control Plant Growth.

PubMed

Huai, Junling; Zhang, Xinyu; Li, Jialong; Ma, Tingting; Zha, Ping; Jing, Yanjun; Lin, Rongcheng

2018-05-02

Plants continuously monitor environmental conditions (such as light and temperature) and adjust their growth and development accordingly. The transcription factor PHYTOCHROME-INTERACTING FACTOR4 (PIF4) regulates both light and temperature signaling pathways. Here, we identified ENHANCED PHOTOMORPHOGENIC2 (EPP2) as a new repressor of photomorphogenesis in red, far-red, and blue light. Map-based cloning revealed that EPP2 encodes the SEUSS (SEU) transcription regulator. The C-terminus of SEU has transcriptional activation activity and SEU physically interacts with PIF4. Moreover, SEU promotes the expression of many genes, including auxin biosynthetic and responsive genes, and regulates IAA levels in plants. SEU associates with regulatory regions in INDOLE-3-ACETIC ACID INDUCIBLE6 (IAA6) and IAA19 in a PIF4-independent manner, whereas the binding of PIF4 to these genes requires SEU. Furthermore, mutations in SEU affect H3K4me3 methylation at IAA6 and IAA19, and SEU positively regulates warm temperature-mediated hypocotyl growth together with PIF4. Therefore, our results reveal that SEU acts as a central regulator to integrate light and temperature signals to control plant growth by coordinating with PIF4. Copyright © 2018 The Author. Published by Elsevier Inc. All rights reserved.

Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport.

PubMed

Jin, Daqing; Ni, Terri T; Sun, Jianjian; Wan, Haiyan; Amack, Jeffrey D; Yu, Guangju; Fleming, Jonathan; Chiang, Chin; Li, Wenyan; Papierniak, Anna; Cheepala, Satish; Conseil, Gwenaëlle; Cole, Susan P C; Zhou, Bin; Drummond, Iain A; Schuetz, John D; Malicki, Jarema; Zhong, Tao P

2014-09-01

Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4(T804M) mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.

Neurotrophin signalling pathways regulating neuronal apoptosis.

PubMed

Miller, F D; Kaplan, D R

2001-07-01

Recent evidence indicates that naturally occurring neuronal death in mammals is regulated by the interplay between receptor-mediated prosurvival and proapoptotic signals. The neurotrophins, a family of growth factors best known for their positive effects on neuronal biology, have now been shown to mediate both positive and negative survival signals, by signalling through the Trk and p75 neurotrophin receptors, respectively. The mechanisms whereby these two neurotrophin receptors interact to determine neuronal survival have been difficult to decipher, largely because both can signal independently or coincidentally, depending upon the cell or developmental context. Nonetheless, the past several years have seen significant advances in our understanding of this receptor signalling system. In this review, we focus on the proapoptotic actions of the p75 neurotrophin receptor (p75NTR), and on the interplay between Trk and p75NTR that determines neuronal survival.

A Pivotal Role of DELLAs in Regulating Multiple Hormone Signals.

PubMed

Davière, Jean-Michel; Achard, Patrick

2016-01-04

Plant phenotypic plasticity is controlled by diverse hormone pathways, which integrate and convey information from multiple developmental and environmental signals. Moreover, in plants many processes such as growth, development, and defense are regulated in similar ways by multiple hormones. Among them, gibberellins (GAs) are phytohormones with pleiotropic actions, regulating various growth processes throughout the plant life cycle. Previous work has revealed extensive interplay between GAs and other hormones, but the molecular mechanism became apparent only recently. Molecular and physiological studies have demonstrated that DELLA proteins, considered as master negative regulators of GA signaling, integrate multiple hormone signaling pathways through physical interactions with transcription factors or regulatory proteins from different families. In this review, we summarize the latest progress in GA signaling and its direct crosstalk with the main phytohormone signaling, emphasizing the multifaceted role of DELLA proteins with key components of major hormone signaling pathways. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

The Protein Kinase CK2 Mediates Cross-Talk between Auxin- and Salicylic Acid-Signaling Pathways in the Regulation of PINOID Transcription

PubMed Central

Armengot, Laia; Caldarella, Eleonora; Marquès-Bueno, Maria Mar; Martínez, M. Carmen

2016-01-01

The protein kinase CK2 is a ubiquitous and highly conserved enzyme, the activity of which is vital for eukaryotic cells. We recently demonstrated that CK2 modulates salicylic acid (SA) homeostasis in Arabidopsis thaliana, and that functional interplay between CK2 and SA sustains transcriptional expression of PIN-FORMED (PIN) genes. In this work, we show that CK2 also plays a key role in the transcriptional regulation of PINOID (PID), an AGC protein kinase that modulates the apical/basal localization of auxin-efflux transporters. We show that PID transcription is up-regulated by auxin and by SA and that CK2 is involved in both pathways. On the one hand, CK2 activity is required for proteosome-dependent degradation of AXR3, a member of the AUX/IAA family of auxin transcriptional repressors that must be degraded to activate auxin-responsive gene expression. On the other hand, the role of CK2 in SA homeostasis and, indirectly, in SA-driven PID transcription, was confirmed by using Arabidopsis NahG transgenic plants, which cannot accumulate SA. In conclusion, our results evidence a role for CK2 as a functional link in the negative cross-talk between auxin- and SA-signaling. PMID:27275924

Regulation of inflammation and redox signaling by dietary polyphenols.

PubMed

Rahman, Irfan; Biswas, Saibal K; Kirkham, Paul A

2006-11-30

Reactive oxygen species (ROS) play a key role in enhancing the inflammation through the activation of NF-kappaB and AP-1 transcription factors, and nuclear histone acetylation and deacetylation in various inflammatory diseases. Such undesired effects of oxidative stress have been found to be controlled by the antioxidant and/or anti-inflammatory effects of dietary polyphenols such as curcumin (diferuloylmethane, a principal component of turmeric) and resveratrol (a flavonoid found in red wine). The phenolic compounds in fruits, vegetables, tea and wine are mostly derivatives, and/or isomers of flavones, isoflavones, flavonols, catechins, tocopherols, and phenolic acids. Polyphenols modulate important cellular signaling processes such as cellular growth, differentiation and host of other cellular features. In addition, they modulate NF-kappaB activation, chromatin structure, glutathione biosynthesis, nuclear redox factor (Nrf2) activation, scavenge effect of ROS directly or via glutathione peroxidase activity and as a consequence regulate inflammatory genes in macrophages and lung epithelial cells. However, recent data suggest that dietary polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. The effects of polyphenols however, have been reported to be more pronounced in vitro using high concentrations which are not physiological in vivo. This commentary discusses the recent data on dietary polyphenols in the control of signaling and inflammation particularly during oxidative stress, their metabolism and bioavailability.

Plastids Are Major Regulators of Light Signaling in Arabidopsis1[W][OA

PubMed Central

Ruckle, Michael E.; Burgoon, Lyle D.; Lawrence, Lauren A.; Sinkler, Christopher A.; Larkin, Robert M.

2012-01-01

We previously provided evidence that plastid signaling regulates the downstream components of a light signaling network and that this signal integration coordinates chloroplast biogenesis with both the light environment and development by regulating gene expression. We tested these ideas by analyzing light- and plastid-regulated transcriptomes in Arabidopsis (Arabidopsis thaliana). We found that the enrichment of Gene Ontology terms in these transcriptomes is consistent with the integration of light and plastid signaling (1) down-regulating photosynthesis and inducing both repair and stress tolerance in dysfunctional chloroplasts and (2) helping coordinate processes such as growth, the circadian rhythm, and stress responses with the degree of chloroplast function. We then tested whether factors that contribute to this signal integration are also regulated by light and plastid signals by characterizing T-DNA insertion alleles of genes that are regulated by light and plastid signaling and that encode proteins that are annotated as contributing to signaling, transcription, or no known function. We found that a high proportion of these mutant alleles induce chloroplast biogenesis during deetiolation. We quantified the expression of four photosynthesis-related genes in seven of these enhanced deetiolation (end) mutants and found that photosynthesis-related gene expression is attenuated. This attenuation is particularly striking for Photosystem II subunit S expression. We conclude that the integration of light and plastid signaling regulates a number of END genes that help optimize chloroplast function and that at least some END genes affect photosynthesis-related gene expression. PMID:22383539

Ursolic Acid Inhibits Leucine-Stimulated mTORC1 Signaling by Suppressing mTOR Localization to Lysosome

PubMed Central

Ou, Xiang; Liu, Meilian; Luo, Hairong; Dong, Lily Q.; Liu, Feng

2014-01-01

Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function. PMID:24740400

Mechanical Regulation of Signaling Pathways in Bone

PubMed Central

Thompson, William R.; Rubin, Clinton T.; Rubin, Janet

2012-01-01

A wide range of cell types depend on mechanically induced signals to enable appropriate physiological responses. The skeleton is particularly dependent on mechanical information to guide the resident cell population towards adaptation, maintenance and repair. Research at the organ, tissue, cell and molecular levels has improved our understanding of how the skeleton can recognize the functional environment, and how these challenges are translated into cellular information that can site-specifically alter phenotype. This review first considers those cells within the skeleton that are responsive to mechanical signals, including osteoblasts, osteoclasts, osteocytes and osteoprogenitors. This is discussed in light of a range of experimental approaches that can vary parameters such as strain, fluid shear stress, and pressure. The identity of mechanoreceptor candidates is approached, with consideration of integrins, pericellular tethers, focal adhesions, ion channels, cadherins, connexins, and the plasma membrane including caveolar and non-caveolar lipid rafts and their influence on integral signaling protein interactions. Several mechanically regulated intracellular signaling cascades are detailed including activation of kinases (Akt, MAPK, FAK), β-catenin, GTPases, and calcium signaling events. While the interaction of bone cells with their mechanical environment is complex, an understanding of mechanical regulation of bone signaling is crucial to understanding bone physiology, the etiology of diseases such as osteoporosis, and to the development of interventions to improve bone strength. PMID:22575727

Redox signaling in plants.

PubMed

Foyer, Christine H; Noctor, Graham

2013-06-01

Our aim is to deliver an authoritative and challenging perspective of current concepts in plant redox signaling, focusing particularly on the complex interface between the redox and hormone-signaling pathways that allow precise control of plant growth and defense in response to metabolic triggers and environmental constraints and cues. Plants produce significant amounts of singlet oxygen and other reactive oxygen species (ROS) as a result of photosynthetic electron transport and metabolism. Such pathways contribute to the compartment-specific redox-regulated signaling systems in plant cells that convey information to the nucleus to regulate gene expression. Like the chloroplasts and mitochondria, the apoplast-cell wall compartment makes a significant contribution to the redox signaling network, but unlike these organelles, the apoplast has a low antioxidant-buffering capacity. The respective roles of ROS, low-molecular antioxidants, redox-active proteins, and antioxidant enzymes are considered in relation to the functions of plant hormones such as salicylic acid, jasmonic acid, and auxin, in the composite control of plant growth and defense. Regulation of redox gradients between key compartments in plant cells such as those across the plasma membrane facilitates flexible and multiple faceted opportunities for redox signaling that spans the intracellular and extracellular environments. In conclusion, plants are recognized as masters of the art of redox regulation that use oxidants and antioxidants as flexible integrators of signals from metabolism and the environment.

New Insights from Drosophila into the Regulation of EGFR Signaling.

PubMed

Harden, Nicholas

2017-01-01

Genetic analysis of Egfr signaling in Drosophila has a long-standing track record of making important contributions to our understanding of the Egfr pathway. While the central Ras/MAPK pathway has long been well defined, there is much to learn with regard to its cross talk with other pathways and how it is regulated. A better understanding of the regulation of Egfr signaling is of particular interest with regard to the participation of misregulated Egfr signaling in tumorigenesis. Recent studies in the fly have led to some surprising results, identifying regulators of Egfr acting in unexpected ways.

Differential Regulation of c-di-GMP Metabolic Enzymes by Environmental Signals Modulates Biofilm Formation in Yersinia pestis.

PubMed

Ren, Gai-Xian; Fan, Sai; Guo, Xiao-Peng; Chen, Shiyun; Sun, Yi-Cheng

2016-01-01

Cyclic diguanylate (c-di-GMP) is essential for Yersinia pestis biofilm formation, which is important for flea-borne blockage-dependent plague transmission. Two diguanylate cyclases (DGCs), HmsT and HmsD and one phosphodiesterase (PDE), HmsP are responsible for the synthesis and degradation of c-di-GMP in Y. pestis. Here, we systematically analyzed the effect of various environmental signals on regulation of the biofilm phenotype, the c-di-GMP levels, and expression of HmsT, HmsD, and HmsP in Y. pestis. Biofilm formation was higher in the presence of non-lethal high concentration of CaCl2, MgCl2, CuSO4, sucrose, sodium dodecyl sulfate, or dithiothreitol, and was lower in the presence of FeCl2 or NaCl. In addition, we found that HmsD plays a major role in biofilm formation in acidic or redox environments. These environmental signals differentially regulated expression of HmsT, HmsP and HmsD, resulting in changes in the intracellular levels of c-di-GMP in Y. pestis. Our results suggest that bacteria can sense various environmental signals, and differentially regulate activity of DGCs and PDEs to coordinately regulate and adapt metabolism of c-di-GMP and biofilm formation to changing environments.

Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

PubMed Central

Kohn, Anat; Rutkowski, Timothy P; Liu, Zhaoyang; Mirando, Anthony J; Zuscik, Michael J; O’Keefe, Regis J; Hilton, Matthew J

2015-01-01

RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissue-specific Rbpjk mutant (Prx1Cre;Rbpjkf/f), Rbpjk mutant/Sox9 haploinsufficient (Prx1Cre;Rbpjkf/f;Sox9f/+), and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors. PMID:26558140

A mechanism regulating G protein-coupled receptor signaling that requires cycles of protein palmitoylation and depalmitoylation.

PubMed

Jia, Lixia; Chisari, Mariangela; Maktabi, Mohammad H; Sobieski, Courtney; Zhou, Hao; Konopko, Aaron M; Martin, Brent R; Mennerick, Steven J; Blumer, Kendall J

2014-02-28

Reversible attachment and removal of palmitate or other long-chain fatty acids on proteins has been hypothesized, like phosphorylation, to control diverse biological processes. Indeed, palmitate turnover regulates Ras trafficking and signaling. Beyond this example, however, the functions of palmitate turnover on specific proteins remain poorly understood. Here, we show that a mechanism regulating G protein-coupled receptor signaling in neuronal cells requires palmitate turnover. We used hexadecyl fluorophosphonate or palmostatin B to inhibit enzymes in the serine hydrolase family that depalmitoylate proteins, and we studied R7 regulator of G protein signaling (RGS)-binding protein (R7BP), a palmitoylated allosteric modulator of R7 RGS proteins that accelerate deactivation of Gi/o class G proteins. Depalmitoylation inhibition caused R7BP to redistribute from the plasma membrane to endomembrane compartments, dissociated R7BP-bound R7 RGS complexes from Gi/o-gated G protein-regulated inwardly rectifying K(+) (GIRK) channels and delayed GIRK channel closure. In contrast, targeting R7BP to the plasma membrane with a polybasic domain and an irreversibly attached lipid instead of palmitate rendered GIRK channel closure insensitive to depalmitoylation inhibitors. Palmitate turnover therefore is required for localizing R7BP to the plasma membrane and facilitating Gi/o deactivation by R7 RGS proteins on GIRK channels. Our findings broaden the scope of biological processes regulated by palmitate turnover on specific target proteins. Inhibiting R7BP depalmitoylation may provide a means of enhancing GIRK activity in neurological disorders.

Signaling mechanisms regulating adult neural stem cells and neurogenesis

PubMed Central

Faigle, Roland; Song, Hongjun

2012-01-01

Background Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain. Scope of review Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity. Major conclusions Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies. General significance A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. PMID:22982587

The R-spondin family of proteins: emerging regulators of WNT signaling

PubMed Central

Jin, Yong-Ri; Yoon, Jeong Kyo

2012-01-01

Recently, the R-spondin (RSPO) family of proteins has emerged as important regulators of WNT signaling. Considering the wide spectrum of WNT signaling functions in normal biological processes and disease conditions, there has been a significantly growing interest in understanding the functional roles of RSPOs in multiple biological processes and determining the molecular mechanisms by which RSPOs regulate the WNT signaling pathway. Recent advances in the RSPO research field revealed some of the in vivo functions of RSPOs and provided new information regarding the mechanistic roles of RSPO activity in regulation of WNT signaling. Herein, we review recent progress in RSPO research with an emphasis on signaling mechanisms and biological functions. PMID:22982762

Arabidopsis YAK1 regulates abscisic acid response and drought resistance.

PubMed

Kim, Dongjin; Ntui, Valentine Otang; Xiong, Liming

2016-07-01

Abscisic acid (ABA) is an important phytohormone that controls several plant processes such as seed germination, seedling growth, and abiotic stress response. Here, we report that AtYak1 plays an important role in ABA signaling and postgermination growth in Arabidopsis. AtYak1 knockout mutant plants were hyposensitive to ABA inhibition of seed germination, cotyledon greening, seedling growth, and stomatal movement. atyak1-1 mutant plants display reduced drought stress resistance, as evidenced by water loss rate and survival rate. Molecular genetic analysis revealed that AtYak1 deficiency led to elevated expression of stomatal-related gene, MYB60, and down-regulation of several stress-responsive genes. Altogether, these results indicate that AtYak1 plays a role as a positive regulator in ABA-mediated drought response in Arabidopsis. © 2016 Federation of European Biochemical Societies.

Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit Gα13.

PubMed

Scherer, Stephanie L; Cain, Matthew D; Kanai, Stanley M; Kaltenbronn, Kevin M; Blumer, Kendall J

2017-06-16

The R7 regulator of G protein signaling family (R7-RGS) critically regulates nervous system development and function. Mice lacking all R7-RGS subtypes exhibit diverse neurological phenotypes, and humans bearing mutations in the retinal R7-RGS isoform RGS9-1 have vision deficits. Although each R7-RGS subtype forms heterotrimeric complexes with Gβ 5 and R7-RGS-binding protein (R7BP) that regulate G protein-coupled receptor signaling by accelerating deactivation of G i/o α-subunits, several neurological phenotypes of R7-RGS knock-out mice are not readily explained by dysregulated G i/o signaling. Accordingly, we used tandem affinity purification and LC-MS/MS to search for novel proteins that interact with R7-RGS heterotrimers in the mouse brain. Among several proteins detected, we focused on Gα 13 because it had not been linked to R7-RGS complexes before. Split-luciferase complementation assays indicated that Gα 13 in its active or inactive state interacts with R7-RGS heterotrimers containing any R7-RGS isoform. LARG (leukemia-associated Rho guanine nucleotide exchange factor (GEF)), PDZ-RhoGEF, and p115RhoGEF augmented interaction between activated Gα 13 and R7-RGS heterotrimers, indicating that these effector RhoGEFs can engage Gα 13 ·R7-RGS complexes. Because Gα 13 /R7-RGS interaction required R7BP, we analyzed phenotypes of neuronal cell lines expressing RGS7 and Gβ 5 with or without R7BP. We found that neurite retraction evoked by Gα 12/13 -dependent lysophosphatidic acid receptors was augmented in R7BP-expressing cells. R7BP expression blunted neurite formation evoked by serum starvation by signaling mechanisms involving Gα 12/13 but not Gα i/o These findings provide the first evidence that R7-RGS heterotrimers interact with Gα 13 to augment signaling pathways that regulate neurite morphogenesis. This mechanism expands the diversity of functions whereby R7-RGS complexes regulate critical aspects of nervous system development and function. © 2017 by

The antagonistic regulation of abscisic acid-inhibited root growth by brassinosteroids is partially mediated via direct suppression of ABSCISIC ACID INSENSITIVE 5 expression by BRASSINAZOLE RESISTANT 1.

PubMed

Yang, Xiaorui; Bai, Yang; Shang, Jianxiu; Xin, Ruijiao; Tang, Wenqiang

2016-09-01

Brassinosteroids (BRs) and abscisic acid (ABA) are plant hormones that antagonistically regulate many aspects of plant growth and development; however, the mechanisms that regulate the crosstalk of these two hormones are still not well understood. BRs regulate plant growth and development by activating BRASSINAZOLE RESISTANT 1 (BZR1) family transcription factors. Here we show that the crosstalk between BRs and ABA signalling is partially mediated by BZR1 regulated gene expression. bzr1-1D is a dominant mutant with enhanced BR signalling; our results showed that bzr1-1D mutant is less sensitive to ABA-inhibited primary root growth. By RNA sequencing, a subset of BZR1 regulated ABA-responsive root genes were identified. Of these genes, the expression of a major ABA signalling component ABA INSENSITIVE 5 (ABI5) was found to be suppressed by BR and by BZR1. Additional evidences showed that BZR1 could bind strongly with several G-box cis-elements in the promoter of ABI5, suppress the expression of ABI5 and make plants less sensitive to ABA. Our study demonstrated that ABI5 is a direct target gene of BZR1, and modulating the expression of ABI5 by BZR1 plays important roles in regulating the crosstalk between the BR and ABA signalling pathways. © 2016 John Wiley & Sons Ltd.

Ubx dynamically regulates Dpp signaling by repressing Dad expression during copper cell regeneration in the adult Drosophila midgut

PubMed Central

Li, Hongjie; Qi, Yanyan; Jasper, Heinrich

2016-01-01

The gastrointestinal (GI) tract of metazoans is lined by a series of regionally distinct epithelia. To maintain structure and function of the GI tract, regionally diversified differentiation of somatic stem cell (SC) lineages is critical. The adult Drosophila midgut provides an accessible model to study SC regulation and specification in a regionally defined manner. SCs of the posterior midgut (PM) have been studied extensively, but the control of SCs in the middle midgut (MM) is less well understood. The MM contains a stomach-like copper cell region (CCR) that is regenerated by gastric stem cells (GSSCs) and contains acid-secreting copper cells (CCs). Bmp-like Decapentaplegic (Dpp) signaling determines the identity of GSSCs, and is required for CC regeneration, yet the precise control of Dpp signaling activity in this lineage remains to be fully established. Here, we show that Dad, a negative feedback regulator of Dpp signaling, is dynamically regulated in the GSSC lineage to allow CC differentiation. Dad is highly expressed in GSSCs and their first daughter cells, the gastroblasts (GBs), but has to be repressed in differentiating CCs to allow Dpp-mediated differentiation into CCs. We find that the Hox gene ultrabithorax (Ubx) is required for this regulation. Loss of Ubx prevents Dad repression in the CCR, resulting in defective CC regeneration. Our study highlights the need for dynamic control of Dpp signaling activity in the differentiation of the GSSC lineage and identifies Ubx as a critical regulator of this process. PMID:27570230

Plant hormone signaling in flowering: An epigenetic point of view.

PubMed

Campos-Rivero, Gerardo; Osorio-Montalvo, Pedro; Sánchez-Borges, Rafael; Us-Camas, Rosa; Duarte-Aké, Fátima; De-la-Peña, Clelia

2017-07-01

Reproduction is one of the most important phases in an organism's lifecycle. In the case of angiosperm plants, flowering provides the major developmental transition from the vegetative to the reproductive stage, and requires genetic and epigenetic reprogramming to ensure the success of seed production. Flowering is regulated by a complex network of genes that integrate multiple environmental cues and endogenous signals so that flowering occurs at the right time; hormone regulation, signaling and homeostasis are very important in this process. Working alone or in combination, hormones are able to promote flowering by epigenetic regulation. Some plant hormones, such as gibberellins, jasmonic acid, abscisic acid and auxins, have important effects on chromatin compaction mediated by DNA methylation and histone posttranslational modifications, which hints at the role that epigenetic regulation may play in flowering through hormone action. miRNAs have been viewed as acting independently from DNA methylation and histone modification, ignoring their potential to interact with hormone signaling - including the signaling of auxins, gibberellins, ethylene, jasmonic acid, salicylic acid and others - to regulate flowering. Therefore, in this review we examine new findings about interactions between epigenetic mechanisms and key players in hormone signaling to coordinate flowering. Copyright © 2017 Elsevier GmbH. All rights reserved.

GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling

PubMed Central

Stretton, Clare; Hoffmann, Thorsten M.; Munson, Michael J.; Prescott, Alan; Taylor, Peter M.; Ganley, Ian G.; Hundal, Harinder S.

2015-01-01

The mammalian or mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a ubiquitously expressed multimeric protein kinase complex that integrates nutrient and growth factor signals for the co-ordinated regulation of cellular metabolism and cell growth. Herein, we demonstrate that suppressing the cellular activity of glycogen synthase kinase-3 (GSK3), by use of pharmacological inhibitors or shRNA-mediated gene silencing, results in substantial reduction in amino acid (AA)-regulated mTORC1-directed signalling, as assessed by phosphorylation of multiple downstream mTORC1 targets. We show that GSK3 regulates mTORC1 activity through its ability to phosphorylate the mTOR-associated scaffold protein raptor (regulatory-associated protein of mTOR) on Ser859. We further demonstrate that either GSK3 inhibition or expression of a S859A mutated raptor leads to reduced interaction between mTOR and raptor and under these circumstances, irrespective of AA availability, there is a consequential loss in phosphorylation of mTOR substrates, such as p70S6K1 (ribosomal S6 kinase 1) and uncoordinated-51-like kinase (ULK1), which results in increased autophagic flux and reduced cellular proliferation. PMID:26348909

Regulation of intestinal health by branched-chain amino acids.

PubMed

Zhou, Hua; Yu, Bing; Gao, Jun; Htoo, John Khun; Chen, Daiwen

2018-01-01

Besides its primary role in the digestion and absorption of nutrients, the intestine also interacts with a complex external milieu, and is the first defense line against noxious pathogens and antigens. Dysfunction of the intestinal barrier is associated with enhanced intestinal permeability and development of various gastrointestinal diseases. The branched-chain amino acids (BCAAs) are important nutrients, which are the essential substrates for protein biosynthesis. Recently, emerging evidence showed that BCAAs are involved in maintaining intestinal barrier function. It has been reported that dietary supplementation with BCAAs promotes intestinal development, enhances enterocyte proliferation, increases intestinal absorption of amino acids (AA) and glucose, and improves the immune defenses of piglets. The underlying mechanism of these effects is mediated by regulating expression of genes and proteins associate with various signaling pathways. In addition, BCAAs promote the production of beneficial bacteria in the intestine of mice. Compelling evidence supports the notion that BCAAs play important roles in both nutrition and intestinal health. Therefore, as functional amino acids with various physiological effects, BCAAs hold key roles in promoting intestinal development and health in animals and humans. © 2017 Japanese Society of Animal Science.

Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon.

PubMed

Kavitha, Jovita V; Rosario, Fredrick J; Nijland, Mark J; McDonald, Thomas J; Wu, Guoyao; Kanai, Yoshikatsu; Powell, Theresa L; Nathanielsz, Peter W; Jansson, Thomas

2014-03-01

The mechanisms by which maternal nutrient restriction (MNR) causes reduced fetal growth are poorly understood. We hypothesized that MNR inhibits placental mechanistic target of rapamycin (mTOR) and insulin/IGF-I signaling, down-regulates placental nutrient transporters, and decreases fetal amino acid levels. Pregnant baboons were fed control (ad libitum, n=11) or an MNR diet (70% of controls, n=11) from gestational day (GD) 30. Placenta and umbilical blood were collected at GD 165. Western blot was used to determine the phosphorylation of proteins in the mTOR, insulin/IGF-I, ERK1/2, and GSK-3 signaling pathways in placental homogenates and expression of glucose transporter 1 (GLUT-1), taurine transporter (TAUT), sodium-dependent neutral amino acid transporter (SNAT), and large neutral amino acid transporter (LAT) isoforms in syncytiotrophoblast microvillous membranes (MVMs). MNR reduced fetal weights by 13%, lowered fetal plasma concentrations of essential amino acids, and decreased the phosphorylation of placental S6K, S6 ribosomal protein, 4E-BP1, IRS-1, Akt, ERK-1/2, and GSK-3. MVM protein expression of GLUT-1, TAUT, SNAT-2 and LAT-1/2 was reduced in MNR. This is the first study in primates exploring placental responses to maternal undernutrition. Inhibition of placental mTOR and insulin/IGF-I signaling resulting in down-regulation of placental nutrient transporters may link maternal undernutrition to restricted fetal growth.

Weights in the balance: jasmonic acid and salicylic acid signaling in root-biotroph interactions.

PubMed

Gutjahr, Caroline; Paszkowski, Uta

2009-07-01

Work on the interaction of aerial plant parts with pathogens has identified the signaling molecules jasmonic acid (JA) and salicylic acid (SA) as important players in induced defense of the plant against invading organisms. Much less is known about the role of JA and SA signaling in root infection. Recent progress has been made in research on plant interactions with biotrophic mutualists and parasites that exclusively associate with roots, namely arbuscular mycorrhizal and rhizobial symbioses on one hand and nematode and parasitic plant interactions on the other hand. Here, we review these recent advances relating JA and SA signaling to specific stages of root colonization and discuss how both signaling molecules contribute to a balance between compatibility and defense in mutualistic as well as parasitic biotroph-root interactions.

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)*

PubMed Central

Foster, David A.; Salloum, Darin; Menon, Deepak; Frias, Maria A.

2014-01-01

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival. PMID:24990952

Co-expression analysis identifies CRC and AP1 the regulator of Arabidopsis fatty acid biosynthesis.

PubMed

Han, Xinxin; Yin, Linlin; Xue, Hongwei

2012-07-01

Fatty acids (FAs) play crucial rules in signal transduction and plant development, however, the regulation of FA metabolism is still poorly understood. To study the relevant regulatory network, fifty-eight FA biosynthesis genes including de novo synthases, desaturases and elongases were selected as "guide genes" to construct the co-expression network. Calculation of the correlation between all Arabidopsis thaliana (L.) genes with each guide gene by Arabidopsis co-expression dating mining tools (ACT) identifies 797 candidate FA-correlated genes. Gene ontology (GO) analysis of these co-expressed genes showed they are tightly correlated to photosynthesis and carbohydrate metabolism, and function in many processes. Interestingly, 63 transcription factors (TFs) were identified as candidate FA biosynthesis regulators and 8 TF families are enriched. Two TF genes, CRC and AP1, both correlating with 8 FA guide genes, were further characterized. Analyses of the ap1 and crc mutant showed the altered total FA composition of mature seeds. The contents of palmitoleic acid, stearic acid, arachidic acid and eicosadienoic acid are decreased, whereas that of oleic acid is increased in ap1 and crc seeds, which is consistent with the qRT-PCR analysis revealing the suppressed expression of the corresponding guide genes. In addition, yeast one-hybrid analysis and electrophoretic mobility shift assay (EMSA) revealed that CRC can bind to the promoter regions of KCS7 and KCS15, indicating that CRC may directly regulate FA biosynthesis. © 2012 Institute of Botany, Chinese Academy of Sciences.

Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion.

PubMed

Luis, Tiago C; Naber, Brigitta A E; Roozen, Paul P C; Brugman, Martijn H; de Haas, Edwin F E; Ghazvini, Mehrnaz; Fibbe, Willem E; van Dongen, Jacques J M; Fodde, Riccardo; Staal, Frank J T

2011-10-04

Canonical Wnt signaling has been implicated in the regulation of hematopoiesis. By employing a Wnt-reporter mouse, we observed that Wnt signaling is differentially activated during hematopoiesis, suggesting an important regulatory role for specific Wnt signaling levels. To investigate whether canonical Wnt signaling regulates hematopoiesis in a dosage-dependent fashion, we analyzed the effect of different mutations in the Adenomatous polyposis coli gene (Apc), a negative modulator of the canonical Wnt pathway. By combining different targeted hypomorphic alleles and a conditional deletion allele of Apc, a gradient of five different Wnt signaling levels was obtained in vivo. We here show that different, lineage-specific Wnt dosages regulate hematopoietic stem cells (HSCs), myeloid precursors, and T lymphoid precursors during hematopoiesis. Differential, lineage-specific optimal Wnt dosages provide a unifying concept that explains the differences reported among inducible gain-of-function approaches, leading to either HSC expansion or depletion of the HSC pool. Copyright © 2011 Elsevier Inc. All rights reserved.

Lysophosphatidic Acid Regulation and Roles in Human Prostate Cancer

DTIC Science & Technology

2006-08-01

phosphatidic acid (PA), regulate pivotal processes related to the pathogenesis of cancer. We characterized a novel lipid kinase, designated...pathways. LPA is produced from phosphatidic acid 5 (PA) in activated platelets and ovarian and prostate cancer cells by phospholipase D and subsequent...lysophosphatidic acid (LPA) and phosphatidic acid (PA), regulate pivotal processes related to the pathogenesis of cancer. Here, we report characterization of a novel

Autotaxin/Lpar3 signaling regulates Kupffer's vesicle formation and left-right asymmetry in zebrafish.

PubMed

Lai, Shih-Lei; Yao, Wan-Ling; Tsao, Ku-Chi; Houben, Anna J S; Albers, Harald M H G; Ovaa, Huib; Moolenaar, Wouter H; Lee, Shyh-Jye

2012-12-01

Left-right (L-R) patterning is essential for proper organ morphogenesis and function. Calcium fluxes in dorsal forerunner cells (DFCs) are known to regulate the formation of Kupffer's vesicle (KV), a central organ for establishing L-R asymmetry in zebrafish. Here, we identify the lipid mediator lysophosphatidic acid (LPA) as a regulator of L-R asymmetry in zebrafish embryos. LPA is produced by Autotaxin (Atx), a secreted lysophospholipase D, and triggers various cellular responses through activation of specific G protein-coupled receptors (Lpar1-6). Knockdown of Atx or LPA receptor 3 (Lpar3) by morpholino oligonucleotides perturbed asymmetric gene expression in lateral plate mesoderm and disrupted organ L-R asymmetries, whereas overexpression of lpar3 partially rescued those defects in both atx and lpar3 morphants. Similar defects were observed in embryos treated with the Atx inhibitor HA130 and the Lpar1-3 inhibitor Ki16425. Knockdown of either Atx or Lpar3 impaired calcium fluxes in DFCs during mid-epiboly stage and compromised DFC cohesive migration, KV formation and ciliogenesis. Application of LPA to DFCs rescued the calcium signal and laterality defects in atx morphants. This LPA-dependent L-R asymmetry is mediated via Wnt signaling, as shown by the accumulation of β-catenin in nuclei at the dorsal side of both atx and lpar3 morphants. Our results suggest a major role for the Atx/Lpar3 signaling axis in regulating KV formation, ciliogenesis and L-R asymmetry via a Wnt-dependent pathway.

High and Low Molecular Weight Hyaluronic Acid Differentially Regulate Human Fibrocyte Differentiation

PubMed Central

Maharjan, Anu S.; Pilling, Darrell; Gomer, Richard H.

2011-01-01

Background Following tissue injury, monocytes can enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but little is known about what regulates this differentiation. Extracellular matrix contains high molecular weight hyaluronic acid (HMWHA; ∼2×106 Da). During injury, HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ∼0.8–8×105 Da). Methods and Findings In this report, we show that HMWHA potentiates the differentiation of human monocytes into fibrocytes, while LMWHA inhibits fibrocyte differentiation. Digestion of HMWHA with hyaluronidase produces small hyaluronic acid fragments, and these fragments inhibit fibrocyte differentiation. Monocytes internalize HMWHA and LMWHA equally well, suggesting that the opposing effects on fibrocyte differentiation are not due to differential internalization of HMWHA or LMWHA. Adding HMWHA to PBMC does not appear to affect the levels of the hyaluronic acid receptor CD44, whereas adding LMWHA decreases CD44 levels. The addition of anti-CD44 antibodies potentiates fibrocyte differentiation, suggesting that CD44 mediates at least some of the effect of hyaluronic acid on fibrocyte differentiation. The fibrocyte differentiation-inhibiting factor serum amyloid P (SAP) inhibits HMWHA-induced fibrocyte differentiation and potentiates LMWHA-induced inhibition. Conversely, LMWHA inhibits the ability of HMWHA, interleukin-4 (IL-4), or interleukin-13 (IL-13) to promote fibrocyte differentiation. Conclusions We hypothesize that hyaluronic acid signals at least in part through CD44 to regulate fibrocyte differentiation, with a dominance hierarchy of SAP>LMWHA≥HMWHA>IL-4 or IL-13. PMID:22022512

Lysophosphatidic acid acts as a nutrient-derived developmental cue to regulate early hematopoiesis

PubMed Central

Li, Haisen; Yue, Rui; Wei, Bin; Gao, Ge; Du, Jiulin; Pei, Gang

2014-01-01

Primitive hematopoiesis occurs in the yolk sac blood islands during vertebrate embryogenesis, where abundant phosphatidylcholines (PC) are available as important nutrients for the developing embryo. However, whether these phospholipids also generate developmental cues to promote hematopoiesis is largely unknown. Here, we show that lysophosphatidic acid (LPA), a signaling molecule derived from PC, regulated hemangioblast formation and primitive hematopoiesis. Pharmacological and genetic blockage of LPA receptor 1 (LPAR1) or autotoxin (ATX), a secretory lysophospholipase that catalyzes LPA production, inhibited hematopoietic differentiation of mouse embryonic stem cells and impaired the formation of hemangioblasts. Mechanistic experiments revealed that the regulatory effect of ATX-LPA signaling was mediated by PI3K/Akt-Smad pathway. Furthermore, during in vivo embryogenesis in zebrafish, LPA functioned as a developmental cue for hemangioblast formation and primitive hematopoiesis. Taken together, we identified LPA as an important nutrient-derived developmental cue for primitive hematopoiesis as well as a novel mechanism of hemangioblast regulation. PMID:24829209

Lysophosphatidic acid acts as a nutrient-derived developmental cue to regulate early hematopoiesis.

PubMed

Li, Haisen; Yue, Rui; Wei, Bin; Gao, Ge; Du, Jiulin; Pei, Gang

2014-06-17

Primitive hematopoiesis occurs in the yolk sac blood islands during vertebrate embryogenesis, where abundant phosphatidylcholines (PC) are available as important nutrients for the developing embryo. However, whether these phospholipids also generate developmental cues to promote hematopoiesis is largely unknown. Here, we show that lysophosphatidic acid (LPA), a signaling molecule derived from PC, regulated hemangioblast formation and primitive hematopoiesis. Pharmacological and genetic blockage of LPA receptor 1 (LPAR1) or autotoxin (ATX), a secretory lysophospholipase that catalyzes LPA production, inhibited hematopoietic differentiation of mouse embryonic stem cells and impaired the formation of hemangioblasts. Mechanistic experiments revealed that the regulatory effect of ATX-LPA signaling was mediated by PI3K/Akt-Smad pathway. Furthermore, during in vivo embryogenesis in zebrafish, LPA functioned as a developmental cue for hemangioblast formation and primitive hematopoiesis. Taken together, we identified LPA as an important nutrient-derived developmental cue for primitive hematopoiesis as well as a novel mechanism of hemangioblast regulation. © 2014 The Authors.

Regucalcin and cell regulation: role as a suppressor protein in signal transduction.

PubMed

Yamaguchi, Masayoshi

2011-07-01

Regucalcin was discovered in 1978 as a calcium-binding protein that does not contain EF-hand motif of calcium-binding domain (Yamaguchi and Yamamoto Chem Pharm Bull 26:1915-1918, 1978). The name regucalcin was proposed for this calcium-binding protein, which can regulate various Ca(2+)-dependent enzyme activations in liver cells. The regucalcin gene is localized on the chromosome X, and the organization of the regucalcin gene consists of seven exons and six introns. AP-1, NF1-A1, and RGPR-p117 bind to the promoter region of the rat regucalcin gene and enhance transcription activity of regucalcin gene expression that is mediated through calcium signaling. Regucalcin plays a pivotal role in the keep of intracellular calcium ion (Ca(2+)) homeostasis due to activating Ca(2+) pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum), mitochondria, and nuclei of many cell types. Regucalcin has a suppressive effect on calcium signaling from the cytoplasm to the nucleus in the proliferative cells. Regucalcin has also been demonstrated to transport to the nucleus, and it can inhibit Ca(2+)-dependent protein kinase and protein phosphatase activities, Ca(2+)-activated deoxyribonucleic acid (DNA) fragmentation, and DNA and ribonucleic acid (RNA) synthesis in the nucleus. Overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells induced by various signaling factors. Regucalcin can inhibit the enhancement of cell proliferation due to hormonal stimulation. Regucalcin plays an important role as a regulatory protein in cell signaling system, and it is proposed to play a pivotal role in keep of cell homeostasis and function.

Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling.

PubMed

Grabner, Gernot F; Zimmermann, Robert; Schicho, Rudolf; Taschler, Ulrike

2017-07-01

Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL. Copyright © 2017 Elsevier Inc. All rights reserved.

Co-option of the hormone-signalling module dafachronic acid-DAF-12 in nematode evolution.

PubMed

Bento, Gilberto; Ogawa, Akira; Sommer, Ralf J

2010-07-22

Morphological novelties are lineage-specific traits that serve new functions. Developmental polyphenisms have been proposed to be facilitators of phenotypic evolution, but little is known about the interplay between the associated genetic and environmental factors. Here, we study two alternative morphologies in the mouth of the nematode Pristionchus pacificus and the formation of teeth-like structures that are associated with bacteriovorous feeding and predatory behaviour on fungi and other worms. These teeth-like denticles represent an evolutionary novelty, which is restricted to some members of the nematode family Diplogastridae but is absent from Caenorhabditis elegans and related nematodes. We show that the mouth dimorphism is a polyphenism that is controlled by starvation and the co-option of an endocrine switch mechanism. Mutations in the nuclear hormone receptor DAF-12 and application of its ligand, the sterol hormone dafachronic acid, strongly influence this switch mechanism. The dafachronic acid-DAF-12 module has been shown to control the formation of arrested dauer larvae in both C. elegans and P. pacificus, as well as related life-history decisions in distantly related nematodes. The comparison of dauer formation and mouth morphology switch reveals that different thresholds of dafachronic acid signalling provide specificity. This study shows how hormonal signalling acts by coupling environmental change and genetic regulation and identifies dafachronic acid as a key hormone in nematode evolution.

Go Signaling in Mushroom Bodies Regulates Sleep in Drosophila

PubMed Central

Guo, Fang; Yi, Wei; Zhou, Mingmin; Guo, Aike

2011-01-01

Study Objectives: Sleep is a fundamental physiological process and its biological mechanisms are poorly understood. In Drosophila melanogaster, heterotrimeric Go protein is abundantly expressed in the brain. However, its post-developmental function has not been extensively explored. Design: Locomotor activity was measured using the Drosophila Activity Monitoring System under a 12:12 LD cycle. Sleep was defined as periods of 5 min with no recorded activity. Results: Pan-neuronal elevation of Go signaling induced quiescence accompanied by an increased arousal threshold in flies. By screening region-specific GAL4 lines, we mapped the sleep-regulatory function of Go signaling to mushroom bodies (MBs), a central brain region which modulates memory, decision making, and sleep in Drosophila. Up-regulation of Go activity in these neurons consolidated sleep while inhibition of endogenous Go via expression of Go RNAi or pertussis toxin reduced and fragmented sleep, indicating that the Drosophila sleep requirement is affected by levels of Go activity in the MBs. Genetic interaction results showed that Go signaling serves as a neuronal transmission inhibitor in a cAMP-independent pathway. Conclusion: Go signaling is a novel signaling pathway in MBs that regulates sleep in Drosophila. Citation: Guo F; Yi W; Zhou M; Guo A. Go signaling in mushroom bodies regulates sleep in drosophila. SLEEP 2011;34(3):273-281. PMID:21358844

Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system.

PubMed

Luo, Jiang-Yun; Zhang, Yang; Wang, Li; Huang, Yu

2015-07-15

Bone morphogenetic proteins (BMPs) play key roles in the regulation of cell proliferation, differentiation and apoptosis in various tissues and organs, including the cardiovascular system. BMPs signal through both Smad-dependent and -independent cascades to exert a wide spectrum of biological activities. Cardiovascular disorders such as abnormal angiogenesis, atherosclerosis, pulmonary hypertension and cardiac hypertrophy have been linked to aberrant BMP signalling. To correct the dysregulated BMP signalling in cardiovascular pathogenesis, it is essential to get a better understanding of how the regulators and effectors of BMP signalling control cardiovascular function and how the dysregulated BMP signalling contributes to cardiovascular dysfunction. We hence highlight several key regulators of BMP signalling such as extracellular regulators of ligands, mechanical forces, microRNAs and small molecule drugs as well as typical BMP effectors like direct downstream target genes, mitogen-activated protein kinases, reactive oxygen species and microRNAs. The insights into these molecular processes will help target both the regulators and important effectors to reverse BMP-associated cardiovascular pathogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Regulation of Root Greening by Light and Auxin/Cytokinin Signaling in Arabidopsis[W

PubMed Central

Kobayashi, Koichi; Baba, Shinsuke; Obayashi, Takeshi; Sato, Mayuko; Toyooka, Kiminori; Keränen, Mika; Aro, Eva-Mari; Fukaki, Hidehiro; Ohta, Hiroyuki; Sugimoto, Keiko; Masuda, Tatsuru

2012-01-01

Tight coordination between plastid differentiation and plant development is best evidenced by the synchronized development of photosynthetic tissues and the biogenesis of chloroplasts. Here, we show that Arabidopsis thaliana roots demonstrate accelerated chlorophyll accumulation and chloroplast development when they are detached from shoots. However, this phenomenon is repressed by auxin treatment. Mutant analyses suggest that auxin transported from the shoot represses root greening via the function of INDOLE-3-ACETIC ACID14, AUXIN RESPONSE FACTOR7 (ARF7), and ARF19. Cytokinin signaling, on the contrary, is required for chlorophyll biosynthesis in roots. The regulation by auxin/cytokinin is dependent on the transcription factor LONG HYPOCOTYL5 (HY5), which is required for the expression of key chlorophyll biosynthesis genes in roots. The expression of yet another root greening transcription factor, GOLDEN2-LIKE2 (GLK2), was found to be regulated in opposing directions by auxin and cytokinin. Furthermore, both the hormone signaling and the GLK transcription factors modified the accumulation of HY5 in roots. Overexpression of GLKs in the hy5 mutant provided evidence that GLKs require HY5 to maximize their activities in root greening. We conclude that the combination of HY5 and GLKs, functioning downstream of light and auxin/cytokinin signaling pathways, is responsible for coordinated expression of the key genes in chloroplast biogenesis. PMID:22415275

Nutritional Signaling via Free Fatty Acid Receptors

PubMed Central

Miyamoto, Junki; Hasegawa, Sae; Kasubuchi, Mayu; Ichimura, Atsuhiko; Nakajima, Akira; Kimura, Ikuo

2016-01-01

Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs’ carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism. PMID:27023530

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

PubMed Central

Sun, Shuguo; Irvine, Kenneth D.

2016-01-01

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated, and to define their respective contributions in vivo. PMID:27268910

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network.

PubMed

Sun, Shuguo; Irvine, Kenneth D

2016-09-01

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated and to define their respective contributions in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Modulating inflammation through the negative regulation of NF-κB signaling.

PubMed

Rothschild, Daniel E; McDaniel, Dylan K; Ringel-Scaia, Veronica M; Allen, Irving C

2018-02-01

Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage underlying a diverse range of auto-inflammatory, hyper-inflammatory, and neoplastic diseases. The NF-κB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF-κB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF-κB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF-receptor-associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies. ©2018 Society for Leukocyte Biology.

Oridonin stabilizes retinoic acid receptor alpha through ROS-activated NF-κB signaling.

PubMed

Cao, Yang; Wei, Wei; Zhang, Nan; Yu, Qing; Xu, Wen-Bin; Yu, Wen-Jun; Chen, Guo-Qiang; Wu, Ying-Li; Yan, Hua

2015-04-10

Retinoic acid receptor alpha (RARα) plays an essential role in the regulation of many biological processes, such as hematopoietic cell differentiation, while abnormal RARα function contributes to the pathogenesis of certain diseases including cancers, especially acute promyelocytic leukemia (APL). Recently, oridonin, a natural diterpenoid isolated from Rabdosia rubescens, was demonstrated to regulate RARα by increasing its protein level. However, the underlying molecular mechanism for this action has not been fully elucidated. In the APL cell line, NB4, the effect of oridonin on RARα protein was analyzed by western blot and real-time quantitative RT-PCR analyses. Flow cytometry was performed to detect intracellular levels of reactive oxygen species (ROS). The association between nuclear factor-kappa B (NF-κB) signaling and the effect of oridonin was assessed using specific inhibitors, shRNA gene knockdown, and immunofluorescence assays. In addition, primary leukemia cells were treated with oridonin and analyzed by western blot in this study. RARα possesses transcriptional activity in the presence of its ligand, all-trans retinoic acid (ATRA). Oridonin remarkably stabilized the RARα protein, which retained transcriptional activity. Oridonin also moderately increased intracellular ROS levels, while pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), dramatically abrogated RARα stabilization by oridonin. More intriguingly, direct exposure to low concentrations of H2O2 also increased RARα protein but not mRNA levels, suggesting a role for ROS in oridonin stabilization of RARα protein. Further investigations showed that NAC antagonized oridonin-induced activation of NF-κB signaling, while the NF-κB signaling inhibitor, Bay 11-7082, effectively blocked the oridonin increase in RARα protein levels. In line with this, over-expression of IκΒα (A32/36), a super-repressor form of IκΒα, or NF-κB-p65 knockdown inhibited oridonin or H2O2-induced

Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle.

PubMed

Ruby, Maxwell A; Riedl, Isabelle; Massart, Julie; Åhlin, Marcus; Zierath, Juleen R

2017-10-01

Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling while stimulating fatty acid oxidation and incorporation into triglycerides and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC-1α and SREBP-1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism. Copyright © 2017 the American Physiological Society.

MRAP2 regulates ghrelin receptor signaling and hunger sensing.

PubMed

Srisai, Dollada; Yin, Terry C; Lee, Abigail A; Rouault, Alix A J; Pearson, Nicole A; Grobe, Justin L; Sebag, Julien A

2017-09-28

Ghrelin is the only known circulating orexigenic hormone. It is primarily secreted by the stomach and acts at its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), in the hypothalamus to signal hunger and promote food intake. The melanocortin receptor accessory protein 2 (MRAP2) was previously shown to regulate energy homeostasis through the modulation of the activity of the melanocortin-4 receptor and prokineticin receptors. In this study we identify MRAP2 as a partner of ghrelin-GHSR1a signaling. We show that MRAP2 interacts with GHSR1a and potentiates ghrelin-stimulated signaling both in vitro and in vivo. We demonstrate that in the absence of MRAP2, fasting fails to activate agouti-related protein neurons. In addition, we show that the orexigenic effect of ghrelin is lost in mice lacking MRAP2. Our results suggest that MRAP2 is an important modulator of the energy homeostasis machinery that operates through the regulation of multiple GPCRs throughout the hypothalamus.Melanocortin receptor accessory protein 2 (MRAP2) is an adaptor protein that contributes to melanocortin-4 receptor and prokineticin receptor 1 signalling. Here the authors show that MRAP2 also regulates ghrelin receptor signalling in the hypothalamus and starvation sensing in mice.

Responsiveness to acidity via metal ion regulators mediates virulence in the gastric pathogen Helicobacter pylori.

PubMed

Bury-Moné, Stéphanie; Thiberge, Jean-Michel; Contreras, Monica; Maitournam, Aboubakar; Labigne, Agnès; De Reuse, Hilde

2004-07-01

The virulence of pathogenic bacteria is dependent on their adaptation to and survival in the stressful conditions encountered in their hosts. Helicobacter pylori exclusively colonizes the acid stomach of primates, making it an ideal study model. Little is known about how H. pylori responds to the moderately acidic conditions encountered at its colonization site, the gastric mucus layer. Thus, we compared gene expression profiles of H. pylori 26695 grown at neutral and acidic pH, and validated the data for a selection of genes by real-time polymerase chain reaction, dot-blots or enzymatic assays. During growth in acidic conditions, 56 genes were upregulated and 45 genes downregulated. We found that acidity is a signal modulating the expression of several virulence factors. Regulation of genes related to metal ion homeostasis suggests protective mechanisms involving diminished transport and enhanced storage. Genes encoding subunits of the F0F1 ATPase and of a newly identified Na+/H+ antiporter (NhaC-HP0946) were downregulated, revealing that this bacterium uses original mechanisms to control proton entry. Five of the upregulated genes encoded proteins controlling intracellular ammonia synthesis, including urease, amidase and formamidase, underlining the major role of this buffering compound in the protection against acidity in H. pylori. Regulatory networks and transcriptome analysis as well as enzymatic assays implicated two metal-responsive transcriptional regulators (NikR and Fur) and an essential two-component response regulator (HP0166, OmpR-like) as effectors of the H. pylori acid response. Finally, a nikR-fur mutant is attenuated in the mouse model, emphasizing the link between response to acidity, metal metabolism and virulence in this gastric pathogen.

Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration

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

Zhu, Zhong Xin; Sun, Cong Cong; Wenzhou People's Hospital, Wenzhou, Zhejiang

Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up-regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Westernmore » blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-β-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of β-catenin, suggesting that β-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy. - Highlights: • bFGF regulates Hedgehog (Hh) signaling in fibroblasts. • The Smo and Gli two master regulators of Hh signaling positively regulate fibroblast migration. • Smo facilitates β-catenin nuclear translocation via activation PI3K/JNK/GSK3β. • β-catenin positively regulates fibroblast cell migration and the expression of Hh signaling genes including Smo and Gli.« less

Rice ABI5-Like1 Regulates Abscisic Acid and Auxin Responses by Affecting the Expression of ABRE-Containing Genes1[W][OA

PubMed Central

Yang, Xi; Yang, Ya-Nan; Xue, Liang-Jiao; Zou, Mei-Juan; Liu, Jian-Ying; Chen, Fan; Xue, Hong-Wei

2011-01-01

Abscisic acid (ABA) regulates plant development and is crucial for plant responses to biotic and abiotic stresses. Studies have identified the key components of ABA signaling in Arabidopsis (Arabidopsis thaliana), some of which regulate ABA responses by the transcriptional regulation of downstream genes. Here, we report the functional identification of rice (Oryza sativa) ABI5-Like1 (ABL1), which is a basic region/leucine zipper motif transcription factor. ABL1 is expressed in various tissues and is induced by the hormones ABA and indole-3-acetic acid and stress conditions including salinity, drought, and osmotic pressure. The ABL1 deficiency mutant, abl1, shows suppressed ABA responses, and ABL1 expression in the Arabidopsis abi5 mutant rescued the ABA sensitivity. The ABL1 protein is localized to the nucleus and can directly bind ABA-responsive elements (ABREs; G-box) in vitro. A gene expression analysis by DNA chip hybridization confirms that a large proportion of down-regulated genes of abl1 are involved in stress responses, consistent with the transcriptional activating effects of ABL1. Further studies indicate that ABL1 regulates the plant stress responses by regulating a series of ABRE-containing WRKY family genes. In addition, the abl1 mutant is hypersensitive to exogenous indole-3-acetic acid, and some ABRE-containing genes related to auxin metabolism or signaling are altered under ABL1 deficiency, suggesting that ABL1 modulates ABA and auxin responses by directly regulating the ABRE-containing genes. PMID:21546455

Regulation of T cell receptor complex-mediated signaling by ubiquitin and ubiquitin-like modifications.

PubMed

Friend, Samantha F; Deason-Towne, Francina; Peterson, Lisa K; Berger, Allison J; Dragone, Leonard L

2014-01-01

Post-translational protein modifications are a dynamic method of regulating protein function in response to environmental signals. As with any cellular process, T cell receptor (TCR) complex-mediated signaling is highly regulated, since the strength and duration of TCR-generated signals governs T cell development and activation. While regulation of TCR complex-mediated signaling by phosphorylation has been well studied, regulation by ubiquitin and ubiquitin-like modifiers is still an emerging area of investigation. This review will examine how ubiquitin, E3 ubiquitin ligases, and other ubiquitin-like modifications such as SUMO and NEDD8 regulate TCR complex-mediated signaling.

Regulation of T cell receptor complex-mediated signaling by ubiquitin and ubiquitin-like modifications

PubMed Central

Friend, Samantha F; Deason-Towne, Francina; Peterson, Lisa K; Berger, Allison J; Dragone, Leonard L

2014-01-01

Post-translational protein modifications are a dynamic method of regulating protein function in response to environmental signals. As with any cellular process, T cell receptor (TCR) complex-mediated signaling is highly regulated, since the strength and duration of TCR-generated signals governs T cell development and activation. While regulation of TCR complex-mediated signaling by phosphorylation has been well studied, regulation by ubiquitin and ubiquitin-like modifiers is still an emerging area of investigation. This review will examine how ubiquitin, E3 ubiquitin ligases, and other ubiquitin-like modifications such as SUMO and NEDD8 regulate TCR complex-mediated signaling. PMID:25628960

A maize death acid, 10-oxo-11-phytoenoic acid, is the predominant cyclopentenone signal present during multiple stress and developmental conditions

PubMed Central

Christensen, Shawn A.; Huffaker, Alisa; Hunter, Charles T.; Alborn, Hans T.; Schmelz, Eric A.

2016-01-01

abstract Recently we investigated the function of the 9-lipoxygenase (LOX) derived cyclopentenones 10-oxo-11-phytoenoic acid (10-OPEA) and 10-oxo-11,15-phytodienoic acid (10-OPDA) and identified their C-14 and C-12 derivatives. 10-OPEA accumulation is elicited by fungal and insect attack and acts as a strong inhibitor of microbial and herbivore growth. Although structurally similar, comparative analyses between 10-OPEA and its 13-LOX analog 12-oxo-phytodienoic acid (12-OPDA) demonstrate specificity in transcript accumulation linked to detoxification, secondary metabolism, jasmonate regulation, and protease inhibition. As a potent cell death signal, 10-OPEA activates cysteine protease activity leading to ion leakage and apoptotic-like DNA fragmentation. In this study we further elucidate the distribution, abundance, and functional roles of 10-OPEA, 10-OPDA, and 12-OPDA, in diverse organs under pathogen- and insect-related stress. PMID:26669723

Lysophosphatidic acid signaling via LPA{sub 1} and LPA{sub 3} regulates cellular functions during tumor progression in pancreatic cancer cells

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

Fukushima, Kaori; Takahashi, Kaede; Yamasaki, Eri

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors exhibits a variety of biological effects, such as cell proliferation, motility and differentiation. The aim of this study was to evaluate the roles of LPA{sub 1} and LPA{sub 3} in cellular functions during tumor progression in pancreatic cancer cells. LPA{sub 1} and LPA{sub 3} knockdown cells were generated from PANC-1 cells. The cell motile and invasive activities of PANC-1 cells were inhibited by LPA{sub 1} and LPA{sub 3} knockdown. In gelatin zymography, LPA{sub 1} and LPA{sub 3} knockdown cells indicated the low activation of matrix metalloproteinase-2 (MMP-2) in the presence ofmore » LPA. Next, to assess whether LPA{sub 1} and LPA{sub 3} regulate cellular functions induced by anticancer drug, PANC-1 cells were treated with cisplatin (CDDP) for approximately 6 months. The cell motile and invasive activities of long-term CDDP treated cells were markedly higher than those of PANC-1 cells, correlating with the expression levels of LPAR1 and LPAR3 genes. In soft agar assay, the long-term CDDP treated cells formed markedly large sized colonies. In addition, the cell motile and invasive activities enhanced by CDDP were significantly suppressed by LPA{sub 1} and LPA{sub 3} knockdown as well as colony formation. These results suggest that LPA signaling via LPA{sub 1} and LPA{sub 3} play an important role in the regulation of cellular functions during tumor progression in PANC-1 cells. - Highlights: • The cell motile and invasive activities of PANC-1 cells were stimulated by LPA{sub 1} and LPA{sub 3}. • LPA{sub 1} and LPA{sub 3} enhanced MMP-2 activation in PANC-1 cells. • The expressions of LPAR1 and LPAR3 genes were elevated in PANC-1 cells treated with cisplatin. • The cell motile and invasive activities of PANC-1 cells treated with cisplatin were suppressed by LPA{sub 1} and LPA{sub 3} knockdown. • LPA{sub 1} and LPA{sub 3} are involved in the regulation of cellular functions

DEG9, a serine protease, modulates cytokinin and light signaling by regulating the level of ARABIDOPSIS RESPONSE REGULATOR 4.

PubMed

Chi, Wei; Li, Jing; He, Baoye; Chai, Xin; Xu, Xiumei; Sun, Xuwu; Jiang, Jingjing; Feng, Peiqiang; Zuo, Jianru; Lin, Rongcheng; Rochaix, Jean-David; Zhang, Lixin

2016-06-21

Cytokinin is an essential phytohormone that controls various biological processes in plants. A number of response regulators are known to be important for cytokinin signal transduction. ARABIDOPSIS RESPONSE REGULATOR 4 (ARR4) mediates the cross-talk between light and cytokinin signaling through modulation of the activity of phytochrome B. However, the mechanism that regulates the activity and stability of ARR4 is unknown. Here we identify an ATP-independent serine protease, degradation of periplasmic proteins 9 (DEG9), which localizes to the nucleus and regulates the stability of ARR4. Biochemical evidence shows that DEG9 interacts with ARR4, thereby targeting ARR4 for degradation, which suggests that DEG9 regulates the stability of ARR4. Moreover, genetic evidence shows that DEG9 acts upstream of ARR4 and regulates the activity of ARR4 in cytokinin and light-signaling pathways. This study thus identifies a role for a ubiquitin-independent selective protein proteolysis in the regulation of the stability of plant signaling components.

N-3 poly-unsaturated fatty acids shift estrogen signaling to inhibit human breast cancer cell growth.

PubMed

Cao, Wenqing; Ma, ZhiFan; Rasenick, Mark M; Yeh, ShuYan; Yu, JiangZhou

2012-01-01

Although evidence has shown the regulating effect of n-3 poly-unsaturated fatty acid (n-3 PUFA) on cell signaling transduction, it remains unknown whether n-3 PUFA treatment modulates estrogen signaling. The current study showed that docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) shifted the pro-survival and proliferative effect of estrogen to a pro-apoptotic effect in human breast cancer (BCa) MCF-7 and T47D cells. 17 β-estradiol (E2) enhanced the inhibitory effect of n-3 PUFAs on BCa cell growth. The IC50 of DHA or EPA in MCF-7 cells decreased when combined with E2 (10 nM) treatment (from 173 µM for DHA only to 113 µM for DHA+E2, and from 187 µm for EPA only to 130 µm for EPA+E2). E2 also augmented apoptosis in n-3 PUFA-treated BCa cells. In contrast, in cells treated with stearic acid (SA, C18:0) as well as cells not treated with fatty acid, E2 promoted breast cancer cell growth. Classical (nuclear) estrogen receptors may not be involved in the pro-apoptotic effects of E2 on the n-3 PUFA-treated BCa cells because ERα agonist failed to elicit, and ERα knockdown failed to block E2 pro-apoptotic effects. Subsequent studies reveal that G protein coupled estrogen receptor 1 (GPER1) may mediate the pro-apoptotic effect of estrogen. N-3 PUFA treatment initiated the pro-apoptotic signaling of estrogen by increasing GPER1-cAMP-PKA signaling response, and blunting EGFR, Erk 1/2, and AKT activity. These findings may not only provide the evidence to link n-3 PUFAs biologic effects and the pro-apoptotic signaling of estrogen in breast cancer cells, but also shed new insight into the potential application of n-3 PUFAs in BCa treatment.

Hsp70-Bag3 interactions regulate cancer-related signaling networks.

PubMed

Colvin, Teresa A; Gabai, Vladimir L; Gong, Jianlin; Calderwood, Stuart K; Li, Hu; Gummuluru, Suryaram; Matchuk, Olga N; Smirnova, Svetlana G; Orlova, Nina V; Zamulaeva, Irina A; Garcia-Marcos, Mikel; Li, Xiaokai; Young, Z T; Rauch, Jennifer N; Gestwicki, Jason E; Takayama, Shinichi; Sherman, Michael Y

2014-09-01

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target. ©2014 American Association for Cancer Research.

Hsp70-Bag3 interactions regulate cancer-related signaling networks

PubMed Central

Colvin, T.A.; Gabai, V.L.; Gong, J.; Calderwood, S.K.; Li, H.; Gummuluru, S.; Matchuk, O.N; Smirnova, S.G; Orlova, N.V; Zamulaeva, I.A; Garcia-Marcos, M.; Li, X.; Young, Z.T.; Rauch, J.N.; Gestwicki, J.E.; Takayama, S.; Sherman, M.Y.

2014-01-01

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling, including by modulating the activity of the transcription factors NF-kB, FoxM1 and Hif1α, the translation regulator HuR and the cell cycle regulators p21 and survivin. We also identified a small molecule inhibitor, YM-1, that disrupts Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anti-cancer target. PMID:24994713

Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated.

PubMed

Suryawan, Agus; Orellana, Renan A; Nguyen, Hanh V; Jeyapalan, Asumthia S; Fleming, Jillian R; Davis, Teresa A

2007-12-01

Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight-fasted 6- (n = 4/group) and 26-day-old (n = 6/ group) pigs were studied during 1) euinsulinemic-euglycemiceuaminoacidemic conditions (controls), 2) euinsulinemic-euglycemichyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1), and these responses were higher in 6-day-old compared with 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GbetaL) or mTORC2 (rictor, mTOR, and GbetaL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated protein kinase and eukaryotic elongation factor 2. Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs.

Activation by Insulin and Amino Acids of Signaling Components Leading to Translation Initiation in Skeletal Muscle of Neonatal Pigs Is Developmentally Regulated

PubMed Central

Suryawan, Agus; Orellana, Renan A.; Nguyen, Hanh V.; Jeyapalan, Asumthia S.; Fleming, Jillian R.; Davis, Teresa A.

2009-01-01

Insulin (INS) and amino acids (AA) act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight fasted 6-day-old (n=4/group) and 26-day-old (n=6/group) pigs were studied during: 1) euinsulinemic-euglycemic-euaminoacidemic conditions (controls), 2) euinsulinemic-euglycemic-hyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and these responses were higher in 6-day-old compared to 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GβL) or mTORC2 (rictor, mTOR, and GβL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated kinase (AMPK) and eukaryotic elongation factor 2 (eEF2). Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs. PMID:17878222

Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

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

Tang, Yuting; Zhou, Lubing; Gunnet, Joseph W.

2006-06-23

HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeuticmore » effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.« less

Low oleic acid-derived repression of jasmonic acid-inducible defense responses requires the WRKY50 and WRKY51 proteins

USDA-ARS?s Scientific Manuscript database

Signaling induced upon a reduction in oleic acid (18:1) levels simultaneously up-regulates salicylic acid (SA)-mediated responses and inhibits jasmonic acid (JA)-inducible defenses, resulting in enhanced resistance to biotrophs but increased susceptibility to necrotrophs. SA and the signaling compon...

FXR signaling in the enterohepatic system

PubMed Central

Matsubara, Tsutomu; Li, Fei; Gonzalez, Frank J.

2012-01-01

Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism. PMID:22609541

FABP4 reversed the regulation of leptin on mitochondrial fatty acid oxidation in mice adipocytes

PubMed Central

Gan, Lu; Liu, Zhenjiang; Cao, Weina; Zhang, Zhenzhen; Sun, Chao

2015-01-01

Fatty acid binding protein 4 (FABP4), plays key role in fatty acid transportation and oxidation, and increases with leptin synergistically during adipose inflammation process. However, the regulation mechanism between FABP4 and leptin on mitochondrial fatty acid oxidation remains unclear. In this study, we found that FABP4 reduced the expression of leptin, CPT-1 and AOX1 in mice adipocytes. Conversely, FABP4 was down-regulated in a time-dependent manner by leptin treatment. Additionally, forced expression of FABP4 attenuated the expression of PGC1-α, UCP2, CPT-1, AOX1 and COX2 compared with leptin incubation. Moreover, mitochondrial membrane potential, fatty acid oxidation enzyme medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD) and Cyt C levels were reduced in response to the overexpression of FABP4. These reductions correspond well with the reduced release of free fatty acid and the inactivation of mitochondrial complexes I and III by FABP4 overexpression. Furthermore, addition of the Akt/mTOR pathway-specific inhibitor (MK2206) blocked the mitochondrial fatty acid oxidation and respiration factors, whereas interference of FABP4 overcame these effects. Taken together, FABP4 could reverse the activation of the leptin-induced mitochondrial fatty acid oxidation, and the inhibition of Akt/mTOR signal pathway played a key role in this process. PMID:26310911

FABP4 reversed the regulation of leptin on mitochondrial fatty acid oxidation in mice adipocytes.

PubMed

Gan, Lu; Liu, Zhenjiang; Cao, Weina; Zhang, Zhenzhen; Sun, Chao

2015-08-27

Fatty acid binding protein 4 (FABP4), plays key role in fatty acid transportation and oxidation, and increases with leptin synergistically during adipose inflammation process. However, the regulation mechanism between FABP4 and leptin on mitochondrial fatty acid oxidation remains unclear. In this study, we found that FABP4 reduced the expression of leptin, CPT-1 and AOX1 in mice adipocytes. Conversely, FABP4 was down-regulated in a time-dependent manner by leptin treatment. Additionally, forced expression of FABP4 attenuated the expression of PGC1-α, UCP2, CPT-1, AOX1 and COX2 compared with leptin incubation. Moreover, mitochondrial membrane potential, fatty acid oxidation enzyme medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD) and Cyt C levels were reduced in response to the overexpression of FABP4. These reductions correspond well with the reduced release of free fatty acid and the inactivation of mitochondrial complexes I and III by FABP4 overexpression. Furthermore, addition of the Akt/mTOR pathway-specific inhibitor (MK2206) blocked the mitochondrial fatty acid oxidation and respiration factors, whereas interference of FABP4 overcame these effects. Taken together, FABP4 could reverse the activation of the leptin-induced mitochondrial fatty acid oxidation, and the inhibition of Akt/mTOR signal pathway played a key role in this process.

Mesolimbic leptin signaling negatively regulates cocaine-conditioned reward.

PubMed

Shen, M; Jiang, C; Liu, P; Wang, F; Ma, L

2016-12-06

The regulatory mechanisms underlying the response to addictive drugs are complex, and increasing evidence indicates that there is a role for appetite-regulating pathways in substance abuse. Leptin, an important adipose hormone that regulates energy balance and appetite, exerts its physiological functions via leptin receptors. However, the role of leptin signaling in regulating the response to cocaine remains unclear. Here we examined the potential role of leptin signaling in cocaine reward using a conditioned place preference (CPP) procedure. Our results showed that inhibition of leptin signaling by intracerebroventricular infusion of the leptin receptor (LepR) antagonist SMLA during cocaine conditioning increased the cocaine-CPP and upregulated the level of dopamine and its metabolites in the nucleus accumbens (NAc). We then selectively knocked down the LepR in the mesolimbic ventral tegmental area (VTA), NAc core and central amygdala (CeA) by injecting AAV-Cre into Lepr flox/flox mice. LepR deletion in the VTA increased the dopamine levels in the NAc and enhanced the cocaine-conditioned reward. LepR deletion in the NAc core enhanced the cocaine-conditioned reward and impaired the effect of the D2-dopamine receptor on cocaine-CPP, whereas LepR deletion in the CeA had no effect on cocaine-CPP but increased the anxiety level of mice. In addition, prior exposure to saccharin increased LepR mRNA and STAT3 phosphorylation in the NAc and VTA and impaired cocaine-CPP. These results indicate that leptin signaling is critically involved in cocaine-conditioned reward and the regulation of drug reward by a natural reward and that these effects are dependent on mesolimbic LepR.

Ethylene Receptors Signal via a Noncanonical Pathway to Regulate Abscisic Acid Responses1[OPEN

PubMed Central

Bakshi, Arkadipta; Fernandez, Jessica C.

2018-01-01

Ethylene is a gaseous plant hormone perceived by a family of receptors in Arabidopsis (Arabidopsis thaliana) including ETHYLENE RESPONSE1 (ETR1) and ETR2. Previously we showed that etr1-6 loss-of-function plants germinate better and etr2-3 loss-of-function plants germinate worse than wild-type under NaCl stress and in response to abscisic acid (ABA). In this study, we expanded these results by showing that ETR1 and ETR2 have contrasting roles in the control of germination under a variety of inhibitory conditions for seed germination such as treatment with KCl, CuSO4, ZnSO4, and ethanol. Pharmacological and molecular biology results support a model where ETR1 and ETR2 are indirectly affecting the expression of genes encoding ABA signaling proteins to affect ABA sensitivity. The receiver domain of ETR1 is involved in this function in germination under these conditions and controlling the expression of genes encoding ABA signaling proteins. Epistasis analysis demonstrated that these contrasting roles of ETR1 and ETR2 do not require the canonical ethylene signaling pathway. To explore the importance of receptor-protein interactions, we conducted yeast two-hybrid screens using the cytosolic domains of ETR1 and ETR2 as bait. Unique interacting partners with either ETR1 or ETR2 were identified. We focused on three of these proteins and confirmed the interactions with receptors. Loss of these proteins led to faster germination in response to ABA, showing that they are involved in ABA responses. Thus, ETR1 and ETR2 have both ethylene-dependent and -independent roles in plant cells that affect responses to ABA. PMID:29158332

Regulation of VEGF signaling by membrane traffic.

PubMed

Horowitz, Arie; Seerapu, Himabindu Reddy

2012-09-01

Recent findings have drawn attention to the role of membrane traffic in the signaling of vascular endothelial growth factor (VEGF). The significance of this development stems from the pivotal function of VEGF in vasculogenesis and angiogenesis. The outline of the regulation of VEGF receptor (VEGFR) signaling by membrane traffic is similar to that of the epidermal growth factor receptor (EGFR), a prototype of the intertwining between membrane traffic and signaling. There are, however, unique features in VEGFR signaling that are conferred in part by the involvement of the co-receptor neuropilin (Nrp). Nrp1 and VEGFR2 are integrated into membrane traffic through the adaptor protein synectin, which recruits myosin VI, a molecular motor that drives inward trafficking [17,21,64]. The recent detection of only mild vascular defects in a knockin mouse model that expresses Nrp1 lacking a cytoplasmic domain [104], questions the co-receptor's role in VEGF signaling and membrane traffic. The regulation of endocytosis by ephrin-B2 is another feature unique to VEGR2/3 [18,19], but it awaits a mechanistic explanation. Current models do not fully explain how membrane traffic bridges between VEGFR and the downstream effectors that produce its functional outcome, such as cell migration. VEGF-A appears to accomplish this task in part by recruiting endocytic vesicles carrying RhoA to internalized active VEGFR2 [58]. Copyright © 2012 Elsevier Inc. All rights reserved.

[The history of optical signals for traffic regulation].

PubMed

Draeger, J; Harsch, V

2008-04-01

For signal transmission in traffic today, different optical, acoustic, or other physical or technical means are used for information. The different kinds of traffic (water navigation, road and rail, and, later air transport) made traffic regulation necessary early on. This regulation, from its very beginning in ancient times, began by means of optical signals; nowadays, this remains the most important method. From the very start, minimum requirements for the navigator's vision, color discrimination, dark adaptation, and even visual field were needed. For historical reasons, it was in seafaring medicine that these first developed. Besides the development of the different signals, methods for checking the requirements were soon developed. National and international requirements have been very different. Only within the last 50 years has international cooperation led to the acceptance of general standards for the different traffic modes. This article discusses the technical development of optical signals for the different kinds of traffic, from ancient times to the present, and explains the development of minimum requirements for the different visual functions.

Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR).

PubMed

Foster, David A; Salloum, Darin; Menon, Deepak; Frias, Maria A

2014-08-15

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation from within: the cytoskeleton in transmembrane signaling

PubMed Central

Jaqaman, Khuloud; Grinstein, Sergio

2013-01-01

There is mounting evidence that the plasma membrane is highly dynamic and organized in a complex manner. The cortical cytoskeleton is proving to be a particularly important regulator of plasmalemmal organization, modulating the mobility of proteins and lipids in the membrane, facilitating their segregation and influencing their clustering. This organization plays a critical role in receptor-mediated signaling, especially in the case of immunoreceptors, which require lateral clustering for their activation. Based on recent developments, we discuss the structures and mechanisms whereby the cortical cytoskeleton regulates membrane dynamics and organization, and how the non-uniform distribution of immunoreceptors and their self-association may affect activation and signaling. PMID:22917551

Ras signaling in aging and metabolic regulation.

PubMed

Slack, Cathy

2017-12-07

Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline.

Cyanidin-3-O-β-glucoside regulates fatty acid metabolism via an AMP-activated protein kinase-dependent signaling pathway in human HepG2 cells

PubMed Central

2012-01-01

Background Hepatic metabolic derangements are key components in the development of fatty liver disease. AMP-activated protein kinase (AMPK) plays a central role in controlling hepatic lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase 1 (CPT-1) pathway. In this study, cyanidin-3-O-β-glucoside (Cy-3-g), a typical anthocyanin pigment was used to examine its effects on AMPK activation and fatty acid metabolism in human HepG2 hepatocytes. Results Anthocyanin Cy-3-g increased cellular AMPK activity in a calmodulin kinase kinase dependent manner. Furthermore, Cy-3-g substantially induced AMPK downstream target ACC phosphorylation and inactivation, and then decreased malonyl CoA contents, leading to stimulation of CPT-1 expression and significant increase of fatty acid oxidation in HepG2 cells. These effects of Cy-3-g are largely abolished by pharmacological and genetic inhibition of AMPK. Conclusion This study demonstrates that Cy-3-g regulates hepatic lipid homeostasis via an AMPK-dependent signaling pathway. Targeting AMPK activation by anthocyanin may represent a promising approach for the prevention and treatment of obesity-related nonalcoholic fatty liver disease. PMID:22243683

Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes.

PubMed

Abu-Remaileh, Monther; Wyant, Gregory A; Kim, Choah; Laqtom, Nouf N; Abbasi, Maria; Chan, Sze Ham; Freinkman, Elizaveta; Sabatini, David M

2017-11-10

The lysosome degrades and recycles macromolecules, signals to the cytosol and nucleus, and is implicated in many diseases. Here, we describe a method for the rapid isolation of mammalian lysosomes and use it to quantitatively profile lysosomal metabolites under various cell states. Under nutrient-replete conditions, many lysosomal amino acids are in rapid exchange with those in the cytosol. Loss of lysosomal acidification through inhibition of the vacuolar H + -adenosine triphosphatase (V-ATPase) increased the luminal concentrations of most metabolites but had no effect on those of the majority of essential amino acids. Instead, nutrient starvation regulates the lysosomal concentrations of these amino acids, an effect we traced to regulation of the mechanistic target of rapamycin (mTOR) pathway. Inhibition of mTOR strongly reduced the lysosomal efflux of most essential amino acids, converting the lysosome into a cellular depot for them. These results reveal the dynamic nature of lysosomal metabolites and that V-ATPase- and mTOR-dependent mechanisms exist for controlling lysosomal amino acid efflux. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Arabidopsis plants deficient in plastidial glyceraldehyde-3-phosphate dehydrogenase show alterations in abscisic acid (ABA) signal transduction: interaction between ABA and primary metabolism

PubMed Central

Muñoz-Bertomeu, Jesús; Bermúdez, María Angeles; Segura, Juan; Ros, Roc

2011-01-01

Abscisic acid (ABA) controls plant development and regulates plant responses to environmental stresses. A role for ABA in sugar regulation of plant development has also been well documented although the molecular mechanisms connecting the hormone with sugar signal transduction pathways are not well understood. In this work it is shown that Arabidopsis thaliana mutants deficient in plastidial glycolytic glyceraldehyde-3-phosphate dehydrogenase (gapcp1gapcp2) are ABA insensitive in growth, stomatal closure, and germination assays. The ABA levels of gapcp1gapcp2 were normal, suggesting that the ABA signal transduction pathway is impaired in the mutants. ABA modified gapcp1gapcp2 gene expression, but the mutant response to the hormone differed from that observed in wild-type plants. The gene expression of the transcription factor ABI4, involved in both sugar and ABA signalling, was altered in gapcp1gapcp2, suggesting that their ABA insensitivity is mediated, at least partially, through this transcriptional regulator. Serine supplementation was able partly to restore the ABA sensitivity of gapcp1gapcp2, indicating that amino acid homeostasis and/or serine metabolism may also be important determinants in the connections of ABA with primary metabolism. Overall, these studies provide new insights into the links between plant primary metabolism and ABA signalling, and demonstrate the importance of plastidial glycolytic glyceraldehyde-3-phosphate dehydrogenase in these interactions. PMID:21068209

Rapid shoot-to-root signalling regulates root hydraulic conductance via aquaporins.

PubMed

Vandeleur, Rebecca K; Sullivan, Wendy; Athman, Asmini; Jordans, Charlotte; Gilliham, Matthew; Kaiser, Brent N; Tyerman, Stephen D

2014-02-01

We investigated how root hydraulic conductance (normalized to root dry weight, Lo ) is regulated by the shoot. Shoot topping (about 30% reduction in leaf area) reduced Lo of grapevine (Vitis vinifera L.), soybean (Glycine max L.) and maize (Zea mays L.) by 50 to 60%. More detailed investigations with soybean and grapevine showed that the reduction in Lo was not correlated with the reduction in leaf area, and shading or cutting single leaves had a similar effect. Percentage reduction in Lo was largest when initial Lo was high in soybean. Inhibition of Lo by weak acid (low pH) was smaller after shoot damage or leaf shading. The half time of reduction in Lo was approximately 5 min after total shoot decapitation. These characteristics indicate involvement of aquaporins. We excluded phloem-borne signals and auxin-mediated signals. Xylem-mediated hydraulic signals are possible since turgor rapidly decreased within root cortex cells after shoot topping. There was a significant reduction in the expression of several aquaporins in the plasma membrane intrinsic protein (PIP) family of both grapevine and soybean. In soybean, there was a five- to 10-fold reduction in GmPIP1;6 expression over 0.5-1 h which was sustained over the period of reduced Lo . © 2013 John Wiley & Sons Ltd.

A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells*

PubMed Central

Ramesh, Mathangi; Krishnan, Navasona; Muthuswamy, Senthil K.; Tonks, Nicholas K.

2015-01-01

We used a loss-of-function screen to investigate the role of classical protein-tyrosine phosphatases (PTPs) in three-dimensional mammary epithelial cell morphogenesis and ERBB2 signaling. The study revealed a novel role for PTPD2 as a positive regulator of ERBB2 signaling. Suppression of PTPD2 attenuated the ERBB2-induced multiacinar phenotype in three-dimensional cultures specifically by inhibiting ERBB2-mediated loss of polarity and lumen filling. In contrast, overexpression of PTPD2 enhanced the ERBB2 phenotype. We also found that a lipid second messenger, phosphatidic acid, bound PTPD2 in vitro and enhanced its catalytic activity. Small molecule inhibitors of phospholipase D (PLD), an enzyme that produces phosphatidic acid in cells, also attenuated the ERBB2 phenotype. Exogenously added phosphatidic acid rescued the PLD-inhibition phenotype, but only when PTPD2 was present. These findings illustrate a novel pathway involving PTPD2 and the lipid second messenger phosphatidic acid that promotes ERBB2 function. PMID:25681440

TGF-β signaling in insects regulates metamorphosis via juvenile hormone biosynthesis.

PubMed

Ishimaru, Yoshiyasu; Tomonari, Sayuri; Matsuoka, Yuji; Watanabe, Takahito; Miyawaki, Katsuyuki; Bando, Tetsuya; Tomioka, Kenji; Ohuchi, Hideyo; Noji, Sumihare; Mito, Taro

2016-05-17

Although butterflies undergo a dramatic morphological transformation from larva to adult via a pupal stage (holometamorphosis), crickets undergo a metamorphosis from nymph to adult without formation of a pupa (hemimetamorphosis). Despite these differences, both processes are regulated by common mechanisms that involve 20-hydroxyecdysone (20E) and juvenile hormone (JH). JH regulates many aspects of insect physiology, such as development, reproduction, diapause, and metamorphosis. Consequently, strict regulation of JH levels is crucial throughout an insect's life cycle. However, it remains unclear how JH synthesis is regulated. Here, we report that in the corpora allata of the cricket, Gryllus bimaculatus, Myoglianin (Gb'Myo), a homolog of Drosophila Myoglianin/vertebrate GDF8/11, is involved in the down-regulation of JH production by suppressing the expression of a gene encoding JH acid O-methyltransferase, Gb'jhamt In contrast, JH production is up-regulated by Decapentaplegic (Gb'Dpp) and Glass-bottom boat/60A (Gb'Gbb) signaling that occurs as part of the transcriptional activation of Gb'jhamt Gb'Myo defines the nature of each developmental transition by regulating JH titer and the interactions between JH and 20E. When Gb'myo expression is suppressed, the activation of Gb'jhamt expression and secretion of 20E induce molting, thereby leading to the next instar before the last nymphal instar. Conversely, high Gb'myo expression induces metamorphosis during the last nymphal instar through the cessation of JH synthesis. Gb'myo also regulates final insect size. Because Myo/GDF8/11 and Dpp/bone morphogenetic protein (BMP)2/4-Gbb/BMP5-8 are conserved in both invertebrates and vertebrates, the present findings provide common regulatory mechanisms for endocrine control of animal development.

The Brassinosteroid Signaling Pathway—New Key Players and Interconnections with Other Signaling Networks Crucial for Plant Development and Stress Tolerance

PubMed Central

Gruszka, Damian

2013-01-01

Brassinosteroids (BRs) are a class of steroid hormones regulating a wide range of physiological processes during the plant life cycle from seed development to the modulation of flowering and senescence. The last decades, and recent years in particular, have witnessed a significant advance in the elucidation of the molecular mechanisms of BR signaling from perception by the transmembrane receptor complex to the regulation of transcription factors influencing expression of the target genes. Application of the new approaches shed light on the molecular functions of the key players regulating the BR signaling cascade and allowed identification of new factors. Recent studies clearly indicated that some of the components of BR signaling pathway act as multifunctional proteins involved in other signaling networks regulating diverse physiological processes, such as photomorphogenesis, cell death control, stomatal development, flowering, plant immunity to pathogens and metabolic responses to stress conditions, including salinity. Regulation of some of these processes is mediated through a crosstalk between BR signalosome and the signaling cascades of other hormones, including auxin, abscisic acid, ethylene and salicylic acid. Unravelling the complicated mechanisms of BR signaling and its interconnections with other molecular networks may be of great importance for future practical applications in agriculture. PMID:23615468

Nuclear movement regulated by non-Smad Nodal signaling via JNK is associated with Smad signaling during zebrafish endoderm specification.

PubMed

Hozumi, Shunya; Aoki, Shun; Kikuchi, Yutaka

2017-11-01

Asymmetric nuclear positioning is observed during animal development, but its regulation and significance in cell differentiation remain poorly understood. Using zebrafish blastulae, we provide evidence that nuclear movement towards the yolk syncytial layer, which comprises extraembryonic tissue, occurs in the first cells fated to differentiate into the endoderm. Nodal signaling is essential for nuclear movement, whereas nuclear envelope proteins are involved in movement through microtubule formation. Positioning of the microtubule-organizing center, which is proposed to be crucial for nuclear movement, is regulated by Nodal signaling and nuclear envelope proteins. The non-Smad JNK signaling pathway, which is downstream of Nodal signaling, regulates nuclear movement independently of the Smad pathway, and this nuclear movement is associated with Smad signal transduction toward the nucleus. Our study provides insight into the function of nuclear movement in Smad signaling toward the nucleus, and could be applied to the control of TGFβ signaling. © 2017. Published by The Company of Biologists Ltd.

Pulsatile Hormonal Signaling to Extracellular Signal-regulated Kinase

PubMed Central

Perrett, Rebecca M.; Voliotis, Margaritis; Armstrong, Stephen P.; Fowkes, Robert C.; Pope, George R.; Tsaneva-Atanasova, Krasimira; McArdle, Craig A.

2014-01-01

Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses that stimulate synthesis and secretion of pituitary gonadotropin hormones and thereby mediate control of reproduction. It acts via G-protein-coupled receptors to stimulate effectors, including ERK. Information could be encoded in GnRH pulse frequency, width, amplitude, or other features of pulse shape, but the relative importance of these features is unknown. Here we examine this using automated fluorescence microscopy and mathematical modeling, focusing on ERK signaling. The simplest scenario is one in which the system is linear, and response dynamics are relatively fast (compared with the signal dynamics). In this case integrated system output (ERK activation or ERK-driven transcription) will be roughly proportional to integrated input, but we find that this is not the case. Notably, we find that relatively slow response kinetics lead to ERK activity beyond the GnRH pulse, and this reduces sensitivity to pulse width. More generally, we show that the slowing of response kinetics through the signaling cascade creates a system that is robust to pulse width. We, therefore, show how various levels of response kinetics synergize to dictate system sensitivity to different features of pulsatile hormone input. We reveal the mathematical and biochemical basis of a dynamic GnRH signaling system that is robust to changes in pulse amplitude and width but is sensitive to changes in receptor occupancy and frequency, precisely the features that are tightly regulated and exploited to exert physiological control in vivo. PMID:24482225

Preoptic leptin signaling modulates energy balance independent of body temperature regulation.

PubMed

Yu, Sangho; Cheng, Helia; François, Marie; Qualls-Creekmore, Emily; Huesing, Clara; He, Yanlin; Jiang, Yanyan; Gao, Hong; Xu, Yong; Zsombok, Andrea; Derbenev, Andrei V; Nillni, Eduardo A; Burk, David H; Morrison, Christopher D; Berthoud, Hans-Rudolf; Münzberg, Heike

2018-05-15

The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight. © 2018, Yu et al.

Conserved Insulin Signaling in the Regulation of Oocyte Growth, Development, and Maturation

PubMed Central

DAS, DEBABRATA; ARUR, SWATHI

2017-01-01

Insulin signaling regulates various aspects of physiology, such as glucose homeostasis and aging, and is a key determinant of female reproduction in metazoans. That insulin signaling is crucial for female reproductive health is clear from clinical data linking hyperinsulinemic and hypoinsulinemic condition with certain types of ovarian dysfunction, such as altered steroidogenesis, polycystic ovary syndrome, and infertility. Thus, understanding the signaling mechanisms that underlie the control of insulin-mediated ovarian development is important for the accurate diagnosis of and intervention for female infertility. Studies of invertebrate and vertebrate model systems have revealed the molecular determinants that transduce insulin signaling as well as which biological processes are regulated by the insulin-signaling pathway. The molecular determinants of the insulin-signaling pathway, from the insulin receptor to its downstream signaling components, are structurally and functionally conserved across evolution, from worms to mammals – yet, physiological differences in signaling still exist. Insulin signaling acts cooperatively with gonadotropins in mammals and lower vertebrates to mediate various aspects of ovarian development, mainly owing to evolution of the endocrine system in vertebrates. In contrast, insulin signaling in Drosophila and Caenorhabditis elegans directly regulates oocyte growth and maturation. In this review, we compare and contrast insulin-mediated regulation of ovarian functions in mammals, lower vertebrates, C. elegans, and Drosophila, and highlight conserved signaling pathways and regulatory mechanisms in general while illustrating insulin’s unique role in specific reproductive processes. PMID:28379636

Endocardial Hippo signaling regulates myocardial growth and cardiogenesis.

PubMed

Artap, Stanley; Manderfield, Lauren J; Smith, Cheryl L; Poleshko, Andrey; Aghajanian, Haig; See, Kelvin; Li, Li; Jain, Rajan; Epstein, Jonathan A

2018-08-01

The Hippo signaling pathway has been implicated in control of cell and organ size, proliferation, and endothelial-mesenchymal transformation. This pathway impacts upon two partially redundant transcription cofactors, Yap and Taz, that interact with other factors, including members of the Tead family, to affect expression of downstream genes. Yap and Taz have been shown to regulate, in a cell-autonomous manner, myocardial proliferation, myocardial hypertrophy, regenerative potential, and overall size of the heart. Here, we show that Yap and Taz also play an instructive, non-cell-autonomous role in the endocardium of the developing heart to regulate myocardial growth through release of the paracrine factor, neuregulin. Without endocardial Yap and Taz, myocardial growth is impaired causing early post-natal lethality. Thus, the Hippo signaling pathway regulates cell size via both cell-autonomous and non-cell-autonomous mechanisms. Furthermore, these data suggest that Hippo may regulate organ size via a sensing and paracrine function in endothelial cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Arachidonic acid induces macrophage cell cycle arrest through the JNK signaling pathway.

PubMed

Shen, Ziying; Ma, Yunqing; Ji, Zhonghao; Hao, Yang; Yan, Xuan; Zhong, Yuan; Tang, Xiaochun; Ren, Wenzhi

2018-02-09

Arachidonic acid (AA) has potent pro-apoptotic effects on cancer cells at a low concentration and on macrophages at a very high concentration. However, the effects of AA on the macrophage cell cycle and related signaling pathways have not been fully investigated. Herein we aim to observe the effect of AA on macrophages cell cycle. AA exposure reduced the viability and number of macrophages in a dose- and time-dependent manner. The reduction in RAW264.7 cell viability was not caused by apoptosis, as indicated by caspase-3 and activated caspase-3 detection. Further research illustrated that AA exposure induced RAW264.7 cell cycle arrested at S phase, and some cell cycle-regulated proteins were altered accordingly. Moreover, JNK signaling was stimulated by AA, and the stimulation was partially reversed by a JNK signaling inhibitor in accordance with cell cycle-related factors. In addition, nuclear and total Foxo1/3a and phosphorylated Foxo1/3a were elevated by AA in a dose- and time-dependent manner, and this elevation was suppressed by the JNK signaling inhibitor. Our study demonstrated that AA inhibits macrophage viability by inducing S phase cell cycle arrest. The JNK signaling pathway and the downstream FoxO transcription factors are involved in AA-induced RAW264.7 cell cycle arrest.

Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling.

PubMed

Zeng, Wei-Zheng; Liu, Di-Shi; Liu, Lu; She, Liang; Wu, Long-Jun; Xu, Tian-Le

2015-09-15

Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system.

TGF-β Signaling Regulates Pancreatic β-Cell Proliferation through Control of Cell Cycle Regulator p27 Expression

PubMed Central

Suzuki, Tomoyuki; Dai, Ping; Hatakeyama, Tomoya; Harada, Yoshinori; Tanaka, Hideo; Yoshimura, Norio; Takamatsu, Tetsuro

2013-01-01

Proliferation of pancreatic β-cells is an important mechanism underlying β-cell mass adaptation to metabolic demands. Increasing β-cell mass by regeneration may ameliorate or correct both type 1 and type 2 diabetes, which both result from inadequate production of insulin by β-cells of the pancreatic islet. Transforming growth factor β (TGF-β) signaling is essential for fetal development and growth of pancreatic islets. In this study, we exposed HIT-T15, a clonal pancreatic β-cell line, to TGF-β signaling. We found that inhibition of TGF-β signaling promotes proliferation of the cells significantly, while TGF-β signaling stimulation inhibits proliferation of the cells remarkably. We confirmed that this proliferative regulation by TGF-β signaling is due to the changed expression of the cell cycle regulator p27. Furthermore, we demonstrated that there is no observed effect on transcriptional activity of p27 by TGF-β signaling. Our data show that TGF-β signaling mediates the cell-cycle progression of pancreatic β-cells by regulating the nuclear localization of CDK inhibitor, p27. Inhibition of TGF-β signaling reduces the nuclear accumulation of p27, and as a result this inhibition promotes proliferation of β-cells. PMID:23720603

Arm-in-Arm Response Regulator Dimers Promote Intermolecular Signal Transduction

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

Baker, Anna W.; Satyshur, Kenneth A.; Moreno Morales, Neydis

2016-02-01

ABSTRACT Bacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacteriumRamlibacter tataouinensis. RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, theR. tataouinensisbacteriophytochrome response regulatormore » (RtBRR), and a homolog, AtBRR fromAgrobacterium tumefaciens, crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRR mon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems. IMPORTANCEBphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of

Transcriptome Profiling Reveals the Negative Regulation of Multiple Plant Hormone Signaling Pathways Elicited by Overexpression of C-Repeat Binding Factors.

PubMed

Li, Aixin; Zhou, Mingqi; Wei, Donghui; Chen, Hu; You, Chenjiang; Lin, Juan

2017-01-01

C-repeat binding factors (CBF) are a subfamily of AP2 transcription factors that play critical roles in the regulation of plant cold tolerance and growth in low temperature. In the present work, we sought to perform a detailed investigation into global transcriptional regulation of plant hormone signaling associated genes in transgenic plants engineered with CBF genes. RNA samples from Arabidopsis thaliana plants overexpressing two CBF genes, CBF2 and CBF3 , were subjected to Illumina HiSeq 2000 RNA sequencing (RNA-Seq). Our results showed that more than half of the hormone associated genes that were differentially expressed in CBF2 or CBF3 transgenic plants were related to auxin signal transduction and metabolism. Most of these alterations in gene expression could lead to repression of auxin signaling. Accordingly, the IAA content was significantly decreased in young tissues of plants overexpressing CBF2 and CBF3 compared with wild type. In addition, genes associated with the biosynthesis of Jasmonate (JA) and Salicylic acid (SA), as well as the signal sensing of Brassinolide (BR) and SA, were down-regulated, while genes associated with Gibberellin (GA) deactivation were up-regulated. In general, overexpression of CBF2 and CBF3 negatively affects multiple plant hormone signaling pathways in Arabidopsis . The transcriptome analysis using CBF2 and CBF3 transgenic plants provides novel and integrated insights into the interaction between CBFs and plant hormones, particularly the modulation of auxin signaling, which may contribute to the improvement of crop yields under abiotic stress via molecular engineering using CBF genes.

Transcriptome Profiling Reveals the Negative Regulation of Multiple Plant Hormone Signaling Pathways Elicited by Overexpression of C-Repeat Binding Factors

PubMed Central

Li, Aixin; Zhou, Mingqi; Wei, Donghui; Chen, Hu; You, Chenjiang; Lin, Juan

2017-01-01

C-repeat binding factors (CBF) are a subfamily of AP2 transcription factors that play critical roles in the regulation of plant cold tolerance and growth in low temperature. In the present work, we sought to perform a detailed investigation into global transcriptional regulation of plant hormone signaling associated genes in transgenic plants engineered with CBF genes. RNA samples from Arabidopsis thaliana plants overexpressing two CBF genes, CBF2 and CBF3, were subjected to Illumina HiSeq 2000 RNA sequencing (RNA-Seq). Our results showed that more than half of the hormone associated genes that were differentially expressed in CBF2 or CBF3 transgenic plants were related to auxin signal transduction and metabolism. Most of these alterations in gene expression could lead to repression of auxin signaling. Accordingly, the IAA content was significantly decreased in young tissues of plants overexpressing CBF2 and CBF3 compared with wild type. In addition, genes associated with the biosynthesis of Jasmonate (JA) and Salicylic acid (SA), as well as the signal sensing of Brassinolide (BR) and SA, were down-regulated, while genes associated with Gibberellin (GA) deactivation were up-regulated. In general, overexpression of CBF2 and CBF3 negatively affects multiple plant hormone signaling pathways in Arabidopsis. The transcriptome analysis using CBF2 and CBF3 transgenic plants provides novel and integrated insights into the interaction between CBFs and plant hormones, particularly the modulation of auxin signaling, which may contribute to the improvement of crop yields under abiotic stress via molecular engineering using CBF genes. PMID:28983312

CD22 and Siglec-G regulate inhibition of B-cell signaling by sialic acid ligand binding and control B-cell tolerance.

PubMed

Nitschke, Lars

2014-09-01

CD22 and Siglec-G are two B-cell expressed members of the Siglec (sialic acid-binding immunoglobulin (Ig)-like lectin) family and are potent inhibitors of B-cell signaling. Genetic approaches have provided evidence that this inhibition of B-cell antigen receptor (BCR) signaling by Siglecs is dependent on ligand binding to sialic acids in specific linkages. The cis-ligand-binding activity of CD22 leads to homo-oligomer formation, which are to a large extent found in membrane domains that are distinct from those containing the BCR. In contrast, Siglec-G is recruited via sialic acid binding to the BCR. This interaction of Siglec-G with mIgM leads to an inhibitory function that seems to be specific for B-1 cells. Both CD22 and Siglec-G control B-cell tolerance and loss of these proteins, its ligands or its inhibitory pathways can increase the susceptibility for autoimmune diseases. CD22 is a target protein both in B-cell leukemias and lymphomas, as well as in B-cell mediated autoimmune diseases. Both antibodies and synthetic chemically modified sialic acids are currently tested to target Siglecs on B cells. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Interplay between sugar and hormone signaling pathways modulate floral signal transduction

PubMed Central

Matsoukas, Ianis G.

2014-01-01

NOMENCLATURE The following nomenclature will be used in this article: Names of genes are written in italicized upper-case letters, e.g., ABI4.Names of proteins are written in non-italicized upper-case letters, e.g., ABI4.Names of mutants are written in italicized lower-case letters, e.g., abi4. The juvenile-to-adult and vegetative-to-reproductive phase transitions are major determinants of plant reproductive success and adaptation to the local environment. Understanding the intricate molecular genetic and physiological machinery by which environment regulates juvenility and floral signal transduction has significant scientific and economic implications. Sugars are recognized as important regulatory molecules that regulate cellular activity at multiple levels, from transcription and translation to protein stability and activity. Molecular genetic and physiological approaches have demonstrated different aspects of carbohydrate involvement and its interactions with other signal transduction pathways in regulation of the juvenile-to-adult and vegetative-to-reproductive phase transitions. Sugars regulate juvenility and floral signal transduction through their function as energy sources, osmotic regulators and signaling molecules. Interestingly, sugar signaling has been shown to involve extensive connections with phytohormone signaling. This includes interactions with phytohormones that are also important for the orchestration of developmental phase transitions, including gibberellins, abscisic acid, ethylene, and brassinosteroids. This article highlights the potential roles of sugar-hormone interactions in regulation of floral signal transduction, with particular emphasis on Arabidopsis thaliana mutant phenotypes, and suggests possible directions for future research. PMID:25165468

Interplay between sugar and hormone signaling pathways modulate floral signal transduction.

PubMed

Matsoukas, Ianis G

2014-01-01

NOMENCLATURE The following nomenclature will be used in this article: Names of genes are written in italicized upper-case letters, e.g., ABI4.Names of proteins are written in non-italicized upper-case letters, e.g., ABI4.Names of mutants are written in italicized lower-case letters, e.g., abi4. The juvenile-to-adult and vegetative-to-reproductive phase transitions are major determinants of plant reproductive success and adaptation to the local environment. Understanding the intricate molecular genetic and physiological machinery by which environment regulates juvenility and floral signal transduction has significant scientific and economic implications. Sugars are recognized as important regulatory molecules that regulate cellular activity at multiple levels, from transcription and translation to protein stability and activity. Molecular genetic and physiological approaches have demonstrated different aspects of carbohydrate involvement and its interactions with other signal transduction pathways in regulation of the juvenile-to-adult and vegetative-to-reproductive phase transitions. Sugars regulate juvenility and floral signal transduction through their function as energy sources, osmotic regulators and signaling molecules. Interestingly, sugar signaling has been shown to involve extensive connections with phytohormone signaling. This includes interactions with phytohormones that are also important for the orchestration of developmental phase transitions, including gibberellins, abscisic acid, ethylene, and brassinosteroids. This article highlights the potential roles of sugar-hormone interactions in regulation of floral signal transduction, with particular emphasis on Arabidopsis thaliana mutant phenotypes, and suggests possible directions for future research.

Signaling Pathways Involved in the Regulation of mRNA Translation

PubMed Central

2018-01-01

ABSTRACT Translation is a key step in the regulation of gene expression and one of the most energy-consuming processes in the cell. In response to various stimuli, multiple signaling pathways converge on the translational machinery to regulate its function. To date, the roles of phosphoinositide 3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK) pathways in the regulation of translation are among the best understood. Both pathways engage the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery. While these pathways regulate protein synthesis in homeostasis, their dysregulation results in aberrant translation leading to human diseases, including diabetes, neurological disorders, and cancer. Here we review the roles of the PI3K/AKT and MAPK pathways in the regulation of mRNA translation. We also highlight additional signaling mechanisms that have recently emerged as regulators of the translational apparatus. PMID:29610153

Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism*

PubMed Central

Dyachok, Julia; Earnest, Svetlana; Iturraran, Erica N.; Cobb, Melanie H.

2016-01-01

The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes l-asparagine, l-glutamine, l-threonine, l-arginine, l-glycine, l-proline, l-serine, l-alanine, and l-glutamic acid. The group of activating amino acids is dominated by l-leucine but also includes l-methionine, l-isoleucine, and l-valine. l-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation. PMID:27587390

Hsp27 regulates Akt activation and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex.

PubMed

Wu, Rui; Kausar, Hina; Johnson, Paul; Montoya-Durango, Diego E; Merchant, Michael; Rane, Madhavi J

2007-07-27

We have shown previously that Akt exists in a signal complex with p38 MAPK, MAPK-activated protein kinase-2 (MK2), and heat shock protein 27 (Hsp27) and MK2 phosphorylates Akt on Ser-473. Additionally, dissociation of Hsp27 from Akt, prior to Akt activation, induced polymorphonuclear leukocyte (PMN) apoptosis. However, the role of Hsp27 in regulating Akt activation was not examined. This study tested the hypothesis that Hsp27 regulates Akt activation and promotes cell survival by scaffolding MK2 to the Akt signal complex. Here we show that loss of Akt/Hsp27 interaction by anti-Hsp27 antibody treatment resulted in loss of Akt/MK2 interaction, loss of Akt-Ser-473 phosphorylation, and induced PMN apoptosis. Transfection of myristoylated Akt (AktCA) in HK-11 cells induced Akt-Ser-473 phosphorylation, activation, and Hsp27-Ser-82 phosphorylation. Cotransfection of AktCA with Hsp27 short interfering RNA, but not scrambled short interfering RNA, silenced Hsp27 expression, without altering Akt expression in HK-11 cells. Silencing Hsp27 expression inhibited Akt/MK2 interaction, inhibited Akt phosphorylation and Akt activation, and induced HK-11 cell death. Deletion mutagenesis studies identified acidic linker region (amino acids 117-128) on Akt as an Hsp27 binding region. Deletion of amino acids 117-128 on Akt resulted in loss of its interaction with Hsp27 and MK2 but not with Hsp90 as demonstrated by immunoprecipitation and glutathione S-transferase pulldown studies. Co-transfection studies demonstrated that constitutively active MK2 (MK2EE) phosphorylated Aktwt (wild type) on Ser-473 but failed to phosphorylate Akt(Delta117-128) mutant in transfixed cells. These studies collectively define a novel role of Hsp27 in regulating Akt activation and cellular apoptosis by mediating interaction between Akt and its upstream activator MK2.

Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System

PubMed Central

Mertens, Kim L.; Kalsbeek, Andries; Soeters, Maarten R.; Eggink, Hannah M.

2017-01-01

Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS). Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acids receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We conclude that when plasma bile acids levels are high all three pathways may contribute in signal transmission to the CNS. However, under normal physiological circumstances, the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain. PMID:29163019

Abscisic acid negatively regulates post-penetration resistance of Arabidopsis to the biotrophic powdery mildew fungus.

PubMed

Xiao, Xiang; Cheng, Xi; Yin, Kangquan; Li, Huali; Qiu, Jin-Long

2017-08-01

Pytohormone abscisic acid (ABA) plays important roles in defense responses. Nonetheless, how ABA regulates plant resistance to biotrophic fungi remains largely unknown. Arabidopsis ABA-deficient mutants, aba2-1 and aba3-1, displayed enhanced resistance to the biotrophic powdery mildew fungus Golovinomyces cichoracearum. Moreover, exogenously administered ABA increased the susceptibility of Arabidopsis to G. cichoracearum. Arabidopsis ABA perception components mutants, abi1-1 and abi2-1, also displayed similar phenotypes to ABA-deficient mutants in resistance to G. cichoracearum. However, the resistance to G. cichoracearum is not changed in downstream ABA signaling transduction mutants, abi3-1, abi4-1, and abi5-1. Microscopic examination revealed that hyphal growth and conidiophore production of G. cichoracearum were compromised in the ABA deficient mutants, even though pre-penetration and penetration growth of the fungus were not affected. In addition, salicylic acid (SA) and MPK3 are found to be involved in ABA-regulated resistance to G. cichoracearum. Our work demonstrates that ABA negatively regulates post-penetration resistance of Arabidopsis to powdery mildew fungus G. cichoracearum, probably through antagonizing the function of SA.

Chrysophanic acid reduces testosterone-induced benign prostatic hyperplasia in rats by suppressing 5α-reductase and extracellular signal-regulated kinase

PubMed Central

Kim, Hye-Lin; Jung, Yunu; Kang, JongWook; Jeong, Mi-Young; Sethi, Gautam; Ahn, Kwang Seok; Um, Jae-Young

2017-01-01

Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in male population, of which incidence increases gradually with age. In this study, we investigated the effect of chrysophanic acid (CA) on BPH. BPH was induced by a 4-week injection of testosterone propionate (TP). Four weeks of further injection with vehicle, TP, TP + CA, TP + finasteride was carried on. In the CA treatment group, the prostate weight was reduced and the TP-induced histological changes were restored as the normal control group. CA treatment suppressed the TP-elevated prostate specific antigen (PSA) expression. In addition, 5α-reductase, a crucial factor in BPH development, was suppressed to the normal level close to the control group by CA treatment. The elevated expressions of androgen receptor (AR), estrogen receptor α and steroid receptor coactivator 1 by TP administration were also inhibited in the CA group when compared to the TP-induced BPH group. Then we evaluated the changes in three major factors of the mitogen-activated protein kinase chain during prostatic hyperplasia; extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38). While ERK was elevated in the process of BPH, JNK and p38 was not changed. This up-regulated ERK was also reduced as normal by CA treatment. Further in vitro studies with RWPE-1 cells confirmed TP-induced proliferation and elevated AR, PSA and p-ERK were all reduced by CA treatment. Overall, these results suggest a potential pharmaceutical feature of CA in the treatment of BPH. PMID:27880726

Dissection of the cis-2-decenoic acid signaling network in Pseudomonas aeruginosa using microarray technique

PubMed Central

Rahmani-Badi, Azadeh; Sepehr, Shayesteh; Fallahi, Hossein; Heidari-Keshel, Saeed

2015-01-01

Many bacterial pathogens use quorum-sensing (QS) signaling to regulate the expression of factors contributing to virulence and persistence. Bacteria produce signals of different chemical classes. The signal molecule, known as diffusible signal factor (DSF), is a cis-unsaturated fatty acid that was first described in the plant pathogen Xanthomonas campestris. Previous works have shown that human pathogen, Pseudomonas aeruginosa, also synthesizes a structurally related molecule, characterized as cis-2-decenoic acid (C10: Δ2, CDA) that induces biofilm dispersal by multiple types of bacteria. Furthermore, CDA has been shown to be involved in inter-kingdom signaling that modulates fungal behavior. Therefore, an understanding of its signaling mechanism could suggest strategies for interference, with consequences for disease control. To identify the components of CDA signaling pathway in this pathogen, a comparative transcritpome analysis was conducted, in the presence and absence of CDA. A protein-protein interaction (PPI) network for differentially expressed (DE) genes with known function was then constructed by STRING and Cytoscape. In addition, the effects of CDA in combination with antimicrobial agents on the biofilm surface area and bacteria viability were evaluated using fluorescence microscopy and digital image analysis. Microarray analysis identified 666 differentially expressed genes in the presence of CDA and gene ontology (GO) analysis revealed that in P. aeruginosa, CDA mediates dispersion of biofilms through signaling pathways, including enhanced motility, metabolic activity, virulence as well as persistence at different temperatures. PPI data suggested that a cluster of five genes (PA4978, PA4979, PA4980, PA4982, PA4983) is involved in the CDA synthesis and perception. Combined treatments using both CDA and antimicrobial agents showed that following exposure of the biofilms to CDA, remaining cells on the surface were easily removed and killed by

Endothelial cell expression of haemoglobin α regulates nitric oxide signalling.

PubMed

Straub, Adam C; Lohman, Alexander W; Billaud, Marie; Johnstone, Scott R; Dwyer, Scott T; Lee, Monica Y; Bortz, Pamela Schoppee; Best, Angela K; Columbus, Linda; Gaston, Benjamin; Isakson, Brant E

2012-11-15

Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle. Here we report a new model for the regulation of NO signalling by demonstrating that haemoglobin (Hb) α (encoded by the HBA1 and HBA2 genes in humans) is expressed in human and mouse arterial endothelial cells and enriched at the myoendothelial junction, where it regulates the effects of NO on vascular reactivity. Notably, this function is unique to Hb α and is abrogated by its genetic depletion. Mechanistically, endothelial Hb α haem iron in the Fe(3+) state permits NO signalling, and this signalling is shut off when Hb α is reduced to the Fe(2+) state by endothelial cytochrome b5 reductase 3 (CYB5R3, also known as diaphorase 1). Genetic and pharmacological inhibition of CYB5R3 increases NO bioactivity in small arteries. These data reveal a new mechanism by which the regulation of the intracellular Hb α oxidation state controls NOS signalling in non-erythroid cells. This model may be relevant to haem-containing globins in a broad range of NOS-containing somatic cells.

Drosophila Spidey/Kar Regulates Oenocyte Growth via PI3-Kinase Signaling

PubMed Central

Cinnamon, Einat; Sawala, Annick; Tittiger, Claus; Paroush, Ze'ev

2016-01-01

Cell growth and proliferation depend upon many different aspects of lipid metabolism. One key signaling pathway that is utilized in many different anabolic contexts involves Phosphatidylinositide 3-kinase (PI3K) and its membrane lipid products, the Phosphatidylinositol (3,4,5)-trisphosphates. It remains unclear, however, which other branches of lipid metabolism interact with the PI3K signaling pathway. Here, we focus on specialized fat metabolizing cells in Drosophila called larval oenocytes. In the presence of dietary nutrients, oenocytes undergo PI3K-dependent cell growth and contain very few lipid droplets. In contrast, during starvation, oenocytes decrease PI3K signaling, shut down cell growth and accumulate abundant lipid droplets. We now show that PI3K in larval oenocytes, but not in fat body cells, functions to suppress lipid droplet accumulation. Several enzymes of fatty acid, triglyceride and hydrocarbon metabolism are required in oenocytes primarily for lipid droplet induction rather than for cell growth. In contrast, a very long chain fatty-acyl-CoA reductase (FarO) and a putative lipid dehydrogenase/reductase (Spidey, also known as Kar) not only promote lipid droplet induction but also inhibit oenocyte growth. In the case of Spidey/Kar, we show that the growth suppression mechanism involves inhibition of the PI3K signaling pathway upstream of Akt activity. Together, the findings in this study show how Spidey/Kar and FarO regulate the balance between the cell growth and lipid storage of larval oenocytes. PMID:27500738

Splenic Immune Response Is Down-Regulated in C57BL/6J Mice Fed Eicosapentaenoic Acid and Docosahexaenoic Acid Enriched High Fat Diet.

PubMed

Soni, Nikul K; Ross, Alastair B; Scheers, Nathalie; Savolainen, Otto I; Nookaew, Intawat; Gabrielsson, Britt G; Sandberg, Ann-Sofie

2017-01-10

Dietary n -3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with reduction of inflammation, although the mechanisms are poorly understood, especially how the spleen, as a secondary lymphoid organ, is involved. To investigate the effects of EPA and DHA on spleen gene expression, male C57BL/6J mice were fed high fat diets (HFD) differing in fatty acid composition, either based on corn oil (HFD-CO), or CO enriched with 2 g/100 g EPA and DHA (HFD-ED), for eight weeks. Spleen tissue was analyzed using transcriptomics and for fatty acids profiling. Biological processes (BPs) related to the immune response, including T-cell receptor signaling pathway, T-cell differentiation and co-stimulation, myeloid dendritic cell differentiation, antigen presentation and processing, and the toll like receptor pathway were downregulated by HFD-ED compared with control and HFD-CO. These findings were supported by the down-regulation of NF-κB in HFD-ED compared with HFD-CO fed mice. Lower phospholipid arachidonic acid levels in HFD-ED compared with HFD-CO, and control mice suggest attenuation of pathways via prostaglandins and leukotrienes. The HFD-ED also upregulated BPs related to erythropoiesis and hematopoiesis compared with control and HFD-CO fed mice. Our findings suggest that EPA and DHA down-regulate the splenic immune response induced by HFD-CO, supporting earlier work that the spleen is a target organ for the anti-inflammatory effects of these n -3 fatty acids.

Splenic Immune Response Is Down-Regulated in C57BL/6J Mice Fed Eicosapentaenoic Acid and Docosahexaenoic Acid Enriched High Fat Diet

PubMed Central

Soni, Nikul K.; Ross, Alastair B.; Scheers, Nathalie; Savolainen, Otto I.; Nookaew, Intawat; Gabrielsson, Britt G.; Sandberg, Ann-Sofie

2017-01-01

Dietary n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with reduction of inflammation, although the mechanisms are poorly understood, especially how the spleen, as a secondary lymphoid organ, is involved. To investigate the effects of EPA and DHA on spleen gene expression, male C57BL/6J mice were fed high fat diets (HFD) differing in fatty acid composition, either based on corn oil (HFD-CO), or CO enriched with 2 g/100 g EPA and DHA (HFD-ED), for eight weeks. Spleen tissue was analyzed using transcriptomics and for fatty acids profiling. Biological processes (BPs) related to the immune response, including T-cell receptor signaling pathway, T-cell differentiation and co-stimulation, myeloid dendritic cell differentiation, antigen presentation and processing, and the toll like receptor pathway were downregulated by HFD-ED compared with control and HFD-CO. These findings were supported by the down-regulation of NF-κB in HFD-ED compared with HFD-CO fed mice. Lower phospholipid arachidonic acid levels in HFD-ED compared with HFD-CO, and control mice suggest attenuation of pathways via prostaglandins and leukotrienes. The HFD-ED also upregulated BPs related to erythropoiesis and hematopoiesis compared with control and HFD-CO fed mice. Our findings suggest that EPA and DHA down-regulate the splenic immune response induced by HFD-CO, supporting earlier work that the spleen is a target organ for the anti-inflammatory effects of these n-3 fatty acids. PMID:28075380

YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

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

Lin, Yi-Ting; Ding, Jing-Ya; Li, Ming-Yang

2012-09-10

Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model tomore » study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. Black-Right-Pointing-Pointer YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. Black-Right-Pointing-Pointer Knockdown of Gli2 rescues the

Signaling hierarchy regulating human endothelial cell development

USDA-ARS?s Scientific Manuscript database

Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of signals that govern human endothelial cell development are unknown and, thus, explored in these stud...

A pair of light signaling factors FHY3 and FAR1 regulates plant immunity by modulating chlorophyll biosynthesis.

PubMed

Wang, Wanqing; Tang, Weijiang; Ma, Tingting; Niu, De; Jin, Jing Bo; Wang, Haiyang; Lin, Rongcheng

2016-01-01

Light and chloroplast function is known to affect the plant immune response; however, the underlying mechanism remains elusive. We previously demonstrated that two light signaling factors, FAR-RED ELONGATED HYPOCOTYL 3 (FHY3) and FAR-RED IMPAIRED RESPONSE 1 (FAR1), regulate chlorophyll biosynthesis and seedling growth via controlling HEMB1 expression in Arabidopsis thaliana. In this study, we reveal that FHY3 and FAR1 are involved in modulating plant immunity. We showed that the fhy3 far1 double null mutant displayed high levels of reactive oxygen species and salicylic acid (SA) and increased resistance to Pseudomonas syringae pathogen infection. Microarray analysis revealed that a large proportion of pathogen-related genes, particularly genes encoding nucleotide-binding and leucine-rich repeat domain resistant proteins, are highly induced in fhy3 far1. Genetic studies indicated that the defects of fhy3 far1 can be largely rescued by reducing SA signaling or blocking SA accumulation, and by overexpression of HEMB1, which encodes a 5-aminolevulinic acid dehydratase in the chlorophyll biosynthetic pathway. Furthermore, we found that transgenic plants with reduced expression of HEMB1 exhibit a phenotype similar to fhy3 far1. Taken together, this study demonstrates an important role of FHY3 and FAR1 in regulating plant immunity, through integrating chlorophyll biosynthesis and the SA signaling pathway. © The Authors. Journal of Integrative Plant Biology published by Wiley Publishing Asia Pty Ltd on behalf of Institute of Botany, Chinese Academy of Sciences.

Abscisic acid and sucrose regulate tomato and strawberry fruit ripening through the abscisic acid-stress-ripening transcription factor.

PubMed

Jia, Haifeng; Jiu, Songtao; Zhang, Cheng; Wang, Chen; Tariq, Pervaiz; Liu, Zhongjie; Wang, Baoju; Cui, Liwen; Fang, Jinggui

2016-10-01

Although great progress has been made towards understanding the role of abscisic acid (ABA) and sucrose in fruit ripening, the mechanisms underlying the ABA and sucrose signalling pathways remain elusive. In this study, transcription factor ABA-stress-ripening (ASR), which is involved in the transduction of ABA and sucrose signalling pathways, was isolated and analysed in the nonclimacteric fruit, strawberry and the climacteric fruit, tomato. We have identified four ASR isoforms in tomato and one in strawberry. All ASR sequences contained the ABA stress- and ripening-induced proteins and water-deficit stress-induced proteins (ABA/WDS) domain and all ASR transcripts showed increased expression during fruit development. The expression of the ASR gene was influenced not only by sucrose and ABA, but also by jasmonic acid (JA) and indole-3-acetic acid (IAA), and these four factors were correlated with each other during fruit development. ASR bound the hexose transporter (HT) promoter, which contained a sugar box that activated downstream gene expression. Overexpression of the ASR gene promoted fruit softening and ripening, whereas RNA interference delayed fruit ripening, as well as affected fruit physiological changes. Change in ASR gene expression influenced the expression of several ripening-related genes such as CHS, CHI, F3H, DFR, ANS, UFGT, PG, PL, EXP1/2, XET16, Cel1/2 and PME. Taken together, this study may provide new evidence on the important role of ASR in cross-signalling between ABA and sucrose to regulate tomato and strawberry fruit ripening. The findings of this study also provide new insights into the regulatory mechanism underlying fruit development. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Post-transcriptional regulation of ethylene perception and signaling in Arabidopsis

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

Schaller, George Eric

2014-03-19

The simple gas ethylene functions as an endogenous regulator of plant growth and development, and modulates such energy relevant processes as photosynthesis and biomass accumulation. Ethylene is perceived in the plant Arabidopsis by a five-member family of receptors related to bacterial histidine kinases. Our data support a general model in which the receptors exist as parts of larger protein complexes. Our goals have been to (1) characterize physical interactions among members of the signaling complex; (2) the role of histidine-kinase transphosphorylation in signaling by the complex; and (3) the role of a novel family of proteins that regulate signal outputmore » by the receptors.« less

Endocannabinoid Signaling Regulates Sleep Stability

PubMed Central

Pava, Matthew J.; Makriyannis, Alexandros; Lovinger, David M.

2016-01-01

The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis. PMID:27031992

Endocannabinoid Signaling Regulates Sleep Stability.

PubMed

Pava, Matthew J; Makriyannis, Alexandros; Lovinger, David M

2016-01-01

The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis.

TGF-β signaling in insects regulates metamorphosis via juvenile hormone biosynthesis

PubMed Central

Ishimaru, Yoshiyasu; Tomonari, Sayuri; Matsuoka, Yuji; Watanabe, Takahito; Miyawaki, Katsuyuki; Bando, Tetsuya; Tomioka, Kenji; Ohuchi, Hideyo; Noji, Sumihare; Mito, Taro

2016-01-01

Although butterflies undergo a dramatic morphological transformation from larva to adult via a pupal stage (holometamorphosis), crickets undergo a metamorphosis from nymph to adult without formation of a pupa (hemimetamorphosis). Despite these differences, both processes are regulated by common mechanisms that involve 20-hydroxyecdysone (20E) and juvenile hormone (JH). JH regulates many aspects of insect physiology, such as development, reproduction, diapause, and metamorphosis. Consequently, strict regulation of JH levels is crucial throughout an insect’s life cycle. However, it remains unclear how JH synthesis is regulated. Here, we report that in the corpora allata of the cricket, Gryllus bimaculatus, Myoglianin (Gb’Myo), a homolog of Drosophila Myoglianin/vertebrate GDF8/11, is involved in the down-regulation of JH production by suppressing the expression of a gene encoding JH acid O-methyltransferase, Gb’jhamt. In contrast, JH production is up-regulated by Decapentaplegic (Gb’Dpp) and Glass-bottom boat/60A (Gb’Gbb) signaling that occurs as part of the transcriptional activation of Gb’jhamt. Gb’Myo defines the nature of each developmental transition by regulating JH titer and the interactions between JH and 20E. When Gb’myo expression is suppressed, the activation of Gb’jhamt expression and secretion of 20E induce molting, thereby leading to the next instar before the last nymphal instar. Conversely, high Gb’myo expression induces metamorphosis during the last nymphal instar through the cessation of JH synthesis. Gb’myo also regulates final insect size. Because Myo/GDF8/11 and Dpp/bone morphogenetic protein (BMP)2/4-Gbb/BMP5–8 are conserved in both invertebrates and vertebrates, the present findings provide common regulatory mechanisms for endocrine control of animal development. PMID:27140602