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Sample records for coactivator gcn5 plays

  1. Subunits of ADA-two-A-containing (ATAC) or Spt-Ada-Gcn5-acetyltrasferase (SAGA) Coactivator Complexes Enhance the Acetyltransferase Activity of GCN5.

    PubMed

    Riss, Anne; Scheer, Elisabeth; Joint, Mathilde; Trowitzsch, Simon; Berger, Imre; Tora, László

    2015-11-27

    Histone acetyl transferases (HATs) play a crucial role in eukaryotes by regulating chromatin architecture and locus specific transcription. GCN5 (KAT2A) is a member of the GNAT (Gcn5-related N-acetyltransferase) family of HATs. In metazoans this enzyme is found in two functionally distinct coactivator complexes, SAGA (Spt Ada Gcn5 acetyltransferase) and ATAC (Ada Two A-containing). These two multiprotein complexes comprise complex-specific and shared subunits, which are organized in functional modules. The HAT module of ATAC is composed of GCN5, ADA2a, ADA3, and SGF29, whereas in the SAGA HAT module ADA2b is present instead of ADA2a. To better understand how the activity of human (h) hGCN5 is regulated in the two related, but different, HAT complexes we carried out in vitro HAT assays. We compared the activity of hGCN5 alone with its activity when it was part of purified recombinant hATAC or hSAGA HAT modules or endogenous hATAC or hSAGA complexes using histone tail peptides and full-length histones as substrates. We demonstrated that the subunit environment of the HAT complexes into which GCN5 incorporates determines the enhancement of GCN5 activity. On histone peptides we show that all the tested GCN5-containing complexes acetylate mainly histone H3K14. Our results suggest a stronger influence of ADA2b as compared with ADA2a on the activity of GCN5. However, the lysine acetylation specificity of GCN5 on histone tails or full-length histones was not changed when incorporated in the HAT modules of ATAC or SAGA complexes. Our results thus demonstrate that the catalytic activity of GCN5 is stimulated by subunits of the ADA2a- or ADA2b-containing HAT modules and is further increased by incorporation of the distinct HAT modules in the ATAC or SAGA holo-complexes.

  2. Cloning of SmNCoA-62, a novel nuclear receptor co-activator from Schistosoma mansoni: assembly of a complex with a SmRXR1/SmNR1 heterodimer, SmGCN5 and SmCBP1.

    PubMed

    Fantappié, Marcelo Rosado; Bastos de Oliveira, Francisco Meirelles; de Moraes Maciel, Renata; Rumjanek, Franklin David; Wu, Wenjie; Loverde, Philip T

    2008-08-01

    The Schistosoma mansoni nuclear receptors (NR) SmRXR1 and SmNR1 have recently been shown to form a heterodimer and to bind to canonic hormone response DNA elements. Recruitment of co-regulatory proteins to NRs is required for their transcriptional and biological activities. Here, we cloned a novel S. mansoni NR co-activator, SmNCoA-62. SmNCoA-62 is highly homologous to the human Vitamin D receptor co-activator NCoA62/SKIP. SmNCoA-62 contains the SNW nuclear receptor interaction domain and a putative C-terminus transactivation domain. By using in vitro pull-down assays, we fully mapped the interaction domains of S. mansoni NR co-activators, SmNCoA-62, SmGCN5 and SmCBP1 with SmRXR1 and SmNR1, as well as the domains that mediate interactions amongst the co-activators themselves. By mutagenesis analysis, we showed that SmCBP1 LxxLL motif 2 and LxxLL motif 3, but not LxxLL motif 1, were essential to mediate the interactions of SmCBP1 with the EF domains of SmRXR1 and SmNR1. Histone acetyltransferases SmGCN5 and SmCBP1 specifically acetylated the C/D domains of SmRXR1 and SmNR1. In addition, two acetylation sites of SmNR1 were identified. SmGCN5 and SmCBP1 also acetylated SmNCoA-62 but with significant differences in their acetylation activities. Using gel shift analysis, we were able to demonstrate, in vitro, the assembly of the co-activators on the SmRXR1/SmNR1 heterodimer bound to DNA. LxxLL motifs 2 and 3 of SmCBP1 seemed to play a crucial role for the assembly of the co-activators to the DNA-bound SmRXR1/SmNR1 heterodimer.

  3. Protein acetylation sites mediated by Schistosoma mansoni GCN5

    SciTech Connect

    Moraes Maciel, Renata de; Furtado Madeiro da Costa, Rodrigo; Meirelles Bastosde Oliveira, Francisco; Rumjanek, Franklin David; Fantappie, Marcelo Rosado

    2008-05-23

    The transcriptional co-activator GCN5, a histone acetyltransferase (HAT), is part of large multimeric complexes that are required for chromatin remodeling and transcription activation. As in other eukaryotes, the DNA from the parasite Schistosome mansoni is organized into nucleosomes and the genome encodes components of chromatin-remodeling complexes. Using a series of synthetic peptides we determined that Lys-14 of histone H3 was acetylated by the recombinant SmGCN5-HAT domain. SmGCN5 was also able to acetylate schistosome non-histone proteins, such as the nuclear receptors SmRXR1 and SmNR1, and the co-activator SmNCoA-62. Electron microscopy revealed the presence of SmGCN5 protein in the nuclei of vitelline cells. Within the nucleus, SmGCN5 was found to be located in interchromatin granule clusters (IGCs), which are transcriptionally active structures. The data suggest that SmGCN5 is involved in transcription activation.

  4. Function and subcellular localization of Gcn5, a histone acetyltransferase in Candida albicans.

    PubMed

    Chang, Peng; Fan, Xueyi; Chen, Jiangye

    2015-08-01

    Candida albicans is an opportunistic fungal pathogen commonly found in humans. It has the ability to switch reversibly between three growth forms: budding yeast, pseudohypha, and hypha. The transition between yeast and hyphal growth forms is critical for the pathogenesis of C. albicans. During the yeast-to-hypha morphologic transition, gene expression is regulated by transcriptional regulators including histone modifying complexes and chromatin remodeling complexes. We previously reported that Esa1, a catalytic subunit in the histone acetyltransferase complex NuA4, is essential for the hyphal development of C. albicans. In this study, we analyzed the functional roles of Gcn5, a catalytic subunit in the histone acetyltransferase complex SAGA, in C. albicans. Gcn5 is required for the invasive and filamentous growth of C. albicans. Deletion of GCN5 impaired hyphal elongation in sensing serum and attenuated the virulence of C. albicans in a mouse systemic infection model. The C. albicans gcn5/gcn5 mutant cells also exhibited sensitivity to cell wall stress. Functional analysis showed that the HAT domain and Bromodomain in Gcn5 play distinct roles in morphogenesis and cell wall stress response of C. albicans. Our results show that the conserved residue Glu188 is crucial for the Gcn5 HAT activity and for Gcn5 function during filamentous growth. In addition, the subcellular distribution of ectopically expressed GFP-Gcn5 correlates with the different growth states of C. albicans. In stationary phase, Gcn5 accumulated in the nucleus, while during vegetative growth it localized in the cytoplasm in a morpha-independent manner. Our results suggest that the nuclear localization of Gcn5 depends on the existence of its N-terminal NLS and HAT domains.

  5. Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance

    PubMed Central

    Atanassov, Boyko S.; Evrard, Yvonne A.; Multani, Asha S.; Zhang, Zhijing; Tora, László; Devys, Didier; Chang, Sandy; Dent, Sharon Y.R.

    2009-01-01

    SUMMARY Histone acetyltransferases (HATs) play important roles in gene regulation and DNA repair by influencing the accessibility of chromatin to transcription factors and repair proteins. Here we show that deletion of Gcn5 leads to telomere dysfunction in mouse and human cells. Biochemical studies reveal that depletion of Gcn5 or ubiquitin specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA complex, increases ubiquitination and turnover of TRF1, a primary component of the telomeric shelterin complex. Inhibition of the proteasome or over expression of USP22 opposes this effect. The USP22 deubiquitinating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Thus, our results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity. PMID:19683498

  6. Gcn5 determines the fate of Drosophila germline stem cells through degradation of Cyclin A.

    PubMed

    Liu, Tianqi; Wang, Qi; Li, Wenqing; Mao, Feiyu; Yue, Shanshan; Liu, Sun; Liu, Xiaona; Xiao, Shan; Xia, Laixin

    2017-02-10

    The fluctuating CDK-CYCLIN complex plays a general role in cell-cycle control. Many types of stem cells use unique features of the cell cycle to facilitate asymmetric division. However, the manner in which these features are established remains poorly understood. The cell cycle of Drosophila female germline stem cells (GSCs) is characterized by short G1 and very long G2 phases, making it an excellent model for the study of cell cycle control in stem cell fate determination. Using a Drosophila female GSCs model, we found Gcn5, the first discovered histone acetyltransferase, to maintain germline stem cells in Drosophila ovaries. Results showed that Gcn5 is dispensable for the transcriptional silencing of bam, but interacts with Cyclin A to facilitate proper turnover in GSCs. Results also showed that Gcn5 promotes Cyclin A ubiquitination, which is dependent on its acetylating activity. Finally, results showed that knockdown of Cyclin A rescued the GSC-loss phenotype caused by lack of Gcn5. Collectively, these findings support the conclusion that Gcn5 acts through acetylation to facilitate Cyclin A ubiquitination and proper turnover, thereby determining the fate of GSCs.-Liu, T., Wang, Q., Li, W., Mao, F., Yue, S., Liu, S., Liu, X., Xiao, S., Xia, L. Gcn5 determines the fate of Drosophila germline stem cells through degradation of Cyclin A.

  7. The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch

    PubMed Central

    Sakai, Mashito; Tujimura-Hayakawa, Tomoko; Yagi, Takashi; Yano, Hiroyuki; Mitsushima, Masaru; Unoki-Kubota, Hiroyuki; Kaburagi, Yasushi; Inoue, Hiroshi; Kido, Yoshiaki; Kasuga, Masato; Matsumoto, Michihiro

    2016-01-01

    Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon–cAMP–protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α–mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions. PMID:27874008

  8. Histone acetyltransferase AtGCN5/HAG1 is a versatile regulator of developmental and inducible gene expression in Arabidopsis.

    PubMed

    Servet, Caroline; Conde e Silva, Natalia; Zhou, Dao-Xiu

    2010-07-01

    Histone acetylation/deacetylation is a dynamic process and plays an important role in gene regulation. Histone acetylation homeostasis is regulated by antagonist actions of histone acetyltransferases (HAT) and deacetylases (HDAC). Plant genome encodes multiple HATs and HDACs. The Arabidopsis HAT gene AtGCN5/HAG1plays an essential role in many plant development processes, such as meristem function, cell differentiation, leaf and floral organogenesis, and responses to environmental conditions such as light and cold, indicating an important role of this HAT in the regulation of both long-term developmental switches and short-term inducible gene expression. AtGCN5 targets to a large number of promoters and is required for acetylation of several histone H3 lysine residues. Recruitment of AtGCN5 to target promoters is likely to be mediated by direct or indirect interaction with DNA-binding transcription factors and/or by interaction with acetylated histone lysine residues on the targets. Interplay between AtGCN5 and other HAT and HDAC is demonstrated to control specific regulatory pathways. Analysis of the role of AtGCN5 in light-inducible gene expression suggests a function of AtGCN5 in preparing chromatin commitment for priming inducible gene activation in plants.

  9. GCN5 is a required cofactor for a ubiquitin ligase that targets NF-κB/RelA

    PubMed Central

    Mao, Xicheng; Gluck, Nathan; Li, Duo; Maine, Gabriel N.; Li, Haiying; Zaidi, Iram W.; Repaka, Aparna; Mayo, Marty W.; Burstein, Ezra

    2009-01-01

    The transcription factor NF-κB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-κB subunits plays an important role in the termination of NF-κB activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses κB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IκB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination. PMID:19339690

  10. Human ATAC Is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein.

    PubMed

    Wang, Yuan-Liang; Faiola, Francesco; Xu, Muyu; Pan, Songqin; Martinez, Ernest

    2008-12-05

    Eukaryotic GCN5 acetyltransferases influence diverse biological processes by acetylating histones and non-histone proteins and regulating chromatin and gene-specific transcription as part of multiprotein complexes. In lower eukaryotes and invertebrates, these complexes include the yeast ADA complex that is still incompletely understood; the SAGA (Spt-Ada-Gcn5 acetylase) complexes from yeast to Drosophila that are mostly coactivators; and the ATAC (Ada Two-A containing) complex, only known in Drosophila and still poorly characterized. In contrast, vertebrate organisms, express two paralogous GCN5-like acetyltransferases (GCN5 and PCAF), which have been found so far only in SAGA-type complexes referred to hereafter as the STAGA (SPT3-TAF9-GCN5/PCAF acetylase) complexes. We now report the purification and characterization of vertebrate (human) ATAC-type complexes and identify novel components of STAGA. We show that human ATAC complexes incorporate in addition to GCN5 or PCAF (GCN5/PCAF), other epigenetic coregulators (ADA2-A, ADA3, STAF36, and WDR5), cofactors of chromatin assembly/remodeling and DNA replication machineries (POLE3/CHRAC17 and POLE4), the stress- and TGFbeta-activated protein kinase (TAK1/MAP3K7) and MAP3-kinase regulator (MBIP), additional cofactors of unknown function, and a novel YEATS2-NC2beta histone fold module that interacts with the TATA-binding protein (TBP) and negatively regulates transcription when recruited to a promoter. We further identify the p38 kinase-interacting protein (p38IP/FAM48A) as a novel component of STAGA with distant similarity to yeast Spt20. These results suggest that vertebrate ATAC-type and STAGA-type complexes link specific extracellular signals to modification of chromatin structure and regulation of the basal transcription machinery.

  11. Distinct but overlapping roles of histone acetylase PCAF and of the closely related PCAF-B/GCN5 in mouse embryogenesis

    PubMed Central

    Yamauchi, Teruo; Yamauchi, Jun; Kuwata, Takeshi; Tamura, Tomohiko; Yamashita, Tsuyoshi; Bae, Nancy; Westphal, Heiner; Ozato, Keiko; Nakatani, Yoshihiro

    2000-01-01

    PCAF plays a role in transcriptional activation, cell-cycle arrest, and cell differentiation in cultured cells. PCAF contributes to transcriptional activation by acetylating chromatin and transcription factors through its intrinsic histone acetylase activity. In this report, we present evidence for the in vivo function of PCAF and the closely related PCAF-B/GCN5. Mice lacking PCAF are developmentally normal without a distinct phenotype. In PCAF null-zygous mice, protein levels of PCAF-B/GCN5 are drastically elevated in lung and liver, where PCAF is abundantly expressed in wild-type mice, suggesting that PCAF-B/GCN5 functionally compensates for PCAF. In contrast, animals lacking PCAF-B/GCN5 die between days 9.5 and 11.5 of gestation. Normally, PCAF-B/GCN5 mRNA is expressed at high levels already by day 8, whereas PCAF mRNA is first detected on day 12.5, which may explain, in part, the distinct knockout phenotypes. These results provide evidence that PCAF and PCAF-B/GCN5 play distinct but functionally overlapping roles in embryogenesis. PMID:11027331

  12. Structural basis for acyl-group discrimination by human Gcn5L2

    PubMed Central

    Ringel, Alison E.; Wolberger, Cynthia

    2016-01-01

    Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, the acyl-chain specificity of the acetyltransferase human Gcn5 (Gcn5L2) was examined. Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 becomes progressively weaker with increasing acyl-chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA were determined. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor of Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl-chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group. PMID:27377381

  13. Coiled-coil coactivators play a structural role mediating interactions in hypoxia-inducible factor heterodimerization.

    PubMed

    Guo, Yirui; Scheuermann, Thomas H; Partch, Carrie L; Tomchick, Diana R; Gardner, Kevin H

    2015-03-20

    The hypoxia-inducible factor complex (HIF-α·aryl hydrocarbon receptor nuclear translocator (ARNT)) requires association with several transcription coactivators for a successful cellular response to hypoxic stress. In addition to the conventional global transcription coactivator CREB-binding protein/p300 (CBP/p300) that binds to the HIF-α transactivation domain, a new group of transcription coactivators called the coiled-coil coactivators (CCCs) interact directly with the second PER-ARNT-SIM (PAS) domain of ARNT (ARNT PAS-B). These less studied transcription coactivators play essential roles in the HIF-dependent hypoxia response, and CCC misregulation is associated with several forms of cancer. To better understand CCC protein recruitment by the heterodimeric HIF transcription factor, we used x-ray crystallography, NMR spectroscopy, and biochemical methods to investigate the structure of the ARNT PAS-B domain in complex with the C-terminal fragment of a coiled-coil coactivator protein, transforming acidic coiled-coil coactivator 3 (TACC3). We found that the HIF-2α PAS-B domain also directly interacts with TACC3, motivating an NMR data-derived model suggesting a means by which TACC3 could form a ternary complex with HIF-2α PAS-B and ARNT PAS-B via β-sheet/coiled-coil interactions. These findings suggest that TACC3 could be recruited as a bridge to cooperatively mediate between the HIF-2α PAS-B·ARNT PAS-B complex, thereby participating more directly in HIF-dependent gene transcription than previously anticipated.

  14. Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia-inducible Factor Heterodimerization*

    PubMed Central

    Guo, Yirui; Scheuermann, Thomas H.; Partch, Carrie L.; Tomchick, Diana R.; Gardner, Kevin H.

    2015-01-01

    The hypoxia-inducible factor complex (HIF-α·aryl hydrocarbon receptor nuclear translocator (ARNT)) requires association with several transcription coactivators for a successful cellular response to hypoxic stress. In addition to the conventional global transcription coactivator CREB-binding protein/p300 (CBP/p300) that binds to the HIF-α transactivation domain, a new group of transcription coactivators called the coiled-coil coactivators (CCCs) interact directly with the second PER-ARNT-SIM (PAS) domain of ARNT (ARNT PAS-B). These less studied transcription coactivators play essential roles in the HIF-dependent hypoxia response, and CCC misregulation is associated with several forms of cancer. To better understand CCC protein recruitment by the heterodimeric HIF transcription factor, we used x-ray crystallography, NMR spectroscopy, and biochemical methods to investigate the structure of the ARNT PAS-B domain in complex with the C-terminal fragment of a coiled-coil coactivator protein, transforming acidic coiled-coil coactivator 3 (TACC3). We found that the HIF-2α PAS-B domain also directly interacts with TACC3, motivating an NMR data-derived model suggesting a means by which TACC3 could form a ternary complex with HIF-2α PAS-B and ARNT PAS-B via β-sheet/coiled-coil interactions. These findings suggest that TACC3 could be recruited as a bridge to cooperatively mediate between the HIF-2α PAS-B·ARNT PAS-B complex, thereby participating more directly in HIF-dependent gene transcription than previously anticipated. PMID:25627682

  15. Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

    PubMed Central

    Jeffers, Victoria; Gao, Hongyu; Checkley, Lisa A.; Liu, Yunlong; Ferdig, Michael T.

    2016-01-01

    Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasite Toxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required for Toxoplasma tachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibits Toxoplasma tachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibits Plasmodium falciparum asexual replication with a 50% inhibitory concentration (IC50) similar to that for Toxoplasma. Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication. PMID:26810649

  16. Diencephalic Size Is Restricted by a Novel Interplay Between GCN5 Acetyltransferase Activity and Retinoic Acid Signaling.

    PubMed

    Wilde, Jonathan J; Siegenthaler, Julie A; Dent, Sharon Y R; Niswander, Lee A

    2017-03-08

    Diencephalic defects underlie an array of neurological diseases. Previous studies have suggested that retinoic acid (RA) signaling is involved in diencephalic development at late stages of embryonic development, but its roles and mechanisms of action during early neural development are still unclear. Here we demonstrate that mice lacking enzymatic activity of the acetyltransferase GCN5 ((Gcn5(hat/hat) )), which were previously characterized with respect to their exencephalic phenotype, exhibit significant diencephalic expansion, decreased diencephalic RA signaling, and increased diencephalic WNT and SHH signaling. Using a variety of molecular biology techniques in both cultured neuroepithelial cells treated with a GCN5 inhibitor and forebrain tissue from (Gcn5(hat/hat) ) embryos, we demonstrate that GCN5, RARα/γ, and the poorly characterized protein TACC1 form a complex in the nucleus that binds specific retinoic acid response elements in the absence of RA. Furthermore, RA triggers GCN5-mediated acetylation of TACC1, which results in dissociation of TACC1 from retinoic acid response elements and leads to transcriptional activation of RA target genes. Intriguingly, RA signaling defects caused by in vitro inhibition of GCN5 can be rescued through RA-dependent mechanisms that require RARβ. Last, we demonstrate that the diencephalic expansion and transcriptional defects seen in (Gcn5(hat/hat) ) mutants can be rescued with gestational RA supplementation, supporting a direct link between GCN5, TACC1, and RA signaling in the developing diencephalon. Together, our studies identify a novel, nonhistone substrate for GCN5 whose modification regulates a previously undescribed, tissue-specific mechanism of RA signaling that is required to restrict diencephalic size during early forebrain development.SIGNIFICANCE STATEMENT Changes in diencephalic size and shape, as well as SNPs associated with retinoic acid (RA) signaling-associated genes, have been linked to neuropsychiatric

  17. Synergistic action of histone acetyltransferase GCN5 and receptor CLAVATA1 negatively affects ethylene responses in Arabidopsis thaliana.

    PubMed

    Poulios, Stylianos; Vlachonasios, Konstantinos E

    2016-02-01

    GENERAL CONTROL NON-REPRESSIBLE 5 (GCN5) is a histone acetyltransferase (HAT) and the catalytic subunit of several multicomponent HAT complexes that acetylate lysine residues of histone H3. Mutants in AtGCN5 display pleiotropic developmental defects including aberrant meristem function. Shoot apical meristem (SAM) maintenance is regulated by CLAVATA1 (CLV1), a receptor kinase that controls the size of the shoot and floral meristems. Upon activation through CLV3 binding, CLV1 signals to the transcription factor WUSCHEL (WUS), restricting WUS expression and thus the meristem size. We hypothesized that GCN5 and CLV1 act together to affect SAM function. Using genetic and molecular approaches, we generated and characterized clv gcn5 mutants. Surprisingly, the clv1-1 gcn5-1 double mutant exhibited constitutive ethylene responses, suggesting that GCN5 and CLV signaling act synergistically to inhibit ethylene responses in Arabidopsis. This genetic and molecular interaction was mediated by ETHYLENE INSENSITIVE 3/ EIN3-LIKE1 (EIN3/EIL1) transcription factors. Our data suggest that signals from the CLV transduction pathway reach the GCN5-containing complexes in the nucleus and alter the histone acetylation status of ethylene-responsive genes, thus translating the CLV information to transcriptional activity and uncovering a link between histone acetylation and SAM maintenance in the complex mode of ethylene signaling.

  18. The oncoprotein HBXIP promotes migration of breast cancer cells via GCN5-mediated microtubule acetylation.

    PubMed

    Li, Leilei; Liu, Bowen; Zhang, Xiaodong; Ye, Lihong

    2015-03-13

    We have documented that the oncoprotein hepatitis B X-interacting protein (HBXIP) is able to promote migration of breast cancer cells. A subset of acetylated microtubules that accumulates in the cell leading edge is necessary for cell polarization and directional migration. In this study, we explored the hypothesis that HBXIP contributes to migration of breast cancer cells by supporting microtubule acetylation in breast cancer cells. We found that HBXIP could induce acetylated microtubules accumulating into the leading protrusion in wound-induced directional migration in breast cancer cells by immunofluorescence staining analysis. Interestingly, HBXIP was able to increase the acetylation of α-tubulin in the cells by immunofluorescence staining and Western blot analysis. Furthermore, we observed that acetyltransferase GCN5 was involved in the event that HBXIP induced increase of acetylated microtubules and their expansion in protrusions in breast cancer cells by Western blot analysis and immunofluorescence staining. Moreover, GCN5 was required for the HBXIP-enhanced migration of breast cancer cells by wound healing assay. Thus, we conclude that HBXIP promotes the migration of breast cancer cells through modulating microtubule acetylation mediated by GCN5. Therapeutically, HBXIP may serve as a novel target in breast cancer.

  19. Gcn5 regulates the dissociation of SWI/SNF from chromatin by acetylation of Swi2/Snf2

    PubMed Central

    Kim, Jeong-Hoon; Saraf, Anita; Florens, Laurence; Washburn, Michael; Workman, Jerry L.

    2010-01-01

    The positive link between the SWI/SNF and the Gcn5 histone acetyltransferase in transcriptional activation has been well described. Here we report an inhibitory role for Gcn5 in SWI/SNF targeting. We demonstrate that Gcn5-containing complexes directly acetylate the Snf2 subunit of the SWI/SNF complex in vitro, as well as in vivo. Moreover, the acetylation of Snf2 facilitates the dissociation of the SWI/SNF complex from acetylated histones, and reduces its association with promoters in vivo. These data reveal a novel mechanism by which Gcn5 modulates chromatin structure not only through the acetylation of histones, but also by directly acetylating Snf2. PMID:21159817

  20. Genome-wide cooperation by HAT Gcn5, remodeler SWI/SNF, and chaperone Ydj1 in promoter nucleosome eviction and transcriptional activation

    PubMed Central

    Qiu, Hongfang; Chereji, Răzvan V.; Hu, Cuihua; Cole, Hope A.; Rawal, Yashpal; Clark, David J.; Hinnebusch, Alan G.

    2016-01-01

    Chaperones, nucleosome remodeling complexes, and histone acetyltransferases have been implicated in nucleosome disassembly at promoters of particular yeast genes, but whether these cofactors function ubiquitously, as well as the impact of nucleosome eviction on transcription genome-wide, is poorly understood. We used chromatin immunoprecipitation of histone H3 and RNA polymerase II (Pol II) in mutants lacking single or multiple cofactors to address these issues for about 200 genes belonging to the Gcn4 transcriptome, of which about 70 exhibit marked reductions in H3 promoter occupancy on induction by amino acid starvation. Examining four target genes in a panel of mutants indicated that SWI/SNF, Gcn5, the Hsp70 cochaperone Ydj1, and chromatin-associated factor Yta7 are required downstream from Gcn4 binding, whereas Asf1/Rtt109, Nap1, RSC, and H2AZ are dispensable for robust H3 eviction in otherwise wild-type cells. Using ChIP-seq to interrogate all 70 exemplar genes in single, double, and triple mutants implicated Gcn5, Snf2, and Ydj1 in H3 eviction at most, but not all, Gcn4 target promoters, with Gcn5 generally playing the greatest role and Ydj1 the least. Remarkably, these three cofactors cooperate similarly in H3 eviction at virtually all yeast promoters. Defective H3 eviction in cofactor mutants was coupled with reduced Pol II occupancies for the Gcn4 transcriptome and the most highly expressed uninduced genes, but the relative Pol II levels at most genes were unaffected or even elevated. These findings indicate that nucleosome eviction is crucial for robust transcription of highly expressed genes but that other steps in gene activation are more rate-limiting for most other yeast genes. PMID:26602697

  1. The impact of a 48-h fast on SIRT1 and GCN5 in human skeletal muscle.

    PubMed

    Edgett, Brittany A; Scribbans, Trisha D; Raleigh, James P; Matusiak, Jennifer B L; Boonstra, Kristen; Simpson, Craig A; Perry, Christopher G R; Quadrilatero, Joe; Gurd, Brendon J

    2016-09-01

    The present study examined the impact of a 48 h fast on the expression and activation status of SIRT1 and GCN5, the relationship between SIRT1/GCN5 and the gene expression of PGC-1α, and the PGC-1α target PDK4 in the skeletal muscle of 10 lean healthy men (age, 22.0 ± 1.5 years; peak oxygen uptake, 47.2 ± 6.7 mL/(min·kg)). Muscle biopsies and blood samples were collected 1 h postprandial (Fed) and following 48 h of fasting (Fasted). Plasma insulin (Fed, 80.8 ± 47.9 pmol/L; Fasted, not detected) and glucose (Fed, 4.36 ± 0.86; Fasted, 3.74 ± 0.25 mmol/L, p = 0.08) decreased, confirming participant adherence to fasting. Gene expression of PGC-1α decreased (p < 0.05, -24%), while SIRT1 and PDK4 increased (p < 0.05, +11% and +1023%, respectively), and GCN5 remained unchanged. No changes were observed for whole-muscle protein expression of SIRT1, GCN5, PGC-1α, or COX IV. Phosphorylation of SIRT1, AMPKα, ACC, p38 MAPK, and PKA substrates as well as nuclear acetylation status was also unaltered. Additionally, nuclear SIRT1 activity, GCN5, and PGC-1α content remained unchanged. Preliminary findings derived from regression analysis demonstrate that changes in nuclear GCN5 and SIRT1 activity/phosphorylation may contribute to the control of PGC-1α, but not PDK4, messenger RNA expression following fasting. Collectively, and in contrast with previous animal studies, our data are inconsistent with the altered activation status of SIRT1 and GCN5 in response to 48 h of fasting in human skeletal muscle.

  2. Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5.

    PubMed

    Wiper-Bergeron, Nadine; Salem, Houssein Abdou; Tomlinson, Julianna J; Wu, Dongmei; Haché, Robert J G

    2007-02-20

    Preadipocyte differentiation in culture is driven by an insulin and cAMP dependant transcriptional cascade which induces the bzip transcription factors C/EBPbeta and C/EBPdelta. We have previously shown that glucocorticoid treatment, which strongly potentiates this differentiation pathway, stimulates the titration of the corepressor histone deacetylase 1 (HDAC1) from C/EBPbeta. This results in a dramatic enhancement of C/EBPbeta-dependent transcription from the C/EBPalpha promoter, concomitant with potentiation of preadipocyte differentiation. Here, we show that C/EBPbeta is acetylated by GCN5 and PCAF within a cluster of lysine residues between amino acids 98-102 and that this acetylation is strongly induced by glucocorticoid treatment. Arginine substitution of the lysine residues within the acetylation motif of C/EBPbeta prevented acetylation and blocked the ability of glucocorticoids to enhance C/EBPbeta-directed transcription and to potentiate C/EBPbeta-dependent preadipocyte differentiation. Moreover, acetylation of C/EBPbeta appeared to directly interfere with the interaction of HDAC1 with C/EBPbeta, suggesting that PCAF/GCN5-dependent acetylation of C/EBPbeta serves as an important molecular switch in determining the transcriptional regulatory potential of this transcription factor.

  3. Autoregulation of the Rsc4 Tandem Bromodomain by Gcn5 Acetylation

    SciTech Connect

    VanDemark,A.; Kasten, M.; Ferris, E.; Heroux, A.; Hill, C.; Cairns, B.

    2007-01-01

    An important issue for chromatin remodeling complexes is how their bromodomains recognize particular acetylated lysine residues in histones. The Rsc4 subunit of the yeast remodeler RSC contains an essential tandem bromodomain (TBD) that binds acetylated K14 of histone H3 (H3K14ac). We report a series of crystal structures that reveal a compact TBD that binds H3K14ac in the second bromodomain and, remarkably, binds acetylated K25 of Rsc4 itself in the first bromodomain. Endogenous Rsc4 is acetylated only at K25, and Gcn5 is identified as necessary and sufficient for Rsc4 K25 acetylation in vivo and in vitro. Rsc4 K25 acetylation inhibits binding to H3K14ac, and mutation of Rsc4 K25 results in altered growth rates. These data suggest an autoregulatory mechanism in which Gcn5 performs both the activating (H3K14ac) and inhibitory (Rsc4 K25ac) modifications, perhaps to provide temporal regulation. Additional regulatory mechanisms are indicated as H3S10 phosphorylation inhibits Rsc4 binding to H3K14ac peptides.

  4. Expression of PCAF, p300 and Gcn5 and more highly acetylated histone H4 in pediatric tumors.

    PubMed

    Armas-Pineda, C; Arenas-Huertero, F; Pérezpeñia-Diazconti, M; Chico-Ponce de León, F; Sosa-Sáinz, G; Lezama, P; Recillas-Targa, F

    2007-06-01

    Any deregulation of histone acetyltransferases (HATs) could affect several processes in tumors. In this paper, the expression of the PCAF, p300 and Gcn5 HATs by RT-PCR in 34 tumor samples was evaluated. Samples of both central nervous system tumors (CNST, 13 cases) and Wilm's tumors (WT, 11 cases) over-expressed PCAF up to 1.6-, and Gcn5 up to 1.3-fold, respectively. In 9 out of 10 samples of benign tumors (BT), PCAF was not expressed. The p300 gene was the least expressed in all tumors. The medians of expression of PCAF (124.0 DU) and Gcn5 (127.0 DU) genes were higher in CNST than in both WT (102.0 and 101.0 DU, respectively) and BT (70.0 and 82.4 DU, respectively). There was a trend to decrease the expression of PCAF and Gcn5 genes in CNST, according to: chemotherapy (110.0 and 96.0 DU, respectively), chemo plus radiotherapy (124.0 and 115.0 DU, respectively) or no treatment (134.0 and 142.0 DU, respectively) in the tumors. A similar trend was observed in WT. Finally, we revealed more highly acetylated forms of histone H4 in CNST and WT. The over-expression of PCAF could represent a new molecular tumor marker in malignant tumors, especially in CNST in pediatric patients.

  5. Repression of GCN5 Histone Acetyltransferase Activity via Bromodomain-Mediated Binding and Phosphorylation by the Ku–DNA-Dependent Protein Kinase Complex

    PubMed Central

    Barlev, Nickolai A.; Poltoratsky, Vladimir; Owen-Hughes, Tom; Ying, Carol; Liu, Lin; Workman, Jerry L.; Berger, Shelley L.

    1998-01-01

    GCN5, a putative transcriptional adapter in humans and yeast, possesses histone acetyltransferase (HAT) activity which has been linked to GCN5’s role in transcriptional activation in yeast. In this report, we demonstrate a functional interaction between human GCN5 (hGCN5) and the DNA-dependent protein kinase (DNA-PK) holoenzyme. Yeast two-hybrid screening detected an interaction between the bromodomain of hGCN5 and the p70 subunit of the human Ku heterodimer (p70-p80), which is the DNA-binding component of DNA-PK. Interaction between intact hGCN5 and Ku70 was shown biochemically using recombinant proteins and by coimmunoprecipitation of endogenous proteins following chromatography of HeLa nuclear extracts. We demonstrate that the catalytic subunit of DNA-PK phosphorylates hGCN5 both in vivo and in vitro and, moreover, that the phosphorylation inhibits the HAT activity of hGCN5. These findings suggest a possible regulatory mechanism of HAT activity. PMID:9488450

  6. Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex in Plants: Genome Wide Identification, Evolutionary Conservation and Functional Determination.

    PubMed

    Srivastava, Rakesh; Rai, Krishan Mohan; Pandey, Bindu; Singh, Sudhir P; Sawant, Samir V

    2015-01-01

    The recruitment of RNA polymerase II on a promoter is assisted by the assembly of basal transcriptional machinery in eukaryotes. The Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex plays an important role in transcription regulation in eukaryotes. However, even in the advent of genome sequencing of various plants, SAGA complex has been poorly defined for their components and roles in plant development and physiological functions. Computational analysis of Arabidopsis thaliana and Oryza sativa genomes for SAGA complex resulted in the identification of 17 to 18 potential candidates for SAGA subunits. We have further classified the SAGA complex based on the conserved domains. Phylogenetic analysis revealed that the SAGA complex proteins are evolutionary conserved between plants, yeast and mammals. Functional annotation showed that they participate not only in chromatin remodeling and gene regulation, but also in different biological processes, which could be indirect and possibly mediated via the regulation of gene expression. The in silico expression analysis of the SAGA components in Arabidopsis and O. sativa clearly indicates that its components have a distinct expression profile at different developmental stages. The co-expression analysis of the SAGA components suggests that many of these subunits co-express at different developmental stages, during hormonal interaction and in response to stress conditions. Quantitative real-time PCR analysis of SAGA component genes further confirmed their expression in different plant tissues and stresses. The expression of representative salt, heat and light inducible genes were affected in mutant lines of SAGA subunits in Arabidopsis. Altogether, the present study reveals expedient evidences of involvement of the SAGA complex in plant gene regulation and stress responses.

  7. Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex in Plants: Genome Wide Identification, Evolutionary Conservation and Functional Determination

    PubMed Central

    Srivastava, Rakesh; Rai, Krishan Mohan; Pandey, Bindu; Singh, Sudhir P.; Sawant, Samir V.

    2015-01-01

    The recruitment of RNA polymerase II on a promoter is assisted by the assembly of basal transcriptional machinery in eukaryotes. The Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex plays an important role in transcription regulation in eukaryotes. However, even in the advent of genome sequencing of various plants, SAGA complex has been poorly defined for their components and roles in plant development and physiological functions. Computational analysis of Arabidopsis thaliana and Oryza sativa genomes for SAGA complex resulted in the identification of 17 to 18 potential candidates for SAGA subunits. We have further classified the SAGA complex based on the conserved domains. Phylogenetic analysis revealed that the SAGA complex proteins are evolutionary conserved between plants, yeast and mammals. Functional annotation showed that they participate not only in chromatin remodeling and gene regulation, but also in different biological processes, which could be indirect and possibly mediated via the regulation of gene expression. The in silico expression analysis of the SAGA components in Arabidopsis and O. sativa clearly indicates that its components have a distinct expression profile at different developmental stages. The co-expression analysis of the SAGA components suggests that many of these subunits co-express at different developmental stages, during hormonal interaction and in response to stress conditions. Quantitative real-time PCR analysis of SAGA component genes further confirmed their expression in different plant tissues and stresses. The expression of representative salt, heat and light inducible genes were affected in mutant lines of SAGA subunits in Arabidopsis. Altogether, the present study reveals expedient evidences of involvement of the SAGA complex in plant gene regulation and stress responses. PMID:26263547

  8. Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT)

    PubMed Central

    Salah Ud-Din, Abu Iftiaf Md; Tikhomirova, Alexandra; Roujeinikova, Anna

    2016-01-01

    General control non-repressible 5 (GCN5)-related N-acetyltransferases (GNAT) catalyze the transfer of an acyl moiety from acyl coenzyme A (acyl-CoA) to a diverse group of substrates and are widely distributed in all domains of life. This review of the currently available data acquired on GNAT enzymes by a combination of structural, mutagenesis and kinetic methods summarizes the key similarities and differences between several distinctly different families within the GNAT superfamily, with an emphasis on the mechanistic insights obtained from the analysis of the complexes with substrates or inhibitors. It discusses the structural basis for the common acetyltransferase mechanism, outlines the factors important for the substrate recognition, and describes the mechanism of action of inhibitors of these enzymes. It is anticipated that understanding of the structural basis behind the reaction and substrate specificity of the enzymes from this superfamily can be exploited in the development of novel therapeutics to treat human diseases and combat emerging multidrug-resistant microbial infections. PMID:27367672

  9. Conformational flexibility and subunit arrangement of the modular yeast Spt-Ada-Gcn5 acetyltransferase complex.

    PubMed

    Setiaputra, Dheva; Ross, James D; Lu, Shan; Cheng, Derrick T; Dong, Meng-Qiu; Yip, Calvin K

    2015-04-17

    The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a highly conserved, 19-subunit histone acetyltransferase complex that activates transcription through acetylation and deubiquitination of nucleosomal histones in Saccharomyces cerevisiae. Because SAGA has been shown to display conformational variability, we applied gradient fixation to stabilize purified SAGA and systematically analyzed this flexibility using single-particle EM. Our two- and three-dimensional studies show that SAGA adopts three major conformations, and mutations of specific subunits affect the distribution among these. We also located the four functional modules of SAGA using electron microscopy-based labeling and transcriptional activator binding analyses and show that the acetyltransferase module is localized in the most mobile region of the complex. We further comprehensively mapped the subunit interconnectivity of SAGA using cross-linking mass spectrometry, revealing that the Spt and Taf subunits form the structural core of the complex. These results provide the necessary restraints for us to generate a model of the spatial arrangement of all SAGA subunits. According to this model, the chromatin-binding domains of SAGA are all clustered in one face of the complex that is highly flexible. Our results relate information of overall SAGA structure with detailed subunit level interactions, improving our understanding of its architecture and flexibility.

  10. Histone modifying proteins Gcn5 and Hda1 affect flocculation in Saccharomyces cerevisiae during high-gravity fermentation.

    PubMed

    Dietvorst, Judith; Brandt, Anders

    2010-02-01

    The performance of yeast is often limited by the constantly changing environmental conditions present during high-gravity fermentation. Poor yeast performance contributes to incomplete and slow utilization of the main fermentable sugars which can lead to flavour problems in beer production. The expression of the FLO and MAL genes, which are important for the performance of yeast during industrial fermentations, is affected by complex proteins associated with Set1 (COMPASS) resulting in the induction of flocculation and improved maltose fermentation capacity during the early stages of high-gravity fermentation. In this study, we investigated a possible role for other histone modifying proteins. To this end, we tested a number of histone deacetylases (HDACs) and histone acetyltransferases and we report that flocculation is induced in absence of the histone deacetylase Hda1 or the histone acetyltransferase Gcn5 during high-gravity fermentation. The absence of Gcn5 protein also improved utilization of high concentrations of maltose. Deletion of SIR2 encoding the HDA of the silent informator regulator complex, did not affect flocculation under high-gravity fermentation conditions. Despite the obvious roles for Hda1 and Gcn5 in flocculation, this work indicates that COMPASS mediated silencing is the most important amongst the histone modifying components to control the expression of the FLO genes during high-gravity fermentation.

  11. Interplay among Gcn5, Sch9 and Mitochondria during Chronological Aging of Wine Yeast Is Dependent on Growth Conditions

    PubMed Central

    Picazo, Cecilia; Orozco, Helena; Matallana, Emilia; Aranda, Agustín

    2015-01-01

    Saccharomyces cerevisiae chronological life span (CLS) is determined by a wide variety of environmental and genetic factors. Nutrient limitation without malnutrition, i.e. dietary restriction, expands CLS through the control of nutrient signaling pathways, of which TOR/Sch9 has proven to be the most relevant, particularly under nitrogen deprivation. The use of prototrophic wine yeast allows a better understanding of the role of nitrogen in longevity in natural and more demanding environments, such as grape juice fermentation. We previously showed that acetyltransferase Gcn5, a member of the SAGA complex, has opposite effects on CLS under laboratory and winemaking conditions, and is detrimental under the latter. Here we demonstrate that integrity of the SAGA complex is necessary for prolonged longevity, as its dismantling by SPT20 deletion causes a drop in CLS under both laboratory and winemaking conditions. The sch9Δ mutant is long-lived in synthetic SC medium, as expected, and the combined deletion of GCN5 partially suppresses this phenotype. However it is short-lived in grape juice, likely due to its low nitrogen/carbon ratio. Therefore, unbalance of nutrients can be more relevant for life span than total amounts of them. Deletion of RTG2, which codes for a protein associated with Gcn5 and is a component of the mitochondrial retrograde signal, and which communicates mitochondrial dysfunction to the nucleus, is detrimental under laboratory, but not under winemaking conditions, where respiration seems not so relevant for longevity. Transcription factor Rgm1 was found to be a novel CLS regulator Sch9-dependently. PMID:25658705

  12. Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

    PubMed

    Wu, Yanna; Ma, Shanshan; Xia, Yong; Lu, Yangpeng; Xiao, Shiyin; Cao, Yali; Zhuang, Sidian; Tan, Xiangpeng; Fu, Qiang; Xie, Longchang; Li, Zhiming; Yuan, Zhongmin

    2017-01-26

    Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.

  13. GCN5 and E2F1 stimulate nucleotide excision repair by promoting H3K9 acetylation at sites of damage

    PubMed Central

    Guo, Ruifeng; Chen, Jie; Mitchell, David L.; Johnson, David G.

    2011-01-01

    Chromatin structure is known to be a barrier to DNA repair and a large number of studies have now identified various factors that modify histones and remodel nucleosomes to facilitate repair. In response to ultraviolet (UV) radiation several histones are acetylated and this enhances the repair of DNA photoproducts by the nucleotide excision repair (NER) pathway. However, the molecular mechanism by which UV radiation induces histone acetylation to allow for efficient NER is not completely understood. We recently discovered that the E2F1 transcription factor accumulates at sites of UV-induced DNA damage and directly stimulates NER through a non-transcriptional mechanism. Here we demonstrate that E2F1 associates with the GCN5 acetyltransferase in response to UV radiation and recruits GCN5 to sites of damage. UV radiation induces the acetylation of histone H3 lysine 9 (H3K9) and this requires both GCN5 and E2F1. Moreover, as previously observed for E2F1, knock down of GCN5 results in impaired recruitment of NER factors to sites of damage and inefficient DNA repair. These findings demonstrate a direct role for GCN5 and E2F1 in NER involving H3K9 acetylation and increased accessibility to the NER machinery. PMID:20972224

  14. A co-activator of nitrogen-regulated transcription in Saccharomyces cerevisiae.

    PubMed

    Soussi-Boudekou, S; André, B

    1999-02-01

    In Saccharomyces cerevisiae, the transcription factors Gln3p and Nil1p of the GATA family play a determinant role in expression of genes that are subject to nitrogen catabolite repression. Here we report the isolation of a new yeast mutant, gan1-1, exhibiting dramatically decreased NAD-linked glutamate dehydrogenase (NAD-GDH) and glutamine synthetase (GS) activities. The GAN1 gene was cloned and found to encode a 488-amino-acid polypeptide bearing no typical DNA binding domain. Gan1p is required for full expression of GLN1, GDH2 and also other nitrogen utilization genes, including GAP1, PUT4, MEP2 and GDH1. The extent to which Gan1p is required, however, varies according to the gene and to the nitrogen source available. We show that Gan1p is in fact involved in Gln3p- and Nil1p-dependent transcription. In the case of Gln3p-dependent transcription, the degree to which Gan1p is required appears to be gene specific. The contribution of Gan1p to gene expression is also influenced by the nitrogen status of the cell. We found that GAN1 is identical to ADA1, which encodes a component of the ADA/GCN5 co-activator complex. Ada1/Gan1p thus represents the first reported case of an accessory protein (a co-activator) linking the GATA-binding proteins Gln3p and Nil1p, mediating nitrogen-regulated transcription, to the basal transcription machinery.

  15. N-acetylglucosamine sensing by a GCN5-related N-acetyltransferase induces transcription via chromatin histone acetylation in fungi

    PubMed Central

    Su, Chang; Lu, Yang; Liu, Haoping

    2016-01-01

    N-acetylglucosamine (GlcNAc) exists ubiquitously as a component of the surface on a wide range of cells, from bacteria to humans. Many fungi are able to utilize environmental GlcNAc to support growth and induce cellular development, a property important for their survival in various host niches. However, how the GlcNAc signal is sensed and subsequently transduced is largely unknown. Here, we identify a gene that is essential for GlcNAc signalling (NGS1) in Candida albicans, a commensal and pathogenic yeast of humans. Ngs1 can bind GlcNAc through the N-terminal β-N-acetylglucosaminidase homology domain. This binding activates N-acetyltransferase activity in the C-terminal GCN5-related N-acetyltransferase domain, which is required for GlcNAc-induced promoter histone acetylation and transcription. Ngs1 is targeted to the promoters of GlcNAc-inducible genes constitutively by the transcription factor Rep1. Ngs1 is conserved in diverse fungi that have GlcNAc catabolic genes. Thus, fungi use Ngs1 as a GlcNAc-sensor and transducer for GlcNAc-induced transcription. PMID:27694804

  16. SWI/SNF recruitment to a DNA double-strand break by the NuA4 and Gcn5 histone acetyltransferases.

    PubMed

    Bennett, Gwendolyn; Peterson, Craig L

    2015-06-01

    The DNA damage response to double-strand breaks (DSBs) is critical for cellular viability. Recent work has shown that a host of chromatin regulators are recruited to a DSB, and that they are important for the DNA damage response. However, the functional relationships between different chromatin regulators at DSBs remain unclear. Here we describe a conserved functional interaction among the chromatin remodeling enzyme, SWI/SNF, the NuA4 and Gcn5 histone acetyltransferases, and phosphorylation of histone H2A.X (γH2AX). Specifically, we find that the NuA4 and Gcn5 enzymes are both required for the robust recruitment of SWI/SNF to a DSB, which in turn promotes the phosphorylation of H2A.X.

  17. The SAGA coactivator complex acts on the whole transcribed genome and is required for RNA polymerase II transcription

    PubMed Central

    Bonnet, Jacques; Wang, Chen-Yi; Baptista, Tiago; Vincent, Stéphane D.; Hsiao, Wei-Chun; Stierle, Matthieu; Kao, Cheng-Fu; Tora, László

    2014-01-01

    The SAGA (Spt–Ada–Gcn5 acetyltransferase) coactivator complex contains distinct chromatin-modifying activities and is recruited by DNA-bound activators to regulate the expression of a subset of genes. Surprisingly, recent studies revealed little overlap between genome-wide SAGA-binding profiles and changes in gene expression upon depletion of subunits of the complex. As indicators of SAGA recruitment on chromatin, we monitored in yeast and human cells the genome-wide distribution of histone H3K9 acetylation and H2B ubiquitination, which are respectively deposited or removed by SAGA. Changes in these modifications after inactivation of the corresponding enzyme revealed that SAGA acetylates the promoters and deubiquitinates the transcribed region of all expressed genes. In agreement with this broad distribution, we show that SAGA plays a critical role for RNA polymerase II recruitment at all expressed genes. In addition, through quantification of newly synthesized RNA, we demonstrated that SAGA inactivation induced a strong decrease of mRNA synthesis at all tested genes. Analysis of the SAGA deubiquitination activity further revealed that SAGA acts on the whole transcribed genome in a very fast manner, indicating a highly dynamic association of the complex with chromatin. Thus, our study uncovers a new function for SAGA as a bone fide cofactor for all RNA polymerase II transcription. PMID:25228644

  18. Arabidopsis thaliana transcriptional co-activators ADA2b and SGF29a are implicated in salt stress responses.

    PubMed

    Kaldis, Athanasios; Tsementzi, Despoina; Tanriverdi, Oznur; Vlachonasios, Konstantinos E

    2011-04-01

    The transcriptional co-activator ADA2b is a component of GCN5-containing complexes in eukaryotes. In Arabidopsis, ada2b mutants result in pleiotropic developmental defects and altered responses to low-temperature stress. SGF29 has recently been identified as another component of GCN5-containing complexes. In the Arabidopsis genome there are two orthologs of yeast SGF29, designated as SGF29a and SGF29b. We hypothesized that, in Arabidopsis, one or both SGF29 proteins may work in concert with ADA2b to regulate genes in response to abiotic stress, and we set out to explore the role of SGF29a and ADA2b in salt stress responses. In root growth and seed germination assays, sgf29a-1 mutants were more resistant to salt stress than their wild-type counterparts, whereas ada2b-1 mutant was hypersensitive. The sgf29a;ada2b double mutant displayed similar phenotypes to ada2b-1 mutant with reduced salt sensitivity. The expression of several abiotic stress-responsive genes was reduced in ada2b-1 mutants after 3 h of salt stress in comparison with sgf29a-1 and wild-type plants. In the sgf29a-1;ada2b-1 double mutant, the salt-induced gene expression was affected similarly to ada2b-1. These results suggest that under salt stress the function of SGF29a was masked by ADA2b and perhaps SGF29a could play an auxiliary role to ADA2b action. In chromatin immunoprecipitation assays, reduced levels of histone H3 and H4 acetylation in the promoter and coding region of COR6.6, RAB18, and RD29b genes were observed in ada2b-1 mutants relative to wild-type plants. In conclusion, ADA2b positively regulates salt-induced gene expression by maintaining the locus-specific acetylation of histones H4 and H3.

  19. Broad-substrate screen as a tool to identify substrates for bacterial Gcn5-related N-acetyltransferases with unknown substrate specificity.

    PubMed

    Kuhn, Misty L; Majorek, Karolina A; Minor, Wladek; Anderson, Wayne F

    2013-02-01

    Due to a combination of efforts from individual laboratories and structural genomics centers, there has been a surge in the number of members of the Gcn5-related acetyltransferasesuperfamily that have been structurally determined within the past decade. Although the number of three-dimensional structures is increasing steadily, we know little about the individual functions of these enzymes. Part of the difficulty in assigning functions for members of this superfamily is the lack of information regarding how substrates bind to the active site of the protein. The majority of the structures do not show ligand bound in the active site, and since the substrate-binding domain is not strictly conserved, it is difficult to predict the function based on structure alone. Additionally, the enzymes are capable of acetylating a wide variety of metabolites and many may exhibit promiscuity regarding their ability to acetylate multiple classes of substrates, possibly having multiple functions for the same enzyme. Herein, we present an approach to identify potential substrates for previously uncharacterized members of the Gcn5-related acetyltransferase superfamily using a variety of metabolites including polyamines, amino acids, antibiotics, peptides, vitamins, catecholamines, and other metabolites. We have identified potential substrates for eight bacterial enzymes of this superfamily. This information will be used to further structurally and functionally characterize them.

  20. Host Cell Factor and an Uncharacterized SANT Domain Protein Are Stable Components of ATAC, a Novel dAda2A/dGcn5-Containing Histone Acetyltransferase Complex in Drosophila

    PubMed Central

    Guelman, Sebastián; Suganuma, Tamaki; Florens, Laurence; Swanson, Selene K.; Kiesecker, Cheri L.; Kusch, Thomas; Anderson, Scott; Yates, John R.; Washburn, Michael P.; Abmayr, Susan M.; Workman, Jerry L.

    2006-01-01

    Gcn5 is a conserved histone acetyltransferase (HAT) found in a number of multisubunit complexes from Saccharomyces cerevisiae, mammals, and flies. We previously identified Drosophila melanogaster homologues of the yeast proteins Ada2, Ada3, Spt3, and Tra1 and showed that they associate with dGcn5 to form at least two distinct HAT complexes. There are two different Ada2 homologues in Drosophila named dAda2A and dAda2B. dAda2B functions within the Drosophila version of the SAGA complex (dSAGA). To gain insight into dAda2A function, we sought to identify novel components of the complex containing this protein, ATAC (Ada two A containing) complex. Affinity purification and mass spectrometry revealed that, in addition to dAda3 and dGcn5, host cell factor (dHCF) and a novel SANT domain protein, named Atac1 (ATAC component 1), copurify with this complex. Coimmunoprecipitation experiments confirmed that these proteins associate with dGcn5 and dAda2A, but not with dSAGA-specific components such as dAda2B and dSpt3. Biochemical fractionation revealed that ATAC has an apparent molecular mass of 700 kDa and contains dAda2A, dGcn5, dAda3, dHCF, and Atac1 as stable subunits. Thus, ATAC represents a novel histone acetyltransferase complex that is distinct from previously purified Gcn5/Pcaf-containing complexes from yeast and mammalian cells. PMID:16428443

  1. The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.

    PubMed

    Donato, Valerio; Bonora, Massimo; Simoneschi, Daniele; Sartini, Davide; Kudo, Yasusei; Saraf, Anita; Florens, Laurence; Washburn, Michael P; Stadtfeld, Matthias; Pinton, Paolo; Pagano, Michele

    2017-03-20

    Self-renewing naive mouse embryonic stem cells (mESCs) contain few mitochondria, which increase in number and volume at the onset of differentiation. KBP (encoded by Kif1bp) is an interactor of the mitochondrial-associated kinesin Kif1Bα. We found that TDH, responsible for mitochondrial production of acetyl-CoA in mESCs, and the acetyltransferase GCN5L1 cooperate to acetylate Lys501 in KBP, allowing its recognition by and degradation via Fbxo15, an F-box protein transcriptionally controlled by the pluripotency core factors and repressed following differentiation. Defects in KBP degradation in mESCs result in an unscheduled increase in mitochondrial biogenesis, enhanced respiration and ROS production, and inhibition of cell proliferation. Silencing of Kif1Bα reverts the aberrant increase in mitochondria induced by KBP stabilization. Notably, following differentiation, Kif1bp(-/-) mESCs display impaired expansion of the mitochondrial mass and form smaller embryoid bodies. Thus, KBP proteolysis limits the accumulation of mitochondria in mESCs to preserve their optimal fitness, whereas KBP accumulation promotes mitochondrial biogenesis in differentiating cells.

  2. Assessment of dual inhibition property of newly discovered inhibitors against PCAF and GCN5 through in silico screening, molecular dynamics simulation and DFT approach.

    PubMed

    Suryanarayanan, Venkatesan; Singh, Sanjeev Kumar

    2015-01-01

    p300/CBP-associated factor (PCAF) is one among the histone acetyltransferase (HAT) family enzymes. It is involved in the regulation of transcription by modifying the chromatin structure indirectly through the acetylation of histones. It has been emerged as a promising drug target for various types of cancer. A four-point pharmacophore with two hydrogen bond acceptor, one aromatic ring and one hydrophobic feature, was generated for six highly active isothiazolone derivatives as PCAF inhibitors in order to elucidate their anticancer activity. The generated pharmacophore was used for screening three different databases such as Maybridge, Life Chemicals and Chembridge databases. The screened compounds were further filtered through docking studies. Then the compounds were further carried for ADME prediction. The best three compounds BTB09406, F1418-0051 and F1880-1727 were docked to GCN5 to explore the dual inhibitory properties. The conformational stability of the protein-ligand complexes were analyzed through molecular dynamics simulation. Three best compounds were finally went through electronic structure analysis using density functional theory (DFT) at B3LYP/6-31**G level to understand their molecular reactivity. The results obtained from this study exploit that the three best compounds (BTB09406, F1418-0051 and F1880-1727) were found to have more potent and dual inhibitory properties.

  3. Play.

    ERIC Educational Resources Information Center

    Rogers, Fred; Sharapan, Hedda

    1993-01-01

    Contends that, in childhood, work and play seem to come together. Says that for young children their play is their work, and the more adults encourage children to play, the more they emphasize important lifelong resource. Examines some uses of children's play, making and building, artwork, dramatic play, monsters and superheroes, gun play, and…

  4. Play

    NASA Astrophysics Data System (ADS)

    Harteveld, Casper

    Designing a game with a serious purpose involves considering the worlds of Reality and Meaning yet it is undeniably impossible to create a game without a third world, one that is specifically concerned with what makes a game a game: the play elements. This third world, the world of people like designers and artists, and disciplines as computer science and game design, I call the world of Play and this level is devoted to it. The level starts off with some of the misperceptions people have of play. Unlike some may think, we play all the time, even when we grow old—this was also very noticeable in designing the game Levee Patroller as the team exhibited very playful behavior at many occasions. From there, I go into the aspects that characterize this world. The first concerns the goal of the game. This relates to the objectives people have to achieve within the game. This is constituted by the second aspect: the gameplay. Taking actions and facing challenges is subsequently constituted by a gameworld, which concerns the third aspect. And all of it is not possible without the fourth and final aspect, the type of technology that creates and facilitates the game. The four aspects together make up a “game concept” and from this world such a concept can be judged on the basis of three closely interrelated criteria: engagement, immersion, and fun.

  5. Human ADA3 regulates RARα transcriptional activity through direct contact between LxxLL motifs and the receptor coactivator pocket

    PubMed Central

    Li, Chia-Wei; Ai, Ni; Dinh, Gia Khanh; Welsh, William J.; Chen, J. Don

    2010-01-01

    The alternation/deficiency in activation-3 (ADA3) is an essential component of the human p300/CBP-associated factor (PCAF) and yeast Spt-Ada-Gcn5-acetyltransferase (SAGA) histone acetyltransferase complexes. These complexes facilitate transactivation of target genes by association with transcription factors and modification of local chromatin structure. It is known that the yeast ADA3 is required for nuclear receptor (NR)-mediated transactivation in yeast cells; however, the role of mammalian ADA3 in NR signaling remains elusive. In this study, we have investigated how the human (h) ADA3 regulates retinoic acid receptor (RAR) α-mediated transactivation. We show that hADA3 interacts directly with RARα in a hormone-dependent manner and this interaction contributes to RARα transactivation. Intriguingly, this interaction involves classical LxxLL motifs in hADA3, as demonstrated by both ‘loss’ and ‘gain’ of function mutations, as well as a functional coactivator pocket of the receptor. Additionally, we show that hADA3 associates with RARα target gene promoter in a hormone-dependent manner and ADA3 knockdown impairs RARβ2 expression. Furthermore, a structural model was established to illustrate an interaction network within the ADA3/RARα complex. These results suggest that hADA3 is a bona fide transcriptional coactivator for RARα, acting through a conserved mechanism involving direct contacts between NR boxes and the receptor’s co-activator pocket. PMID:20413580

  6. Maintenance of Glucose Homeostasis through Acetylation of the Metabolic Transcriptional Coactivator PGC1-alpha

    DTIC Science & Technology

    2009-02-01

    highlight that PGC-1α chemical acetylation is directly controlled by two enzymes: GCN5 and SIRT1 ; this strengths the possibility to use small...acetylated through GCN5 acetyltransferase activity, however under low nutrient conditions Sirt1 deacetylase will keep PGC-1α de-acetylated in an active form...acetylated by GCN5, we decided to use R13 because it did not respond to low glucose levels or Sirt1 activators. We think that the additional acetylation

  7. Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation following Endurance Exercise*

    PubMed Central

    Philp, Andrew; Chen, Ai; Lan, Debin; Meyer, Gretchen A.; Murphy, Anne N.; Knapp, Amy E.; Olfert, I. Mark; McCurdy, Carrie E.; Marcotte, George R.; Hogan, Michael C.; Baar, Keith; Schenk, Simon

    2011-01-01

    The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise. PMID:21757760

  8. The crystal structure of Rv1347c, a putative antibiotic resistance protein from Mycobacterium tuberculosis, reveals a GCN5-related fold and suggests an alternative function in siderophore biosynthesis

    SciTech Connect

    Card, G L; Peterson, N A; Smith, C A; Rupp, B; Schick, B M; Baker, E N

    2005-02-15

    Mycobacterium tuberculosis, the cause of TB, is a devastating human pathogen. The emergence of multi-drug resistance in recent years has prompted a search for new drug targets and for a better understanding of mechanisms of resistance. Here we focus on the gene product of an open reading frame from M. tuberculosis, Rv1347c, which is annotated as a putative aminoglycoside N-acetyltransferase. The Rv1347c protein does not show this activity, however, and we show from its crystal structure, coupled with functional and bioinformatic data, that its most likely role is in the biosynthesis of mycobactin, the M. tuberculosis siderophore. The crystal structure of Rv1347c was determined by MAD phasing from selenomethionine-substituted protein and refined at 2.2 {angstrom} resolution (R = 0.227, R{sub free} = 0.257). The protein is monomeric, with a fold that places it in the GCN5-related N-acetyltransferase (GNAT) family of acyltransferases. Features of the structure are an acylCoA binding site that is shared with other GNAT family members, and an adjacent hydrophobic channel leading to the surface that could accommodate long-chain acyl groups. Modeling the postulated substrate, the N{sup {var_epsilon}}-hydroxylysine side chain of mycobactin, into the acceptor substrate binding groove identifies two residues at the active site, His130 and Asp168, that have putative roles in substrate binding and catalysis.

  9. Maintenance of Glucose Homeostasis through Acetylation of the Metabolic Transcriptional Coactivator PGC-1alpha

    DTIC Science & Technology

    2008-02-01

    GCN5 in cells using adenoviruses that encode both proteins. 12 hours before harvesting, cells were treated with nicotinamide (a SIRT1 deacetylase...Hepatic SIRT1 . Proc. Natl. Acad. Sci. USA. 2007 104(31) 12861-12866. C. Lerin, T.J. Kelly, W. Haas, S.P. Gygi, and P. Puigserver. GCN5-Mediated...Puigserver. Metabolic Adaptations Through PGC-1α and SIRT1 Pathways. FEBS Letters. 582: 46-53. 2008 - University of Utah. Department of

  10. PGC-1 coactivators in cardiac development and disease

    PubMed Central

    Rowe, Glenn C.; Jiang, Aihua; Arany, Zolt

    2010-01-01

    The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last ten years have seen a resurgent interest in cardiac intermediary metabolism, and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-gamma coactivator (PGC)-1 family of proteins plays a central role in these pathways. The mechanisms by which PGC-1 proteins regulate transcriptional networks and are regulated by physiological cues, and the roles they play in cardiac development and disease, are reviewed here. PMID:20884884

  11. Maintenance of Glucose Homeostasis Through Acetylation of the Metabolic Transcriptional Coactivator PGC1-alpha

    DTIC Science & Technology

    2011-02-01

    transcriptional components have been identified that control gene expression of these enzymes including transcription factors CREB, FOXO1, HNF4a, GR and C /EBPs...estingly, the repression of PGC-1a by GCN5 also affected the mitochondrial genes cytochrome c and b-ATP-synthase (Figure 5A). These results indicate that...zymatic activity may provide a target for therapeutic drugs to435 A R T I C L EFigure 6. Inhibition of gluconeogenic gene expres- sion by GCN5

  12. A B-cell coactivator of octamer-binding transcription factors.

    PubMed

    Gstaiger, M; Knoepfel, L; Georgiev, O; Schaffner, W; Hovens, C M

    1995-01-26

    The octamer motif (ATGCAAAT) paradoxically plays a central role in mediating the activity of both B-cell specific and ubiquitous promoters. It has been widely assumed that the predominantly lymphoid-restricted octamer-binding factor Oct-2 mediates tissue-specific promoter activity, whereas the ubiquitously expressed Oct-1 mediates general promoter activity, but this view has been challenged. Here we use a modified yeast one-hybrid assay to isolate a B-cell factor, Bob1, which associates with either Oct-2 or Oct-1. In transfection experiments, this factor boosts Oct-1-mediated promoter activity and to a lesser extent, that of Oct-2. This coactivation is strictly dependent on the specific interaction with Oct-1 or Oct-2 because deletion of the octamer motif abolishes coactivation. We conclude that Bob1 could represent a new tissue-specific transcriptional coactivator which may convert a ubiquitously expressed transcription factor to a cell-type-specific activator.

  13. Fluorescence anisotropy microplate assay to investigate the interaction of full-length steroid receptor coactivator-1a with steroid receptors

    PubMed Central

    Zhang, Chen; Nordeen, Steven K.; Shapiro, David J.

    2013-01-01

    Estrogens, acting via estrogen receptor (ER) play key roles in growth, differentiation and gene regulation in the reproductive, central nervous and skeletal systems. ER-mediated gene transcription contributes to the development and spread of breast, uterine, and liver cancer. Steroid receptor coactivator-1a (SRC1a) belongs to the P160 family of coactivators, which is the best known of the many coactivators implicated in ER-mediated transactivation. Binding of full-length P160 coactivators to steroid receptors has been difficult to investigate in vitro. This chapter details how to investigate the interaction of SRC1a with ER using the fluorescence anisotropy/polarization microplate assay (FAMA). PMID:23436375

  14. Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator.

    PubMed

    Takeshita, A; Yen, P M; Misiti, S; Cardona, G R; Liu, Y; Chin, W W

    1996-08-01

    Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that regulate target gene transcription. The conserved carboxy-terminal region of the ligand-binding domain (AF-2) has been thought to play a critical role in mediating ligand-dependent transactivation by the interaction with coactivator(s). Using bacterially-expressed TR as a probe, far-Western-based expression cDNA library screening identified cDNAs that encode, in part, the recently reported partial steroid receptor coactivator-1 (SRC-1) sequence. Additional work, including 5' RACE, has characterized a full-length cDNA that encodes a approximately 160 kD protein as a putative thyroid hormone receptor coactivator (F-SRC-1). In vitro binding studies show that F-SRC-1 binds to a variety of nuclear hormone receptors in a ligand-dependent manner, along with TBP and TFIIB, suggesting that F-SRC-1 may play a role as a bridging molecule between nuclear hormone receptors and general transcription factors. Interestingly, AF-2 mutants also retain ligand-dependent interaction with F-SRC-1. Although F-SRC-1 recognizes the ligand-induced conformational changes of nuclear hormone receptors, our observations suggest that F-SRC-1 may bind directly with subregion(s) in nuclear hormone receptors other than the AF-2 region.

  15. Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

    SciTech Connect

    Kanno, Yuichiro Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

    2015-03-27

    The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR.

  16. The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators.

    PubMed

    Teo, Jia-Ling; Kahn, Michael

    2010-09-30

    Wnt signaling pathways play divergent roles during development, normal homeostasis and disease. The responses that result from the activation of the pathway control both proliferation and differentiation. Tight regulation and controlled coordination of the Wnt signaling cascade is required to maintain the balance between proliferation and differentiation. The non-redundant roles of the coactivator proteins CBP and p300, within the context of Wnt signaling are discussed. We highlight their roles as integrators of the various inputs that a cell receives to elicit the correct and coordinated response. We propose that essentially all cellular information - i.e. from other signaling pathways, nutrient levels, etc. - is funneled down into a choice of coactivators usage, either CBP or p300, by their interacting partner beta-catenin (or catenin-like molecules in the absence of beta-catenin) to make the critical decision to either remain quiescent, or once entering cycle to proliferate without differentiation or to initiate the differentiation process.

  17. Exploiting receptor tyrosine kinase co-activation for cancer therapy

    PubMed Central

    Tan, Aik-Choon; Vyse, Simon; Huang, Paul H

    2017-01-01

    Studies over the past decade have shown that Receptor Tyrosine Kinase (RTK) co-activation is prevalent in many cancer types. Compelling data demonstrates that cancers are likely to have evolved RTK co-activation as a generic means for driving tumour growth and providing a buffering system to limit the lethal effects of microenvironmental insults including therapy. In this review, we summarise the general principles of RTK co-activation gleaned from key studies over the last decade. We discuss direct and indirect approaches to exploit RTK co-activation for cancer therapy and describe recent developments in computational approaches to predict kinase co-dependencies by integrating drug screening data and kinase inhibitor selectivity profiles. We offer a perspective on the outstanding questions in the field focusing on the implications of RTK co-activation on tumour heterogeneity and cancer evolution and conclude by surveying emerging computational and experimental approaches that will provide further insights into the biology of RTK co-activation and deliver new developments in effective cancer therapies. PMID:27452454

  18. Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions

    PubMed Central

    Scholes, Natalie S.; Weinzierl, Robert O. J.

    2016-01-01

    Transcriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relationships of such contacts. Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 AD and variants thereof, either free in solution, or bound to the GAL11 coactivator surface. We show that the AD-coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points. We also demonstrate that a prediction of α-helical propensity correlates directly with the experimentally measured transactivation potential of a large set of mutagenized ADs. The link between α-helical propensity and the stimulatory activity of ADs has fundamental practical and theoretical implications concerning the recruitment of ADs to coactivators. PMID:27175900

  19. Co-activation Probability Estimation (CoPE): An approach for modeling functional co-activation architecture based on neuroimaging coordinates

    PubMed Central

    Chu, Congying; Fan, Lingzhong; Eickhoff, Claudia R.; Liu, Yong; Yang, Yong; Eickhoff, Simon B.; Jiang, Tianzi

    2016-01-01

    Recent progress in functional neuroimaging has prompted studies of brain activation during various cognitive tasks. Coordinate-based meta-analysis has been utilized to discover the brain regions that are consistently activated across experiments. However, within-experiment co-activation relationships, which can reflect the underlying functional relationships between different brain regions, have not been widely studied. In particular, voxel-wise co-activation, which may be able to provide a detailed configuration of the co-activation network, still needs to be modeled. To estimate the voxel-wise co-activation pattern and deduce the co-activation network, a Co-activation Probability Estimation (CoPE) method was proposed to model within-experiment activations for the purpose of defining the co-activations. A permutation test was adopted as a significance test. Moreover, the co-activations were automatically separated into local and long-range ones, based on distance. The two types of co-activations describe distinct features: the first reflects convergent activations; the second represents co-activations between different brain regions. The validation of CoPE was based on five simulation tests and one real dataset derived from studies of working memory. Both the simulated and the real data demonstrated that CoPE was not only able to find local convergence but also significant long-range co-activation. In particular, CoPE was able to identify a ‘core’ co-activation network in the working memory dataset. As a data-driven method, the CoPE method can be used to mine underlying co-activation relationships across experiments in future studies. PMID:26037052

  20. A Coactive Sign System for Children Who Are Dual-Sensory Impaired.

    ERIC Educational Resources Information Center

    Watkins, Susan; Clark, Thomas C.

    1991-01-01

    The SKI*HI Institute (Utah) has developed a system of coactive signing for children who are deaf and blind. The system includes optimized coactive signs that are functional, easy to feel, easy to relate to the referent, and easy to make. It also includes techniques for effective coactive sign use. Videotapes of lessons are described. (Author/DB)

  1. Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor α activity and co-activator synergy

    PubMed Central

    Ji Yu, Eun; Kim, Seok-Hyung; Heo, Kyu; Ou, Chen-Yin; Kim, Jeong Hoon

    2011-01-01

    Estrogen receptor α (ERα) plays critical roles in development and progression of breast cancer. Because ERα activity is strictly dependent upon the interaction with coregulators, coregulators are also believed to contribute to breast tumorigenesis. Cell Cycle and Apoptosis Regulator 1 (CCAR1) is an important co-activator for estrogen-induced gene expression and estrogen-dependent growth of breast cancer cells. Here, we identified Deleted in Breast Cancer 1 (DBC1) as a CCAR1 binding protein. DBC1 was recently shown to function as a negative regulator of the NAD-dependent protein deacetylase SIRT1. DBC1 associates directly with ERα and cooperates synergistically with CCAR1 to enhance ERα function. DBC1 is required for estrogen-induced expression of a subset of ERα target genes as well as breast cancer cell proliferation and for estrogen-induced recruitment of ERα to the target promoters in a gene-specific manner. The mechanism of DBC1 action involves inhibition of SIRT1 interaction with ERα and of SIRT1-mediated deacetylation of ERα. SIRT1 also represses the co-activator synergy between DBC1 and CCAR1 by binding to DBC1 and disrupting its interaction with CCAR1. Our results indicate that DBC1 and SIRT1 play reciprocal roles as major regulators of ERα activity, by regulating DNA binding by ERα and by regulating co-activator synergy. PMID:21596782

  2. Outdoor Play and Play Equipment.

    ERIC Educational Resources Information Center

    Naylor, Heather

    1985-01-01

    Discusses aspects of the play environment and its effect on children's play behavior. Indoor and outdoor play spaces are considered along with factors affecting the use of outdoor environments for play. Children's preferences for different outdoor play environments and for various play structures are explored. Guides for choosing play equipment…

  3. Transcription Coactivators p300 and CBP Are Necessary for Photoreceptor-Specific Chromatin Organization and Gene Expression

    PubMed Central

    Hennig, Anne K.; Peng, Guang-Hua; Chen, Shiming

    2013-01-01

    Rod and cone photoreceptor neurons in the mammalian retina possess specialized cellular architecture and functional features for converting light to a neuronal signal. Establishing and maintaining these characteristics requires appropriate expression of a specific set of genes, which is tightly regulated by a network of photoreceptor transcription factors centered on the cone-rod homeobox protein CRX. CRX recruits transcription coactivators p300 and CBP to acetylate promoter-bound histones and activate transcription of target genes. To further elucidate the role of these two coactivators, we conditionally knocked out Ep300 and/or CrebBP in differentiating rods or cones, using opsin-driven Cre recombinase. Knockout of either factor alone exerted minimal effects, but loss of both factors severely disrupted target cell morphology and function: the unique nuclear chromatin organization seen in mouse rods was reversed, accompanied by redistribution of nuclear territories associated with repressive and active histone marks. Transcription of many genes including CRX targets was severely impaired, correlating with reduced histone H3/H4 acetylation (the products of p300/CBP) on target gene promoters. Interestingly, the presence of a single wild-type allele of either coactivator prevented many of these defects, with Ep300 more effective than Cbp. These results suggest that p300 and CBP play essential roles in maintaining photoreceptor-specific structure, function and gene expression. PMID:23922782

  4. Development of Novel Vitamin D Receptor–Coactivator Inhibitors

    PubMed Central

    2014-01-01

    Nuclear receptor coregulators are master regulators of transcription and selectively interact with the vitamin D receptor (VDR) to modulate cell differentiation, cell proliferation, and calcium homeostasis. Herein, we report the syntheses and evaluation of highly potent and selective VDR–coactivator inhibitors based on a recently identified 3-indolylmethanamine scaffold. The most active compound, PS121912, selectively inhibited VDR-mediated transcription among eight other nuclear receptors tested. PS121912 is also selectively disrupting the binding between VDR and the third nuclear receptor interaction domain of the coactivator SRC2. Genetic studies revealed that PS121912 behaves like a VDR antagonist by repressing 1,25-(OH)2D3 activated gene transcription. In addition, PS121912 induced apoptosis in HL-60. PMID:24799995

  5. Playful Gaming.

    ERIC Educational Resources Information Center

    Makedon, Alexander

    A philosophical analysis of play and games is undertaken in this paper. Playful gaming, which is shown to be a synthesis of play and games, is utilized as a category for undertaking the examination of play and games. The significance of playful gaming to education is demonstrated through analyses of Plato's, Dewey's, Sartre's, and Marcuse's…

  6. Can co-activation reduce kinematic variability? A simulation study.

    PubMed

    Selen, Luc P J; Beek, Peter J; van Dieën, Jaap H

    2005-11-01

    Impedance modulation has been suggested as a means to suppress the effects of internal 'noise' on movement kinematics. We investigated this hypothesis in a neuro-musculo-skeletal model. A prerequisite is that the muscle model produces realistic force variability. We found that standard Hill-type models do not predict realistic force variability in response to variability in stimulation. In contrast, a combined motor-unit pool model and a pool of parallel Hill-type motor units did produce realistic force variability as a function of target force, largely independent of how the force was transduced to the tendon. To test the main hypothesis, two versions of the latter model were simulated as an antagonistic muscle pair, controlling the position of a frictionless hinge joint, with a distal segment having realistic inertia relative to the muscle strength. Increasing the impedance through co-activation resulted in less kinematic variability, except for the lowest levels of co-activation. Model behavior in this region was affected by the noise amplitude and the inertial properties of the model. Our simulations support the idea that muscular co-activation is in principle an effective strategy to meet accuracy demands.

  7. Promoter-specific co-activation by Drosophila Mastermind

    PubMed Central

    Caudy, Michael A.

    2008-01-01

    Mastermind (Mam) is a co-activator protein of binary complexes consisting of Suppressor of Hairless (Su(H)) and Notch Intracellular Domain (NICD) proteins assembled on cis-regulatory regions of target genes activated by Notch signaling. Current evidence indicates that Mastermind is necessary and sufficient for the formation of a functional Su(H)/NICD/Mam ternary complex on at least one specific architecture of Su(H) binding sites, called the SPS element (Su(H) Paired Sites). However, using transcription assays with a combination of native and synthetic Notch target gene promoters in Drosophila cultured cells, we show here that co-activation of Su(H)/NICD complexes on SPS elements by Mam is promoter-specific. Our novel results suggest this promoter specificity is mediated by additional unknown cis-regulatory elements present in the native promoters that are required for the recruitment of Mam and formation of functional Su(H)/NICD/Mam complexes on SPS elements. Together, the findings in this study suggest Mam is not always necessary and sufficient for co-activation of binary Su(H)/NICD complexes on SPS elements. PMID:18930034

  8. PGC-1-Related Coactivator, a Novel, Serum-Inducible Coactivator of Nuclear Respiratory Factor 1-Dependent Transcription in Mammalian Cells

    PubMed Central

    Andersson, Ulf; Scarpulla, Richard C.

    2001-01-01

    The thermogenic peroxisome proliferator-activated receptor γ (PPAR-γ) coactivator 1 (PGC-1) has previously been shown to activate mitochondrial biogenesis in part through a direct interaction with nuclear respiratory factor 1 (NRF-1). In order to identify related coactivators that act through NRF-1, we searched the databases for sequences with similarities to PGC-1. Here, we describe the first characterization of a 177-kDa transcriptional coactivator, designated PGC-1-related coactivator (PRC). PRC is ubiquitously expressed in murine and human tissues and cell lines; but unlike PGC-1, PRC was not dramatically up-regulated during thermogenesis in brown fat. However, its expression was down-regulated in quiescent BALB/3T3 cells and was rapidly induced by reintroduction of serum, conditions where PGC-1 was not detected. PRC activated NRF-1-dependent promoters in a manner similar to that observed for PGC-1. Moreover, NRF-1 was immunoprecipitated from cell extracts by antibodies directed against PRC, and both proteins were colocalized to the nucleoplasm by confocal laser scanning microscopy. PRC interacts in vitro with the NRF-1 DNA binding domain through two distinct recognition motifs that are separated by an unstructured proline-rich region. PRC also contains a potent transcriptional activation domain in its amino terminus adjacent to an LXXLL motif. The spatial arrangement of these functional domains coincides with those found in PGC-1, supporting the conclusion that PRC and PGC-1 are structurally and functionally related. We conclude that PRC is a functional relative of PGC-1 that operates through NRF-1 and possibly other activators in response to proliferative signals. PMID:11340167

  9. Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible factor 1α.

    PubMed

    Zhao, Wei; Chang, Cunjie; Cui, Yangyan; Zhao, Xiaozhi; Yang, Jun; Shen, Lan; Zhou, Ji; Hou, Zhibo; Zhang, Zhen; Ye, Changxiao; Hasenmayer, Donald; Perkins, Robert; Huang, Xiaojing; Yao, Xin; Yu, Like; Huang, Ruimin; Zhang, Dianzheng; Guo, Hongqian; Yan, Jun

    2014-04-18

    Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as "Warburg effect," to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

  10. The role of peroxisome proliferator-activated receptor-coactivator-1 gene in skin aging

    PubMed Central

    Aghaei, Shahrzad; Nilforoushzadeh, Mohammad Ali; Aghaei, Maryam

    2016-01-01

    Skin aging is a continuous process that exhibits fine and deep wrinkles, thin and transparent skin, loss of underlying fat, dry skin and itch, following decreased collagen and elastin synthesis. Both extrinsic and intrinsic agents are considered in the pathogenesis on skin aging. Extrinsic factors such as sun exposure, windy and dry weather, nutrition, and lifestyle may induce premature aging, toxic-free radicals, and reactive oxygen species due to decreasing normal function of mitochondria which play the major intrinsic factors in premature skin aging. One of the major genetic factors in mitochondrial function is peroxisome proliferator-activated receptor-coactivator-1 (PGC-1) gene. This factor could delay skin aging by increasing the mitochondrial biogenesis and replication and oxidative phosphorylation and so may induce free radical scavenging. This review is focused on intrinsic skin aging and the role of PGC-1 protein in decreasing effect of aging causes. PMID:27904582

  11. CRTC2 Is a Coactivator of GR and Couples GR and CREB in the Regulation of Hepatic Gluconeogenesis.

    PubMed

    Hill, Micah J; Suzuki, Shigeru; Segars, James H; Kino, Tomoshige

    2016-01-01

    Glucocorticoid hormones play essential roles in the regulation of gluconeogenesis in the liver, an adaptive response that is required for the maintenance of circulating glucose levels during fasting. Glucocorticoids do this by cooperating with glucagon, which is secreted from pancreatic islets to activate the cAMP-signaling pathway in hepatocytes. The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting. We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. CRTC2 physically interacts with the ligand-binding domain of the GR through a region spanning amino acids 561-693. Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB. CRTC2 is required for the maintenance of blood glucose levels during fasting in mice by enhancing the GR transcriptional activity on both the G6p and phosphoenolpyruvate carboxykinase (Pepck) genes. Finally, CRTC2 modulates the transcriptional activity of the progesterone receptor, indicating that it may influence the transcriptional activity of other steroid/nuclear receptors. Taken together, these results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.

  12. Play Therapy

    PubMed Central

    Kool, Ritesh

    2010-01-01

    Play therapy represents a unique form of treatment that is not only geared toward young children, but is translated into a language children can comprehend and utilize—the language of play. For the referring provider or practitioner, questions may remain regarding the nature, course, and efficacy of play therapy. This article reviews the theoretical underpinnings of play therapy, some practical considerations, and finally a summary of the current state of research in regard to play therapy. The authors present the practicing psychiatrist with a road map for referring a patient to play therapy or initiating it in appropriate cases. PMID:21103141

  13. City Play.

    ERIC Educational Resources Information Center

    Dargan, Amanda; Zeitlin, Steve

    2000-01-01

    Today, fewer city blocks preserve the confidence of lifestyle and urban geography that sustain traditional games and outdoor play. Large groups of children choosing sides and organizing Red Rover games are no longer commonplace. Teachers must encourage free play; urban planners must build cities that are safe play havens. (MLH)

  14. Coactivator Recruitment of AhR/ARNT1

    PubMed Central

    Endler, Alexander; Chen, Li; Shibasaki, Futoshi

    2014-01-01

    A common feature of nuclear receptors (NRs) is the transformation of external cell signals into specific transcriptions of the signal molecule. Signal molecules function as ligands for NRs and, after their uptake, activated NRs form homo- or heterodimers at promoter recognition sequences of the specific genes in the nucleus. Another common feature of NRs is their dependence on coactivators, which bridge the basic transcriptional machinery and other cofactors to the target genes, in order to initiate transcription and to unwind histone-bound DNA for exposing additional promoter recognition sites via their histone acetyltransferase (HAT) function. In this review, we focus on our recent findings related to the recruitment of steroid receptor coactivator 1 (SRC1/NCoA1) by the estrogen receptor-α (ERα) and by the arylhydrocarbon receptor/arylhydrocarbon receptor nuclear translocator 1 (AhR/ARNT1) complex. We also describe the extension of our previously published findings regarding the binding between ARNT1.1 exon16 and SRC1e exon 21, via in silico analyses of androgen receptor (AR) NH2-carboxyl-terminal interactions, the results of which were verified by in vitro experiments. Based on these data, we suggest a newly derived tentative binding site of nuclear coactivator 2/glucocorticoid receptor interacting protein-1/transcriptional intermediary factor 2 (NCOA-2/ GRIP-1/TIF-2) for ARNT1.1 exon 16. Furthermore, results obtained by immunoprecipitation have revealed a second leucine-rich binding site for hARNT1.1 exon 16 in SRC1e exon 21 (LSSTDLL). Finally, we discuss the role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an endocrine disruptor for estrogen related transcription. PMID:24950180

  15. The Role of Steroid Receptor Coactivator-1 in Breat Cancer

    DTIC Science & Technology

    2000-06-01

    Mifepristone (RU486): a review. Fertil Steril, 68, 967-976. McKenna, N.J., Lanz, R.B. and O’Malley, B.W. (1999) Nuclear receptor coregulators: cellular...histones has long been known to be SRC-1. In addition. LXXLL motifs within a given cor- an important preface to transcriptional activity in vito ...to act as tran- The discovery that p300. CBP and a p300’CBP as- scriptional coactivators for a host of diverse sociated factor (PCAF) all contained

  16. Quadriceps and Hamstrings Coactivation During Common Therapeutic Exercises

    PubMed Central

    Begalle, Rebecca L.; DiStefano, Lindsay J.; Blackburn, Troy; Padua, Darin A.

    2012-01-01

    Context Anterior tibial shear force and knee valgus moment increase anterior cruciate ligament (ACL) loading. Muscle coactivation of the quadriceps and hamstrings influences anterior tibial shear force and knee valgus moment, thus potentially influencing ACL loading and injury risk. Therefore, identifying exercises that facilitate balanced activation of the quadriceps and hamstrings might be beneficial in ACL injury rehabilitation and prevention. Objective To quantify and compare quadriceps with hamstrings coactivation electromyographic (EMG) ratios during commonly used closed kinetic chain exercises. Design Cross-sectional study. Setting Research laboratory. Patients or Other Participants Twenty-seven healthy, physically active volunteers (12 men, 15 women; age = 22.1 ± 3.1 years, height = 171.4 ± 10 cm, mass = 72.4 ± 16.7 kg). Intervention(s) Participants completed 9 separate closed chain therapeutic exercises in a randomized order. Main Outcome Measure(s) Surface electromyography quantified the activity level of the vastus medialis (VM), vastus lateralis (VL), medial hamstrings (MH), and biceps femoris (BF) muscles. The quadriceps-to-hamstrings (Q:H) coactivation ratio was computed as the sum of average quadriceps (VM, VL) EMG amplitude divided by the sum of average hamstrings (MH, BF) EMG amplitude for each trial. We used repeated-measures analyses of variance to compare Q:H ratios and individual muscle contributions across exercises (α = .05), then used post hoc Tukey analyses. Results We observed a main effect for exercise (F3,79 = 22.6, P < .001). The post hoc Tukey analyses revealed smaller Q:H ratios during the single-limb dead lift (2.87 ± 1.77) than the single-limb squat (5.52 ± 2.89) exercise. The largest Q:H ratios were observed during the transverse-lunge (7.78 ± 5.51, P < .001), lateral-lunge (9.30 ± 5.53, P < .001), and forward-lunge (9.70 ± 5.90, P < .001) exercises. Conclusions The most balanced (smallest) coactivation ratios were

  17. Play Therapy

    PubMed Central

    Lawver, Timothy; Blankenship, Kelly

    2008-01-01

    Play therapy is a treatment modality in which the therapist engages in play with the child. Its use has been documented in a variety of settings and with a variety of diagnoses. Treating within the context of play brings the therapist and the therapy to the level of the child. By way of an introduction to this approach, a case is presented of a six-year-old boy with oppositional defiant disorder. The presentation focuses on the events and interactions of a typical session with an established patient. The primary issues of the session are aggression, self worth, and self efficacy. These themes manifest themselves through the content of the child’s play and narration of his actions. The therapist then reflects these back to the child while gently encouraging the child toward more positive play. Though the example is one of nondirective play therapy, a wide range of variation exists under the heading of play therapy. PMID:19724720

  18. Sertad1 encodes a novel transcriptional co-activator of SMAD1 in mouse embryonic hearts

    SciTech Connect

    Peng, Yin; Zhao, Shaomin; Song, Langying; Wang, Manyuan; Jiao, Kai

    2013-11-29

    Highlights: •SERTAD1 interacts with SMAD1. •Sertad1 is expressed in mouse embryonic hearts. •SERTAD1 is localized in both cytoplasm and nucleus of cardiomyocytes. •SERTAD1 enhances expression of BMP target cardiogenic genes as a SMAD1 co-activator. -- Abstract: Despite considerable advances in surgical repairing procedures, congenital heart diseases (CHDs) remain the leading noninfectious cause of infant morbidity and mortality. Understanding the molecular/genetic mechanisms underlying normal cardiogenesis will provide essential information for the development of novel diagnostic and therapeutic strategies against CHDs. BMP signaling plays complex roles in multiple cardiogenic processes in mammals. SMAD1 is a canonical nuclear mediator of BMP signaling, the activity of which is critically regulated through its interaction partners. We screened a mouse embryonic heart yeast two-hybrid library using Smad1 as bait and identified SERTAD1 as a novel interaction partner of SMAD1. SERTAD1 contains multiple potential functional domains, including two partially overlapping transactivation domains at the C terminus. The SERTAD1-SMAD1 interaction in vitro and in mammalian cells was further confirmed through biochemical assays. The expression of Sertad1 in developing hearts was demonstrated using RT-PCR, western blotting and in situ hybridization analyses. We also showed that SERTAD1 was localized in both the cytoplasm and nucleus of immortalized cardiomyocytes and primary embryonic cardiomyocyte cultures. The overexpression of SERTAD1 in cardiomyocytes not only enhanced the activity of two BMP reporters in a dose-dependent manner but also increased the expression of several known BMP/SMAD regulatory targets. Therefore, these data suggest that SERTAD1 acts as a SMAD1 transcriptional co-activator to promote the expression of BMP target genes during mouse cardiogenesis.

  19. The Steroid Receptor Coactivator-3 Is Required for the Development of Castration-resistant Prostate Cancer

    PubMed Central

    Tien, Jean Ching-Yi; Liu, Zhaoliang; Liao, Lan; Wang, Fen; Xu, Yixiang; Wu, Ye-Lin; Zhou, Niya; Ittmann, Michael; Xu, Jianming

    2013-01-01

    The transcriptional coactivator SRC-3 plays a key role to enhance prostate cancer (CaP) cell proliferation. Although SRC-3 is highly expressed in advanced CaP, its role in castration resistant CaP (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human CaP. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both Pten and SRC-3 were inactivated in prostate epithelial cells (Pten3CKO mice), comparing them to mice in which only Pten was inactivated in these cells (PtenCKO mice). SRC-3 deletion impaired cellular proliferation and reduced tumor size. Notably, while castration of PtenCKO control mice increased the aggressiveness of prostate tumors relative to non-castrated counterparts, deletion of SRC-3 in Pten3CKO mice reversed all these changes. In support of this finding, castrated Pten3CKO mice also exhibited decreased levels of phospho-Akt, S6 kinase (RPS6KB1) and phosphorylated S6 protein (RPS6), all of which mediate cell growth and proliferation. Moreover, these tumors appeared to be more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. Lastly, these tumors also displayed lower levels of certain androgen-repressed genes such as cyclin E2 and MMP10. Together, our results show that SRC-3 drives CRPC formation and offer preclinical proof of concept for a transcriptional coactivator as a therapeutic target to abrogate CRPC progression. PMID:23650284

  20. Play Sheets. Let's Play! Project.

    ERIC Educational Resources Information Center

    State Univ. of New York, Buffalo. Center for Assistive Technology.

    This collection of play sheets for parents and early intervention personnel was developed by the "Let's Play! Project," a 3-year federally supported project that worked to promote play in infants and toddlers with disabilities through the use of "low-tech" assistive technology. Each single page guide provides guidance to…

  1. A histone chaperone, DEK, transcriptionally coactivates a nuclear receptor

    PubMed Central

    Sawatsubashi, Shun; Murata, Takuya; Lim, Jinseon; Fujiki, Ryoji; Ito, Saya; Suzuki, Eriko; Tanabe, Masahiko; Zhao, Yue; Kimura, Shuhei; Fujiyama, Sally; Ueda, Takashi; Umetsu, Daiki; Ito, Takashi; Takeyama, Ken-ichi; Kato, Shigeaki

    2010-01-01

    Chromatin reorganization is essential for transcriptional control by sequence-specific transcription factors. However, the molecular link between transcriptional control and chromatin reconfiguration remains unclear. By colocalization of the nuclear ecdysone receptor (EcR) on the ecdysone-induced puff in the salivary gland, Drosophila DEK (dDEK) was genetically identified as a coactivator of EcR in both insect cells and intact flies. Biochemical purification and characterization of the complexes containing fly and human DEKs revealed that DEKs serve as histone chaperones via phosphorylation by forming complexes with casein kinase 2. Consistent with the preferential association of the DEK complex with histones enriched in active epigenetic marks, dDEK facilitated H3.3 assembly during puff formation. In some human myeloid leukemia patients, DEK was fused to CAN by chromosomal translocation. This mutation significantly reduced formation of the DEK complex, which is required for histone chaperone activity. Thus, the present study suggests that at least one histone chaperone can be categorized as a type of transcriptional coactivator for nuclear receptors. PMID:20040570

  2. Measuring Mathematics Teachers' Professional Competence by Using Video Clips (COACTIV Video)

    ERIC Educational Resources Information Center

    Bruckmaier, G.; Krauss, S.; Blum, W.; Leiss, D.

    2016-01-01

    The COACTIV video study is part of the COACTIV research program in which secondary mathematics teachers whose students participated in PISA 03/04 were examined, with respect to their professional knowledge, motivational orientations, beliefs, and self-regulation. In the video study, 284 German secondary mathematics teachers were asked to specify…

  3. Coactivation of Lower Limb Muscles during Gait in Patients with Multiple Sclerosis

    PubMed Central

    Boudarham, Julien; Hameau, Sophie; Zory, Raphael; Hardy, Alexandre; Bensmail, Djamel; Roche, Nicolas

    2016-01-01

    Background Coactivation of agonist and antagonist lower limb muscles during gait stiffens joints and ensures stability. In patients with multiple sclerosis, coactivation of lower limb muscles might be a compensatory mechanism to cope with impairments of balance and gait. Objective The aim of this study was to assess coactivation of agonist and antagonist muscles at the knee and ankle joints during gait in patients with multiple sclerosis, and to evaluate the relationship between muscle coactivation and disability, gait performance, dynamic ankle strength measured during gait, and postural stability. Methods The magnitude and duration of coactivation of agonist-antagonist muscle pairs at the knee and ankle were determined for both lower limbs (more and less-affected) in 14 patients with multiple sclerosis and 11 healthy subjects walking at a spontaneous speed, using 3D-gait analysis. Results In the patient group, coactivation was increased in the knee muscles during single support (proximal strategy) and in the ankle muscles during double support (distal strategy). The magnitude of coactivation was highest in the patients with the slowest gait, the greatest motor impairment and the most instability. Conclusion Increased muscle coactivation is likely a compensatory mechanism to limit the number of degrees of freedom during gait in patients with multiple sclerosis, particularly when postural stability is impaired. PMID:27336442

  4. Why Play?

    ERIC Educational Resources Information Center

    Weininger, O.

    This paper draws together briefly theories and knowledge from research in morphology and cognitive psychology, as well as some hypothetical information from traditional psychiatry, to show the ramifications of play in children's development. Play is defined as any of a wide variety of behaviors through which an individual attempts to discover what…

  5. Playful Gaming.

    ERIC Educational Resources Information Center

    Makedon, Alex

    1984-01-01

    Discusses the concept of playful gaming (an idea not expressed fully by either term alone) and uses it as an analytical tool to study the playfulness of games in the context of several social phenomena; i.e., social change, socialization, utopian systems, and educational gaming. An extensive reference list is provided. (MBR)

  6. Playing Shakespeare.

    ERIC Educational Resources Information Center

    Bashian, Kathleen Ryniker

    1993-01-01

    Describes a yearlong project at 12 Catholic middle schools in the Diocese of Arlington, Virginia, to incorporate the plays of William Shakespeare into the curriculum. Teachers attended university lectures and directed students in performances of the plays. Concludes that Shakespeare can be understood and enjoyed by middle school students. (BCY)

  7. Shadow Play

    ERIC Educational Resources Information Center

    Trundle, Kathy Cabe; Hilson, Margilee P.

    2012-01-01

    A bunny rabbit playfully hops across the wall. Then hands realign and fingers shift to make a hawk soar toward the ceiling. Most children have enjoyed the delightful experience of playing with shadow puppets. The authors build on this natural curiosity to help students link shadows to complex astronomical concepts such as seasons. The…

  8. Expression, purification, crystallization and preliminary crystallographic study of isolated modules of the mouse coactivator-associated arginine methyltransferase 1

    SciTech Connect

    Troffer-Charlier, Nathalie; Cura, Vincent; Hassenboehler, Pierre; Moras, Dino; Cavarelli, Jean

    2007-04-01

    Isolated modules of mouse coactivator-associated arginine methyltransferase 1 encompassing the protein arginine N-methyltransferase catalytic domain have been overexpressed, purified and crystallized. X-ray diffraction data have been collected and have enabled determination of the structures by multiple isomorphous replacement using anomalous scattering. Coactivator-associated arginine methyltransferase 1 (CARM1) plays a crucial role in gene expression as a coactivator of several nuclear hormone receptors and also of non-nuclear receptor systems. Its recruitment by the transcriptional machinery induces protein methylation, leading to chromatin remodelling and gene activation. CARM1{sub 28–507} and two structural states of CARM1{sub 140–480} were expressed, purified and crystallized. Crystals of CARM1{sub 28–507} belong to space group P6{sub 2}22, with unit-cell parameters a = b = 136.0, c = 125.3 Å; they diffract to beyond 2.5 Å resolution using synchrotron radiation and contain one monomer in the asymmetric unit. The structure of CARM1{sub 28–507} was solved by multiple isomorphous replacement and anomalous scattering methods. Crystals of apo CARM1{sub 140–480} belong to space group I222, with unit-cell parameters a = 74.6, b = 99.0, c = 207.4 Å; they diffract to beyond 2.7 Å resolution and contain two monomers in the asymmetric unit. Crystals of CARM1{sub 140–480} in complex with S-adenosyl-l-homocysteine belong to space P2{sub 1}2{sub 1}2, with unit-cell parameters a = 74.6, b = 98.65, c = 206.08 Å; they diffract to beyond 2.6 Å resolution and contain four monomers in the asymmetric unit. The structures of apo and holo CARM1{sub 140–480} were solved by molecular-replacement techniques from the structure of CARM1{sub 28–507}.

  9. The protooncogene TCL1 is an Akt kinase coactivator.

    PubMed

    Laine, J; Künstle, G; Obata, T; Sha, M; Noguchi, M

    2000-08-01

    Human T cell prolymphocytic leukemia can result from chromosomal translocations involving 14q32.1 or Xq28 regions. The regions encode a family of protooncogenes (TCL1, MTCP1, and TCL1b) of unknown function. In yeast two-hybrid screening, we found that TCL1 interacts with Akt. All TCL1 isoforms bind to the Akt pleckstrin homology domain. Both in vitro and in vivo TCL1 increases Akt kinase activity and as a consequence enhances substrate phosphorylation. In vivo, TCL1 stabilizes the mitochondrial transmembrane potential and enhances cell proliferation and survival. In vivo, TCL1 forms trimers, which associate with Akt. TCL1 facilitates the oligomerization and activation of Akt. Our data show that TCL1 is a novel Akt kinase coactivator, which promotes Akt-induced cell survival and proliferation.

  10. Heterogeneous fractionation profiles of meta-analytic coactivation networks.

    PubMed

    Laird, Angela R; Riedel, Michael C; Okoe, Mershack; Jianu, Radu; Ray, Kimberly L; Eickhoff, Simon B; Smith, Stephen M; Fox, Peter T; Sutherland, Matthew T

    2017-04-01

    Computational cognitive neuroimaging approaches can be leveraged to characterize the hierarchical organization of distributed, functionally specialized networks in the human brain. To this end, we performed large-scale mining across the BrainMap database of coordinate-based activation locations from over 10,000 task-based experiments. Meta-analytic coactivation networks were identified by jointly applying independent component analysis (ICA) and meta-analytic connectivity modeling (MACM) across a wide range of model orders (i.e., d=20-300). We then iteratively computed pairwise correlation coefficients for consecutive model orders to compare spatial network topologies, ultimately yielding fractionation profiles delineating how "parent" functional brain systems decompose into constituent "child" sub-networks. Fractionation profiles differed dramatically across canonical networks: some exhibited complex and extensive fractionation into a large number of sub-networks across the full range of model orders, whereas others exhibited little to no decomposition as model order increased. Hierarchical clustering was applied to evaluate this heterogeneity, yielding three distinct groups of network fractionation profiles: high, moderate, and low fractionation. BrainMap-based functional decoding of resultant coactivation networks revealed a multi-domain association regardless of fractionation complexity. Rather than emphasize a cognitive-motor-perceptual gradient, these outcomes suggest the importance of inter-lobar connectivity in functional brain organization. We conclude that high fractionation networks are complex and comprised of many constituent sub-networks reflecting long-range, inter-lobar connectivity, particularly in fronto-parietal regions. In contrast, low fractionation networks may reflect persistent and stable networks that are more internally coherent and exhibit reduced inter-lobar communication.

  11. Transcriptional Coactivator PC4, a Chromatin-Associated Protein, Induces Chromatin Condensation▿ †

    PubMed Central

    Das, Chandrima; Hizume, Kohji; Batta, Kiran; Kumar, B. R. Prashanth; Gadad, Shrikanth S.; Ganguly, Semanti; Lorain, Stephanie; Verreault, Alain; Sadhale, Parag P.; Takeyasu, Kunio; Kundu, Tapas K.

    2006-01-01

    Human transcriptional coactivator PC4 is a highly abundant multifunctional protein which plays diverse important roles in cellular processes, including transcription, replication, and repair. It is also a unique activator of p53 function. Here we report that PC4 is a bona fide component of chromatin with distinct chromatin organization ability. PC4 is predominantly associated with the chromatin throughout the stages of cell cycle and is broadly distributed on the mitotic chromosome arms in a punctate manner except for the centromere. It selectively interacts with core histones H3 and H2B; this interaction is essential for PC4-mediated chromatin condensation, as demonstrated by micrococcal nuclease (MNase) accessibility assays, circular dichroism spectroscopy, and atomic force microscopy (AFM). The AFM images show that PC4 compacts the 100-kb reconstituted chromatin distinctly compared to the results seen with the linker histone H1. Silencing of PC4 expression in HeLa cells results in chromatin decompaction, as evidenced by the increase in MNase accessibility. Knocking down of PC4 up-regulates several genes, leading to the G2/M checkpoint arrest of cell cycle, which suggests its physiological role as a chromatin-compacting protein. These results establish PC4 as a new member of chromatin-associated protein family, which plays an important role in chromatin organization. PMID:16982701

  12. The association between antagonist hamstring coactivation and episodes of knee joint shifting and buckling

    PubMed Central

    Segal, N.A.; Nevitt, M.C.; Welborn, R.D.; Nguyen, U.-S.D.T.; Niu, J.; Lewis, C.E.; Felson, D.T.; Frey-Law, L.

    2016-01-01

    SUMMARY Objective Hamstring coactivation during quadriceps activation is necessary to counteract the quadriceps pull on the tibia, but coactivation can be elevated with symptomatic knee osteoarthritis (OA). To guide rehabilitation to attenuate risk for mobility limitations and falls, this study evaluated whether higher antagonistic open kinetic chain hamstring coactivation is associated with knee joint buckling (sudden loss of support) and shifting (a sensation that the knee might give way). Design At baseline, median hamstring coactivation was assessed during maximal isokinetic knee extensor strength testing and at baseline and 24-month follow-up, knee buckling and shifting was self-reported. Associations between tertiles of co-activation and knee (1) buckling, (2) shifting and (3) either buckling or shifting were assessed using logistic regression, adjusted for age, sex, knee OA and pain. Results 1826 participants (1089 women) were included. Mean ± SD age was 61.7 ± 7.7 years, BMI was 30.3 ± 5.5 kg/m2 and 38.2% of knees had OA. There were no consistent statistically significant associations between hamstring coactivation and ipsilateral prevalent or incident buckling or the combination of buckling and shifting. The odds ratios for incident shifting in the highest in comparison with the lowest tertile of coactivation had similar magnitudes in the combined and medial hamstrings, but only reached statistical significance for lateral hamstring coactivation, OR(95%CI) 1.53 (0.99, 2.36). Conclusions Hamstring coactivation during an open kinetic chain quadriceps exercise was not consistently associated with prevalent or incident self-reported knee buckling or shifting in older adults with or at risk for knee OA. PMID:25765501

  13. Playing Teacher.

    ERIC Educational Resources Information Center

    Gilbert, Juan E.

    The acceptance of animation technologies is increasing. Video games, such as Sony PlayStation (SONY, 2002), have become part of the culture for young people from kindergarten through undergraduate school. Animation technologies have been implemented into educational systems in the form of animated pedagogical agents (Johnson, 2000). The research…

  14. Sweet Play

    ERIC Educational Resources Information Center

    Leung, Shuk-kwan S.; Lo, Jane-Jane

    2010-01-01

    This article features Sweet play math, a "math by the month" activity that involves decorating and making sugar cubes. Teachers may want to substitute straws, paper squares, alphabet blocks, or such commercially made manipulatives as Unifix[R] cubes for the real sweets. Given no allergy concerns, teachers and students alike would enjoy some sweet…

  15. Clay Play

    ERIC Educational Resources Information Center

    Rogers, Liz; Steffan, Dana

    2009-01-01

    This article describes how to use clay as a potential material for young children to explore. As teachers, the authors find that their dialogue about the potential of clay as a learning medium raises many questions: (1) What makes clay so enticing? (2) Why are teachers noticing different play and conversation around the clay table as compared to…

  16. Expression, purification and primary crystallographic study of human androgen receptor in complex with DNA and coactivator motifs

    SciTech Connect

    Zhou, X. Edward; Suino-Powell, Kelly; Ludidi, Phumzile L.; McDonnell, Donald P.; Xu, H. Eric

    2012-10-24

    The androgen receptor (AR) is a DNA-binding and hormone-activated transcription factor that plays critical roles in the development and progression of prostate cancer. The transcriptional function of AR is modulated by intermolecular interactions with DNA elements and coactivator proteins, as well as intramolecular interactions between AR domains; thus, the structural information from the full-length AR or a multi-domain fragment is essential for understanding the molecular basis of AR functions. Here we report the expression and purification of full-length AR protein and of a fragment containing its DNA-binding and ligand-binding domains connected by the hinge region in the presence of its natural ligand, dihydrotestosterone. Crystals of ligand-bound full-length AR and of the AR fragment in complex with DNA elements and coactivator motifs have been obtained and diffracted to low resolutions. These results help establish a foundation for pursuing further crystallographic studies of an AR/DNA complex.

  17. Developmental expression of the SRF co-activator MAL in brain: role in regulating dendritic morphology.

    PubMed

    Shiota, Jun; Ishikawa, Mitsuru; Sakagami, Hiroyuki; Tsuda, Masaaki; Baraban, Jay M; Tabuchi, Akiko

    2006-09-01

    The dynamic changes in dendritic morphology displayed by developing and mature neurons have stimulated interest in deciphering the signaling pathways involved. Recent studies have identified megakaryocytic acute leukemia (MAL), a serum response factor (SRF) co-activator, as a key component of a signaling pathway linking changes in the actin cytoskeleton to SRF-mediated transcription. To help define the role of this pathway in regulating dendritic morphology, we have characterized the pattern of MAL expression in the developing and adult brain, and have examined its role in regulating dendritic morphology in cultured cortical neurons. In histological studies of mouse brain, we found prominent expression of MAL in neurons in adult hippocampus and cerebral cortex. MAL immunostaining revealed localization of this protein in neuronal cell bodies and apical dendrites. During development, an increase in MAL expression occurs during the second post-natal week. Expression of dominant negative MAL constructs or MAL siRNA in cortical neurons grown in primary culture reduces the number of dendritic processes and decreases the basal level of SRF-mediated transcription. Taken together, these findings indicate that the MAL-SRF signaling pathway plays a key role in regulating dendritic morphology.

  18. Identification and expression of an encoding steroid receptor coactivator (SRA) in amphioxus (Branchiostoma japonicum).

    PubMed

    Sun, Huanhuan; Gao, Lili; Pang, Qiuxiang; Sun, Lele; Wu, Di; Bai, Yun; Zhao, Bosheng; Dong, Juan

    2013-11-01

    Steroid receptor coactivator (SRA), a class of genes encoding both functional RNA and protein, has been shown to be present in vertebrates but little is known in invertebrates. Here we isolated a cDNA encoding a SRA homolog from amphioxus Branchiostoma japonicum, named AmphiSRA. The cDNA contained a 525 bp open reading frame corresponding to a deduced protein of 174 amino acids with a predicted molecular mass of ~21 kDa. Phylogenetic analysis showed that AmphiSRA was located at the base of its vertebrate counterparts, suggesting that it represents the archetype of vertebrate SRA. The genomic DNA sequence of AmphiSRA contained four exons and three introns, which was similar to B. floridae SRA exon/intron organization. The recombinant SRAP expressed in vitro shows a band with a molecular mass of 21 kDa and western blot confirmed it, which proved it is an encoding isoform. AmphiSRA is found to display a tissue specific expression pattern, with a predominant expression in gill, intestine, testis, neural tube and notochord. The whole-mount in situ hybridization demonstrated the expression of AmphiSRA in all the stages of development assayed. These implicated that SRA maybe play an important role during embryonic development of cephalochordate amphioxus.

  19. PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation

    NASA Astrophysics Data System (ADS)

    Kolodziej, Stephan; Kuvardina, Olga N.; Oellerich, Thomas; Herglotz, Julia; Backert, Ingo; Kohrs, Nicole; Buscató, Estel. La; Wittmann, Sandra K.; Salinas-Riester, Gabriela; Bonig, Halvard; Karas, Michael; Serve, Hubert; Proschak, Ewgenij; Lausen, Jörn

    2014-05-01

    The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.

  20. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.

    PubMed

    Bhat, Krishna P L; Salazar, Katrina L; Balasubramaniyan, Veerakumar; Wani, Khalida; Heathcock, Lindsey; Hollingsworth, Faith; James, Johanna D; Gumin, Joy; Diefes, Kristin L; Kim, Se Hoon; Turski, Alice; Azodi, Yasaman; Yang, Yuhui; Doucette, Tiffany; Colman, Howard; Sulman, Erik P; Lang, Frederick F; Rao, Ganesh; Copray, Sjef; Vaillant, Brian D; Aldape, Kenneth D

    2011-12-15

    Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.

  1. SIP, a novel ankyrin repeat containing protein, sequesters steroid receptor coactivators in the cytoplasm.

    PubMed

    Zhang, Ying; Zhang, Hua; Liang, Jing; Yu, Wenhua; Shang, Yongfeng

    2007-06-06

    Steroid receptor coactivators (SRCs) exert profound effects on animal development and physiology. These coactivators are nuclear proteins and transcription co-regulators that function to facilitate the transcription initiation mediated by nuclear receptors, as well as by other well-known transcription factors. However, how these co-regulators are functionally regulated is poorly understood. During genome-wide screening for SRC-interacting proteins, we identified a novel ankyrin repeat containing protein, SIP (SRC-Interacting Protein), which interacts with SRC coactivators in the cytoplasm. We demonstrated that extracellular stimuli such as the addition of estrogen, induced phosphorylation of SIP in its PEST (Proline, Glutamate, Serine, and Threonine rich) domain by casein kinase II. The phosphorylation of SIP resulted in dissociation of SRC proteins from SIP in the cytoplasm and led to subsequent nuclear translocation of SRC proteins and gene coactivation. Both gain-of-function and loss-of-function experiments indicate that SIP functions to sequester SRC coactivators in the cytoplasm and buffer the availability of these coactivators, thus providing a mechanism for the regulation of the transcription regulators.

  2. A structural model of the anaphase promoting complex co-activator (Cdh1) and in silico design of inhibitory compounds

    PubMed Central

    Rahimi, H.; Negahdari, B.; Shokrgozar, M.A.; Madadkar-Sobhani, A.; Mahdian, R.; Foroumadi, A.; Amin, M. Kafshdouzi; Karimipoor, M.

    2015-01-01

    Anaphase promoting complex (APC) controls cell cycle and chromosome segregation. The APC activation occurs after binding of co-activators, cdh1 and cdc20. Cdh1 plays a role in cancer pathogenesis and is known as a potential drug target. The main aim of this study was prediction of 3D structure of cdh1 and designing the inhibitory compounds based on the structural model. First, 3D structure of cdh1 was predicted by means of homology modelling and molecular dynamics tools, MODELLER and Gromacs package, respectively. Then, inhibitory compounds were designed using virtual screening and molecular docking by means AutoDock package. The overall structure of cdh1 is propeller like and each DW40 repeat contains four anti-parallel beta-sheets. Moreover, binding pocket of the inhibitory compounds was determined. The results might be helpful in finding a suitable cdh1 inhibitor for the treatment of cancer. PMID:26430458

  3. A structural model of the anaphase promoting complex co-activator (Cdh1) and in silico design of inhibitory compounds.

    PubMed

    Rahimi, H; Negahdari, B; Shokrgozar, M A; Madadkar-Sobhani, A; Mahdian, R; Foroumadi, A; Amin, M Kafshdouzi; Karimipoor, M

    2015-01-01

    Anaphase promoting complex (APC) controls cell cycle and chromosome segregation. The APC activation occurs after binding of co-activators, cdh1 and cdc20. Cdh1 plays a role in cancer pathogenesis and is known as a potential drug target. The main aim of this study was prediction of 3D structure of cdh1 and designing the inhibitory compounds based on the structural model. First, 3D structure of cdh1 was predicted by means of homology modelling and molecular dynamics tools, MODELLER and Gromacs package, respectively. Then, inhibitory compounds were designed using virtual screening and molecular docking by means AutoDock package. The overall structure of cdh1 is propeller like and each DW40 repeat contains four anti-parallel beta-sheets. Moreover, binding pocket of the inhibitory compounds was determined. The results might be helpful in finding a suitable cdh1 inhibitor for the treatment of cancer.

  4. Developing through relationships: an embodied coactive systems framework.

    PubMed

    Mascolo, Michael F

    2013-01-01

    In recent decades, the developmental sciences have undergone a relational turn. Epigenetic (Gottlieb & Lickliter, 2007), embodied (Thompson, 2007), relational (Lerner & Overton, 2008) and systems (Kelso, 2003) approaches are transforming the ways in which we think about the nature and origins of psychological structures. At their most basic level, relational and systems approaches analyze the developmental origins of order and variability not in terms of sets of separable causal forces but instead in analyses of relations between causal systems. From this view, genes and environment, biology and culture, cognition and emotion, self and other, and so forth are inseparable as causal processes in the development of action and experience. Drawing on these principles, this paper contains an outline of an embodied coactive systems framework for understanding how individual psychological structures develop as a product of socially distributed coactions that occur among elements of the extended person-environment system. Based on these principles, a system for the Developmental Analysis of Joint Action is described. This system provides a set of conceptual and empirical tools for making precise assessments of dynamic structure of jointly constructed patterns of thinking, feeling and acting. By tracking developmental changes in joint action, the system allows researchers to track the origins of higher order psychological structures through particular sequences of coconstructive activity. The holistic analytic system is illustrated through microdevelopmental analyses of (1) the joint construction of shoe-tying skill between a 5-year-old boy and a caregiver, and (2) socioemotional organization developing representations of self in a young adult over the course of a single session of psychotherapy.

  5. Identification of SRC3/AIB1 as a Preferred Coactivator for Hormone-activated Androgen Receptor

    SciTech Connect

    Zhou, X. Edward; Suino-Powell, Kelly M.; Li, Jun; He, Yuanzheng; MacKeigan, Jeffrey P.; Melcher, Karsten; Yong, Eu-Leong; Xu, H.Eric

    2010-09-17

    Transcription activation by androgen receptor (AR), which depends on recruitment of coactivators, is required for the initiation and progression of prostate cancer, yet the mechanisms of how hormone-activated AR interacts with coactivators remain unclear. This is because AR, unlike any other nuclear receptor, prefers its own N-terminal FXXLF motif to the canonical LXXLL motifs of coactivators. Through biochemical and crystallographic studies, we identify that steroid receptor coactivator-3 (SRC3) (also named as amplified in breast cancer-1 or AIB1) interacts strongly with AR via synergistic binding of its first and third LXXLL motifs. Mutagenesis and functional studies confirm that SRC3 is a preferred coactivator for hormone-activated AR. Importantly, AR mutations found in prostate cancer patients correlate with their binding potency to SRC3, corroborating with the emerging role of SRC3 as a prostate cancer oncogene. These results provide a molecular mechanism for the selective utilization of SRC3 by hormone-activated AR, and they link the functional relationship between AR and SRC3 to the development and growth of prostate cancer.

  6. The variability of co-activation pattern of antagonist muscles in human infant crawling.

    PubMed

    Xiong, Qi L; Wu, Xiao Y; Nong Xiao; Zeng, Si Y; Zheng, Xiao L; Di Wu; Hou, Wen S

    2016-08-01

    Infant crawling is part of normal human gross motor development, and a 4-beat gait that involves rhythmical flexion and extension of limbs and the underlying muscle co-activation of antagonist muscle around the joint. However, detection the co-activation pattern of antagonist muscle are sparse due to the general difficulty of measuring locomotion in human infants. In this paper, sEMG of antagonist muscles and the corresponding kinematics data of limbs were collected when infants were crawling on hands and knees at their self-selected speed. The infant's gross motor developmental status was assessed by the global Gross Motor Function Measure Scale (GMFM-88) as well. The method based on EMG-EMG plots was used to quantify the variability of co-activation pattern of antagonist muscle. After that, we observed that antagonist muscles of upper limb (triceps brachii and biceps brachii) showed less variability of co-activation pattern of muscles than lower limb(quadriceps femoris and hamstrings) during crawling, and this variability was also varied in different crawling phases (stance and swing). Furthermore, we found some varied behaviors in the co-activation patterns of antagonist muscles when gross motor developmental level increased. The preliminary work suggests that such adaptive changes may be related to the adjustment of neuromuscular in the early stage of gross motor development.

  7. BOB.1 of the channel catfish, Ictalurus punctatus: Not a transcriptional coactivator?

    PubMed Central

    Richard, Mara L. Lennard; Hikima, Jun-ichi; Wilson, Melanie R.; Miller, Norman W.; Cunningham, Charles; Warr, Gregory W.

    2010-01-01

    Expression of the immunoglobulin heavy chain (IGH) locus of the channel catfish (Ictalurus punctatus)is driven by the Eμ3′ enhancer, whose core region contains two octamer motifs and a μE5 site. Orthologues of the Oct1 and Oct2 transcription factors have been cloned in the channel catfish and shown to bind to the octamer motifs within the core enhancer. While catfish Oct2 is an activator of transcription, catfish Oct1 failed to drive transcription and may act as a negative regulator of IGH transcription. In mammals, the Oct co-activator BOB.1 (B cell Oct-binding protein1, also known as OCA-B and OBF-1) greatly enhances the transcriptional activity of Oct factors and plays an important role in the development of the immune system. An orthologue of BOB.1 has been cloned in the catfish, and its function characterized. The POU binding domain of the catfish BOB.1 was found to be 95% identical at the amino acid level with the binding domain of human BOB.1, and all the residues directly involved in binding to the Oct-DNA complex were conserved. Despite this conservation, catfish BOB.1 failed to enhance transcriptional activation mediated by endogenous or co-transfected catfish Oct2, and failed to rescue the activity of the inactive catfish Oct1. Electrophoretic mobility shift assays showed that catfish BOB.1 was capable of binding both catfish Oct1 and Oct2 when they formed a complex with the Oct motif. Analysis of recombinant chimeric catfish and human BOB.1 proteins demonstrated that the failure to drive transcription was due to the lack of a functional activation domain within the catfish BOB.1. PMID:19041136

  8. The Hippo coactivator YAP1 mediates EGFR overexpression and confers chemo-resistance in esophageal cancer

    PubMed Central

    Song, Shumei; Honjo, Soichiro; Jin, Jiankang; Chang, Shih-Shin; Scott, Ailing W; Chen, Qiongrong; Kalhor, Neda; Correa, Arlene M.; Hofstetter, Wayne L.; Albarracin, Constance T.; Wu, Tsung-Teh; Johnson, Randy L.; Hung, Mien-Chie; Ajani, Jaffer A.

    2015-01-01

    Purpose Esophageal cancer (EC) is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of EC patients. However, clinical trials using EGFR inhibitors have not provided benefit for EC patients. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design In this study, expression of YAP1 and EGFR were examined in EAC resistant tumor tissues vs sensitive tissues by immunohistochemistry. Western blot, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis and in vitro and in vivo functional assays were performed to elucidate the YAP1 mediate EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results We demonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant EC tissues compared to sensitive EC tissues. Further, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEAD binding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-FU and docetaxcel, while knockdown of YAP sensitizes EC cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions Our data provide evidence that YAP1 up-regulation of EGFR plays an important role in conferring therapy resistance in EC cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in EC. PMID:25739674

  9. A key role of PGC-1α transcriptional coactivator in production of VEGF by a novel angiogenic agent COA-Cl in cultured human fibroblasts.

    PubMed

    Igarashi, Junsuke; Okamoto, Ryuji; Yamashita, Tetsuo; Hashimoto, Takeshi; Karita, Sakiko; Nakai, Kozo; Kubota, Yasuo; Takata, Maki; Yamaguchi, Fuminori; Tokuda, Masaaki; Sakakibara, Norikazu; Tsukamoto, Ikuko; Konishi, Ryoji; Hirano, Katsuya

    2016-03-01

    We previously demonstrated a potent angiogenic effect of a newly developed adenosine-like agent namedCOA-Cl.COA-Cl exerted tube forming activity in human umbilical vein endothelial cells in the presence of normal human dermal fibroblasts (NHDF). We therefore explored whether and howCOA-Cl modulates gene expression and protein secretion ofVEGF, a master regulator of angiogenesis, inNHDFRT-PCRandELISArevealed thatCOA-Cl upregulatedVEGF mRNAexpression and protein secretion inNHDFHIF1α(hypoxia-inducible factor 1α), a transcription factor, andPGC-1α(peroxisome proliferator-activated receptor-γcoactivator-1α), a transcriptional coactivator, are known to positively regulate theVEGFgene. Immunoblot andRT-PCRanalyses revealed thatCOA-Cl markedly upregulated the expression ofPGC-1αprotein andmRNACOA-Cl had no effect on the expression ofHIF1αprotein andmRNAin both hypoxia and normoxia. SilencingPGC-1αgene, but notHIF1αgene, by small interferingRNAattenuated the ability ofCOA-Cl to promoteVEGFsecretion. When an N-terminal fragment ofPGC-1αwas cotransfected with its partner transcription factorERRα(estrogen-related receptor-α) inCOS-7 cells,COA-Cl upregulated the expression of the endogenousVEGF mRNA However,COA-Cl had no effect on the expression ofVEGF, whenHIF1αwas transfected.COA-Cl inducesVEGFgene expression and protein secretion in fibroblasts. The transcriptional coactivatorPGC-1α, in concert withERRα, plays a key role in theCOA-Cl-inducedVEGFproduction.COA-Cl-induced activation ofPGC-1α-ERRα-VEGFpathway has a potential as a novel means for therapeutic angiogenesis.

  10. The Structure of A Biologically Active Estrogen Receptor-Coactivator Complex on DNA

    PubMed Central

    Yi, Ping; Wang, Zhao; Feng, Qin; Pintilie, Grigore D.; Foulds, Charles E.; Lanz, Rainer B.; Ludtke, Steven J.; Schmid, Michael F.; Chiu, Wah; O’Malley, Bert W.

    2015-01-01

    SUMMARY Estrogen receptor (ER) is a transcription factor critical for development, reproduction, metabolism and cancer. ER function hinges on its ability to recruit primary and secondary coactivators, yet structural information on the full-length receptor-coactivator complex to complement pre-existing and sometimes controversial biochemical information is lacking. Here we use cryo-EM to determine the quaternary structure of an active complex of DNA-bound ERα, steroid receptor coactivator 3 (SRC-3) and a secondary coactivator (p300). Our structural model suggests the following assembly mechanism for the complex: each of the two ligand-bound ERα monomers independently recruits one SRC-3 protein via the transactivation domain of ERα; the two SRC-3s in turn bind to different regions of one p300 protein through multiple contacts. We also present structural evidence for the location of activation function 1 (AF-1) in a full-length nuclear receptor, which supports a role for AF-1 in SRC-3 recruitment. PMID:25728767

  11. Effects of Response Task and Accessory Stimuli on Redundancy Gain: Tests of the Hemispheric Coactivation Model

    ERIC Educational Resources Information Center

    Miller, Jeff; Van Nes, Fenna

    2007-01-01

    Two experiments tested predictions of the hemispheric coactivation model for redundancy gain (J. O. Miller, 2004). Simple reaction time was measured in divided attention tasks with visual stimuli presented to the left or right of fixation or redundantly to both sides. Experiment 1 tested the prediction that redundancy gain--the decrease in…

  12. Involvement of Novel Multifunctional Steroid Hormone Receptor Coactivator, E6-Associated Protein, in Prostate Gland Tumorigenesis

    DTIC Science & Technology

    2008-01-01

    Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol 19:1182-9. 26. Hsiao PW, Chang C...Albrecht U, Atkins CM, Noebels JL, Eichele G, Sweatt JD, Beaudet AL 1998 Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic

  13. Superficial shoulder muscle co-activations during lifting tasks: Influence of lifting height, weight and phase.

    PubMed

    Blache, Y; Dal Maso, F; Desmoulins, L; Plamondon, A; Begon, M

    2015-04-01

    This study aimed to assess the level of co-activation of the superficial shoulder muscles during lifting movement. Boxes containing three different loads (6, 12, and 18 kg) were lifted by fourteen subjects from the waist to shoulder or eye level. The 3D kinematics and electromyograms of the three deltoids, latissimus dorsi and pectoralis major were recorded. A musculoskeletal model was used to determine direction of the moment arm of these muscles. Finally an index of muscle co-activation named the muscle focus was used to evaluate the effects of lifting height, weight lifted and phase (pulling, lifting and dropping phases) on superficial shoulder muscle coactivation. The muscle focus was lower (more co-contraction) during the dropping phase compared to the two other phases (-13%, p<0.001). This was explained by greater muscle activations and by a change in the direction of the muscle moment arm as a function of glenohumeral joint position. Consequently, the function of the shoulder superficial muscles varied with respect to the glenohumeral joint position. To increase the superficial muscle coactivation during the dropping phase may be a solution to increase glenohumeral joint stiffness.

  14. Resisting the Marginalization of Science in an Urban School: Coactivating Social, Cultural, Material, and Strategic Resources

    ERIC Educational Resources Information Center

    Rivera Maulucci, Maria S.

    2010-01-01

    This study describes the resources and strategies middle school teachers, urban fellows, and a district science staff developer coactivated to resist the marginalization of science in a high-poverty, low-performing urban school. Through critical narrative inquiry, I document factors that marginalized science in three teachers' classrooms. The…

  15. SRC-2 is an essential coactivator for orchastrating metabolism and circadian rhythm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:C...

  16. The Race that Precedes Coactivation: Development of Multisensory Facilitation in Children

    ERIC Educational Resources Information Center

    Barutchu, Ayla; Crewther, David P.; Crewther, Sheila G.

    2009-01-01

    Rationale: The facilitating effect of multisensory integration on motor responses in adults is much larger than predicted by race-models and is in accordance with the idea of coactivation. However, the development of multisensory facilitation of endogenously driven motor processes and its relationship to the development of complex cognitive skills…

  17. Novel interaction between nuclear co-activator CBP and the CDK5 activator binding protein - C53.

    PubMed

    Yin, Xiaolong; Warner, Dennis R; Roberts, Emily A; Pisano, M Michele; Greene, Robert M

    2005-08-01

    cAMP response element-binding protein (CREB)-binding protein (CBP) is a multifunctional transcriptional co-activator that plays important roles in cell proliferation and differentiation. CBP is expressed in murine embryonic orofacial tissue and is developmentally regulated. To identify nuclear factors associating with CBP in developing orofacial tissue, a yeast two-hybrid screen of a cDNA library derived from embryonic orofacial tissue from gestational days 11-13 mouse embryos was conducted. The carboxy terminal region of CBP (including the C/H3 region) was utilized as a bait. C53, a 57 kDa protein known to bind to the p25 activator of cyclin-dependent kinase 5, was identified as a novel binding partner of CBP. The association of C53 with CBP was confirmed in vitro by glutathione S-transferase pull-down assays, and in vivo by co-immunoprecipitation. Reporter assays demonstrated that C53 had little effect on CBP mediated transcriptional activation. These results identify C53 as a novel binding partner for CBP. Recent research on presenilin-loss induced neurodegeneration demonstrated decreased expression of CBP and increased levels of the Cdk5 activator p25, both C53 binding proteins, suggesting that C53 might play a role in regulating neuronal proliferation, migration and/or differentiation in embryonic development.

  18. A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism.

    PubMed

    Chen, Wei; Zhang, Xiaoting; Birsoy, Kivanc; Roeder, Robert G

    2010-06-01

    As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific Med1 knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet-induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific UCP-1 and Cidea genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1-nuclear receptor interactions.

  19. FLASH interacts with p160 coactivator subtypes and differentially suppresses transcriptional activity of steroid hormone receptors.

    PubMed

    Kino, Tomoshige; Ichijo, Takamasa; Chrousos, George P

    2004-12-01

    We previously reported that tumor necrosis factor alpha receptor- and Fas-associated FLASH interacts with one of the p160 nuclear receptor coactivators, glucocorticoid receptor-interacting protein (GRIP) 1, at its nuclear receptor-binding (NRB) domain, and that inhibits the transcriptional activity of the glucocorticoid receptor (GR) by interfering with association of GR and GRIP1. Here, we further examined the specificity of FLASH suppressive effect and the physical/functional interactions between this protein and two other p160 family subtypes. The suppressive effect of FLASH on GR transactivation was observed in several cell lines and on the chromatin-integrated mouse mammary tumor virus (MMTV) promoter. FLASH strongly interacted with the NRB domain of the thyroid hormone receptor activator molecule (TRAM) 1, a member of the steroid hormone receptor coactivator (SRC) 3/nuclear receptor coactivator (N-CoA) 3 subtypes, as well as with SRC2/N-CoA2 p160 coactivator GRIP1, while its interaction with SRC1a, one of the SRC1/N-CoA1 proteins, was faint in yeast two-hybrid assays. Accordingly, FLASH strongly suppressed TRAM1- and GRIP1-induced enhancement of GR-stimulated transactivation of the MMTV promoter in HCT116 cells, while it did not affect SRC1a-induced potentiation of transcription. Furthermore, FLASH suppressed androgen- and progesterone receptor-induced transcriptional activity, but did not influence estrogen receptor-induced transactivation, possibly due to their preferential use of p160 coactivators in HCT116 and HeLa cells. Thus, FLASH differentially suppresses steroid hormone receptor-induced transcriptional activity by interfering with their association with SRC2/N-CoA2 and SRC3/N-CoA3 but not with SRC1/N-CoA1.

  20. NRC-interacting factor 1 is a novel cotransducer that interacts with and regulates the activity of the nuclear hormone receptor coactivator NRC.

    PubMed

    Mahajan, Muktar A; Murray, Audrey; Samuels, Herbert H

    2002-10-01

    We previously reported the cloning and characterization of a novel nuclear hormone receptor transcriptional coactivator, which we refer to as NRC. NRC is a 2,063-amino-acid nuclear protein which contains a potent N-terminal activation domain and several C-terminal modules which interact with CBP and ligand-bound nuclear hormone receptors as well as c-Fos and c-Jun. In this study we sought to clone and identify novel factors that interact with NRC to modulate its transcriptional activity. Here we describe the cloning and characterization of a novel protein we refer to as NIF-1 (NRC-interacting factor 1). NIF-1 was cloned from rat pituitary and human cell lines and was found to interact in vivo and in vitro with NRC. NIF-1 is a 1,342-amino-acid nuclear protein containing a number of conserved domains, including six Cys-2/His-2 zinc fingers, an N-terminal stretch of acidic amino acids, and a C-terminal leucine zipper-like motif. Zinc fingers 1 to 3 are potential DNA-binding BED finger domains recently proposed to play a role in altering local chromatin architecture. We mapped the interaction domains of NRC and NIF-1. Although NIF-1 does not directly interact with nuclear receptors, it markedly enhances ligand-dependent transcriptional activation by nuclear hormone receptors in vivo as well as activation by c-Fos and c-Jun. These results, and the finding that NIF-1 interacts with NRC in vivo, suggest that NIF-1 functions to regulate transcriptional activation through NRC. We suggest that NIF-1, and factors which associate with coactivators but not receptors, be referred to as cotransducers, which act in vivo either as part of a coactivator complex or downstream of a coactivator complex to modulate transcriptional activity. Our findings suggest that NIF-1 may be a functional component of an NRC complex and acts as a regulator or cotransducer of NRC function.

  1. Ligand-dependent interactions of the Ah receptor with coactivators in a mammalian two-hybrid assay

    SciTech Connect

    Zhang Shu; Rowlands, Craig; Safe, Stephen

    2008-03-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a high affinity ligand for the aryl hydrocarbon receptor (AhR). In this study, we investigated structure-dependent differences in activation of the AhR by a series of halogenated aromatic hydrocarbons. TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB126) induced CYP1A1-dependent activities in HEK293 human embryonic kidney, Panc1 pancreatic cancer, and Hepa1c1c7 mouse hepatoma cell lines. There was a structure-dependent difference in the efficacy of TCDF and PCB126 in HEK293 and Panc1 cells since induced CYP1A1 mRNA levels were lower than observed for the other congeners. A mammalian two-hybrid assay in cells transfected with GAL4-coactivator and AhR-VP16 chimeras was used to investigate structure-dependent interactions of these chimeras in Panc1, HEK293, and Hepa1c1c7 cells. The reporter construct pGAL4-luc contains five tandem GAL4 response elements linked to the luciferase gene and the GAL4-coactivator chimeras express several coactivators including steroid receptor coactivator 1 (SRC-1), SRC-2 and SRC-3, the mediator coactivator TRAP220, coactivator associated arginine methyl transferase 1 (CARM-1), and peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1). Results of the mammalian two-hybrid studies clearly demonstrate that activation of pGAL4-luc in cells transfected with VP-AhR and GAL4-coactivator chimeras is dependent on the structure of the HAH congener, cell context, and coactivator, suggesting that the prototypical HAH congeners used in this study exhibit selective AhR modulator activity.

  2. The p160/steroid receptor coactivator family: potent arbiters of uterine physiology and dysfunction.

    PubMed

    Szwarc, Maria M; Kommagani, Ramakrishna; Lessey, Bruce A; Lydon, John P

    2014-11-01

    The p160/steroid receptor coactivator (SRC) family comprises three pleiotropic coregulators (SRC-1, SRC-2, and SRC-3; otherwise known as NCOA1, NCOA2, and NCOA3, respectively), which modulate a wide spectrum of physiological responses and clinicopathologies. Such pleiotropy is achieved through their inherent structural complexity, which allows this coregulator class to control both nuclear receptor and non-nuclear receptor signaling. As observed in other physiologic systems, members of the SRC family have recently been shown to play pivotal roles in uterine biology and pathobiology. In the murine uterus, SRC-1 is required to launch a full steroid hormone response, without which endometrial decidualization is markedly attenuated. From "dovetailing" clinical and mouse studies, an isoform of SRC-1 was recently identified which promotes endometriosis by reprogramming endometrial cells to evade apoptosis and to colonize as endometriotic lesions within the peritoneal cavity. The endometrium fails to decidualize without SRC-2, which accounts for the infertility phenotype exhibited by mice devoid of this coregulator. In related studies on human endometrial stromal cells, SRC-2 was shown to act as a molecular "pacemaker" of the glycolytic flux. This finding is significant because acceleration of the glycolytic flux provides the necessary bioenergy and biomolecules for endometrial stromal cells to switch from quiescence to a proliferative phenotype, a critical underpinning in the decidual progression program. Although studies on uterine SRC-3 function are in their early stages, clinical studies provide tantalizing support for the proposal that SRC-3 is causally linked to endometrial hyperplasia as well as with endometrial pathologies in patients diagnosed with polycystic ovary syndrome. This proposal is now driving the development and application of innovative technologies, particularly in the mouse, to further understand the functional role of this elusive uterine

  3. Macrophage PPAR gamma Co-activator-1 alpha participates in repressing foam cell formation and atherosclerosis in response to conjugated linoleic acid

    PubMed Central

    McCarthy, Cathal; Lieggi, Nora T; Barry, Denis; Mooney, Declan; de Gaetano, Monica; James, William G; McClelland, Sarah; Barry, Mary C; Escoubet-Lozach, Laure; Li, Andrew C; Glass, Christopher K; Fitzgerald, Desmond J; Belton, Orina

    2013-01-01

    Conjugated linoleic acid (CLA) has the unique property of inducing regression of pre-established murine atherosclerosis. Understanding the mechanism(s) involved may help identify endogenous pathways that reverse human atherosclerosis. Here, we provide evidence that CLA inhibits foam cell formation via regulation of the nuclear receptor coactivator, peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α, and that macrophage PGC-1α plays a role in atheroprotection in vivo. PGC-1α was identified as a hub gene within a cluster in the aorta of the apoE−/− mouse in the CLA-induced regression model. PGC-1α was localized to macrophage/foam cells in the murine aorta where its expression was increased during CLA-induced regression. PGC-1α expression was also detected in macrophages in human atherosclerosis and was inversely linked to disease progression in patients with the disease. Deletion of PGC-1α in bone marrow derived macrophages promoted, whilst over expression of the gene inhibited foam cell formation. Importantly, macrophage specific deletion of PGC-1α accelerated atherosclerosis in the LDLR−/− mouse in vivo. These novel data support a functional role for PGC-1α in atheroprotection. PMID:23964012

  4. Neural co-activation as a yardstick of implicit motor learning and the propensity for conscious control of movement.

    PubMed

    Zhu, F F; Poolton, J M; Wilson, M R; Maxwell, J P; Masters, R S W

    2011-04-01

    Two studies examined EEG co-activation (coherence) between the verbal-analytical (T3) and motor planning (Fz) regions during a golf putting task. In Study 1, participants with a strong propensity to consciously monitor and control their movements, determined psychometrically by high scores on a movement specific Reinvestment Scale, displayed more alpha2 T3-Fz co-activation than participants with a weak propensity. In Study 2, participants who practiced a golf putting task implicitly (via an errorless learning protocol) displayed less alpha2 T3-Fz co-activation than those who practiced explicitly (by errorful learning). In addition, explicit but not implicit motor learners displayed more T3-Fz co-activation during golf putting under pressure, implying that verbal-analytical processing of putting movements increased under pressure. These findings provide neuropsychological evidence that supports claims that implicit motor learning can be used to limit movement specific reinvestment.

  5. MiR130b-Regulation of PPARγ Coactivator- 1α Suppresses Fat Metabolism in Goat Mammary Epithelial Cells

    PubMed Central

    Chen, Zhi; Luo, Jun; Ma, LiuAn; Wang, Hui; Cao, WenTing; Xu, HuiFei; Zhu, JiangJiang; Sun, YuTing; Li, Jun; Yao, DaWei; Kang, Kang; Gou, Deming

    2015-01-01

    Fat metabolism is a complicated process regulated by a series of factors. microRNAs (miRNAs) are a class of negative regulator of proteins and play crucial roles in many biological processes; including fat metabolism. Although there have been some researches indicating that miRNAs could influence the milk fat metabolism through targeting some factors, little is known about the effect of miRNAs on goat milk fat metabolism. Here we utilized an improved miRNA detection assay, S-Poly-(T), to profile the expression of miRNAs in the goat mammary gland in different periods, and found that miR-130b was abundantly and differentially expressed in goat mammary gland. Additionally, overexpressing miR-130b impaired adipogenesis while inhibiting miR-130b enhanced adipogenesis in goat mammary epithelial cells. Utilizing 3’-UTR assay and Western Blot analusis, the protein peroxisome proliferator-activated receptor coactivator-1α (PGC1α), a major regulator of fat metabolism, was demonstrated to be a potential target of miR-130b. Interestingly, miR-130b potently repressed PGC1α expression by targeting both the PGC1α mRNA coding and 3’ untranslated regions. These findings have some insight of miR-130b in mediating adipocyte differentiation by repressing PGC1α expression and this contributes to further understanding about the functional significance of miRNAs in milk fat synthesis. PMID:26579707

  6. Inhibition of CCAR1, a Coactivator of β-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells

    PubMed Central

    Chang, Te-Sheng; Wei, Kuo-Liang; Lu, Chung-Kuang; Chen, Yi-Hsing; Cheng, Ying-Tung; Tung, Shui-Yi; Wu, Cheng-Shyong; Chiang, Ming-Ko

    2017-01-01

    The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/β-catenin signaling, and which plays an important role in transcriptional regulation by β-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target. PMID:28230774

  7. The RXR{alpha} C-terminus T462 is a NMR sensor for coactivator peptide binding

    SciTech Connect

    Lu Jianyun Chen Minghe; DeKoster, Gregory T.; Cistola, David P.; Li, Ellen

    2008-02-22

    The C-terminal activation function-2 (AF-2) helix plays a crucial role in retinoid X receptor alpha (RXR{alpha})-mediated gene expression. Here, we report a nuclear magnetic resonance (NMR) study of the RXR{alpha} ligand-binding domain complexed with 9-cis-retinoic acid and a glucocorticoid receptor-interacting protein 1 peptide. The AF-2 helix and most of the C-terminal residues were undetectable due to a severe line-broadening effect. Due to its outstanding signal-to-noise ratio, the C-terminus residue, threonine 462 (T462) exhibited two distinct crosspeaks during peptide titration, suggesting that peptide binding was in a slow exchange regime on the chemical shift timescale. Consistently, the K{sub d} derived from T462 intensity decay agreed with that derived from isothermal titration calorimetry. Furthermore, the exchange contribution to the {sup 15}N transverse relaxation rate was measurable in either T462 or the bound peptide. These results suggest that T462 is a sensor for coactivator binding and is a potential probe for AF-2 helix mobility.

  8. Preparatory co-activation of the ankle muscles may prevent ankle inversion injuries.

    PubMed

    DeMers, Matthew S; Hicks, Jennifer L; Delp, Scott L

    2017-02-08

    Ankle inversion sprains are the most frequent acute musculoskeletal injuries occurring in physical activity. Interventions that retrain muscle coordination have helped rehabilitate injured ankles, but it is unclear which muscle coordination strategies, if any, can prevent ankle sprains. The purpose of this study was to determine whether coordinated activity of the ankle muscles could prevent excessive ankle inversion during a simulated landing on a 30° incline. We used a set of musculoskeletal simulations to evaluate the efficacy of two strategies for coordinating the ankle evertor and invertor muscles during simulated landing scenarios: planned co-activation and stretch reflex activation with physiologic latency (60-ms delay). A full-body musculoskeletal model of landing was used to generate simulations of a subject dropping onto an inclined surface with each coordination condition. Within each condition, the intensity of evertor and invertor co-activity or stretch reflexes were varied systematically. The simulations revealed that strong preparatory co-activation of the ankle evertors and invertors prior to ground contact prevented ankle inversion from exceeding injury thresholds by rapidly generating eversion moments after initial contact. Conversely, stretch reflexes were too slow to generate eversion moments before the simulations reached the threshold for inversion injury. These results suggest that training interventions to protect the ankle should focus on stiffening the ankle with muscle co-activation prior to landing. The musculoskeletal models, controllers, software, and simulation results are freely available online at http://simtk.org/home/ankle-sprains, enabling others to reproduce the results and explore new injury scenarios and interventions.

  9. Nuclear Control of Respiratory Chain Expression by Nuclear Respiratory Factors and PGC-1-Related Coactivator

    PubMed Central

    Scarpulla, Richard C.

    2010-01-01

    Expression of the respiratory apparatus depends on both nuclear and mitochondrial genes. Although these genes are sequestered in distinct cellular organelles, their transcription relies on nucleus-encoded factors. Certain of these factors are directed to the mitochondria, where they sponsor the bi-directional transcription of mitochondrial DNA. Others act on nuclear genes that encode the majority of the respiratory subunits and many other gene products required for the assembly and function of the respiratory chain. The nuclear respiratory factors, NRF-1 and NRF-2, contribute to the expression of respiratory subunits and mitochondrial transcription factors and thus have been implicated in nucleo-mitochondrial interactions. In addition, coactivators of the PGC-1 family serve as mediators between the environment and the transcriptional machinery governing mitochondrial biogenesis. One family member, peroxisome proliferator-activated receptor γ coactivator PGC-1-related coactivator (PRC), is an immediate early gene product that is rapidly induced by mitogenic signals in the absence of de novo protein synthesis. Like other PGC-1 family members, PRC binds NRF-1 and activates NRF-1 target genes. In addition, PRC complexes with NRF-2 and HCF-1 (host cell factor-1) in the activation of NRF-2-dependent promoters. HCF-1 functions in cell-cycle progression and has been identified as an NRF-2 coactivator. The association of these factors with PRC is suggestive of a role for the complex in cell growth. Finally, shRNA-mediated knock down of PRC expression results in a complex phenotype that includes the inhibition of respiratory growth on galactose and the loss of respiratory complexes. Thus, PRC may help integrate the expression of the respiratory apparatus with the cell proliferative program. PMID:19076454

  10. Transient neuronal coactivations embedded in globally propagating waves underlie resting-state functional connectivity

    PubMed Central

    Matsui, Teppei; Murakami, Tomonari; Ohki, Kenichi

    2016-01-01

    Resting-state functional connectivity (FC), which measures the correlation of spontaneous hemodynamic signals (HemoS) between brain areas, is widely used to study brain networks noninvasively. It is commonly assumed that spatial patterns of HemoS-based FC (Hemo-FC) reflect large-scale dynamics of underlying neuronal activity. To date, studies of spontaneous neuronal activity cataloged heterogeneous types of events ranging from waves of activity spanning the entire neocortex to flash-like activations of a set of anatomically connected cortical areas. However, it remains unclear how these various types of large-scale dynamics are interrelated. More importantly, whether each type of large-scale dynamics contributes to Hemo-FC has not been explored. Here, we addressed these questions by simultaneously monitoring neuronal calcium signals (CaS) and HemoS in the entire neocortex of mice at high spatiotemporal resolution. We found a significant relationship between two seemingly different types of large-scale spontaneous neuronal activity—namely, global waves propagating across the neocortex and transient coactivations among cortical areas sharing high FC. Different sets of cortical areas, sharing high FC within each set, were coactivated at different timings of the propagating global waves, suggesting that spatial information of cortical network characterized by FC was embedded in the phase of the global waves. Furthermore, we confirmed that such transient coactivations in CaS were indeed converted into spatially similar coactivations in HemoS and were necessary to sustain the spatial structure of Hemo-FC. These results explain how global waves of spontaneous neuronal activity propagating across large-scale cortical network contribute to Hemo-FC in the resting state. PMID:27185944

  11. Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors

    DTIC Science & Technology

    2005-09-01

    Gutendorf, andJ. Westendorf. 2000. Endocrine disruptors in fried meat: PhIP is an estrogen. Proceedings of the American Association for Cancer...binding site of the ERa LBD [3-5]. Because these studies have focused on the estradiol binding site, new potential ER disruptors that bind in the co...activator site have been missed. Our proposal focuses on developing a new computational approach to predict therapeutically useful ERa disruptors by

  12. Agonist ligands mediate the transcriptional response of nuclear receptor heterodimers through distinct stoichiometric assemblies with coactivators.

    PubMed

    Pavlin, Mark Remec; Brunzelle, Joseph S; Fernandez, Elias J

    2014-09-05

    The constitutive androstane (CAR) and retinoid X receptors (RXR) are ligand-mediated transcription factors of the nuclear receptor protein superfamily. Functional CAR:RXR heterodimers recruit coactivator proteins, such as the steroid receptor coactivator-1 (SRC1). Here, we show that agonist ligands can potentiate transactivation through both coactivator binding sites on CAR:RXR, which distinctly bind two SRC1 molecules. We also observe that SRC1 transitions from a structurally plastic to a compact form upon binding CAR:RXR. Using small angle x-ray scattering (SAXS) we show that the CAR(tcp):RXR(9c)·SRC1 complex can encompass two SRC1 molecules compared with the CAR(tcp):RXR·SRC1, which binds only a single SRC1. Moreover, sedimentation coefficients and molecular weights determined by analytical ultracentrifugation confirm the SAXS model. Cell-based transcription assays show that disrupting the SRC1 binding site on RXR alters the transactivation by CAR:RXR. These data suggest a broader role for RXR within heterodimers, whereas offering multiple strategies for the assembly of the transcription complex.

  13. Antagonist muscle co-activation of limbs in human infant crawling: A pilot study.

    PubMed

    Xiong, Qi L; Wu, Xiao Y; Xiao, Nong; Zeng, Si Y; Wan, Xiao P; Zheng, Xiao L; Hou, Wen S

    2015-01-01

    Muscle Co-activation (MCo) is the simultaneous muscular activation of agonist and antagonist muscle groups, which provides adequate joint stability, movement accuracy during movement. Infant crawling is an important stage of motor function development that manifests non-synchronization growth and development of upper and lower limbs due to the well-known gross motor development principle of head to toe. However, the effect of MCo level for agonist and antagonist muscle groups on motor function development of limbs has not been previously reported. In this paper, sEMG signals were collected from triceps brachii (TB) and biceps brachii (BB), quadriceps femoris (QF) and hamstrings (HS) of limbs when fourteen infants were crawling at their self-selected speed. Antagonist muscle co-activation was evaluated by measuring two common indexes (co-activation index and Pearson's correlation coefficient).A significant difference was observed between upper limbs and lower limbs, but the relationship between MCo and speed of crawling was poor. This study is an opening for further investigation including a longitudinal study and compare against infant with CNS disorders.

  14. Human ZCCHC12 activates AP-1 and CREB signaling as a transcriptional co-activator.

    PubMed

    Li, Hong; Liu, Qian; Hu, Xiang; Feng, Du; Xiang, Shuanglin; He, Zhicheng; Hu, Xingwang; Zhou, Jianlin; Ding, Xiaofeng; Zhou, Chang; Zhang, Jian

    2009-07-01

    Mouse zinc finger CCHC domain containing 12 gene (ZCCHC12) has been identified as a transcriptional co-activator of bone morphogenetic protein (BMP) signaling, and human ZCCHC12 was reported to be related to non-syndromic X-linked mental retardation (NS-XLMR). However, the details of how human ZCCHC12 involve in the NS-XLMR still remain unclear. In this study, we identified a novel nuclear localization signal (NLS) in the middle of human ZCCHC12 protein which is responsible for the nuclear localization. Multiple-tissue northern blot analysis indicated that ZCCHC12 is highly expressed in human brain. Furthermore, in situ hybridization showed that ZCCHC12 is specifically expressed in neuroepithelium of forebrain, midbrain, and diencephalon regions of mouse E10.5 embryos. Luciferase reporter assays demonstrated that ZCCHC12 enhanced the transcriptional activities of activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as a coactivator. In conclusion, we identified a new NLS in ZCCHC12 and figured out that ZCCHC12 functions as a transcriptional co-activator of AP-1 and CREB.

  15. Physical and functional interactions of human papillomavirus E2 protein with nuclear receptor coactivators

    SciTech Connect

    Wu, M.-H.; Huang, C.-J.; Liu, S.-T.; Liu, P.-Y.; Ho, C.-L. . E-mail: shihming@ndmctsgh.edu.tw

    2007-05-11

    In addition to the human papillomavirus (HPV)-induced immortalization of epithelial cells, which usually requires integration of the viral DNA into the host cell genome, steroid hormone-activated nuclear receptors (NRs) are thought to bind to specific DNA sequences within transcriptional regulatory regions on the long control region to either increase or suppress transcription of dependent genes. In this study, our data suggest that the NR coactivator function of HPV E2 proteins might be mediated through physical and functional interactions with not only NRs but also the NR coactivators GRIP1 (glucocorticoid receptor-interacting protein 1) and Zac1 (zinc-finger protein which regulates apoptosis and cell cycle arrest 1), reciprocally regulating their transactivation activities. GRIP1 and Zac1 both were able to act synergistically with HPV E2 proteins on the E2-, androgen receptor-, and estrogen receptor-dependent transcriptional activation systems. GRIP1 and Zac1 might selectively function with HPV E2 proteins on thyroid receptor- and p53-dependent transcriptional activation, respectively. Hence, the transcriptional function of E2 might be mediated through NRs and NR coactivators to regulate E2-, NR-, and p53-dependent transcriptional activations.

  16. Identification of the functional domains of ANT-1, a novel coactivator of the androgen receptor

    SciTech Connect

    Fan Shuli; Goto, Kiminobu; Chen Guangchun; Morinaga, Hidetaka; Nomura, Masatoshi; Okabe, Taijiro; Nawata, Hajime; Yanase, Toshihiko . E-mail: yanase@intmed3.med.kyushu-u.ac.jp

    2006-03-03

    Previously, we identified a transcriptional coactivator for the activation function-1 (AF-1) domain of the human androgen receptor (AR) and designated it androgen receptor N-terminal domain transactivating protein-1 (ANT-1). This coactivator, which contains multiple tetratricopeptide repeat (TPR) motifs from amino acid (aa) 294, is identical to a component of U5 small nuclear ribonucleoprotein particles and binds specifically to the AR or glucocorticoid receptor. Here, we identified four distinct functional domains. The AR-AF-1-binding domain, which bound to either aa 180-360 or 360-532 in AR-AF-1, clearly overlapped with TAU-1 and TAU-5. This domain and the subnuclear speckle formation domain in ANT-1 were assigned within the TPR motifs, while the transactivating and nuclear localization signal domains resided within the N-terminal sequence. The existence of these functional domains may further support the idea that ANT-1 can function as an AR-AF-1-specific coactivator while mediating a transcription-splicing coupling.

  17. Play Therapy: A Review

    ERIC Educational Resources Information Center

    Porter, Maggie L.; Hernandez-Reif, Maria; Jessee, Peggy

    2009-01-01

    This article discusses the current issues in play therapy and its implications for play therapists. A brief history of play therapy is provided along with the current play therapy approaches and techniques. This article also touches on current issues or problems that play therapists may face, such as interpreting children's play, implementing…

  18. Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis▿

    PubMed Central

    Xu, Bin; Yang, Wei-Hsiung; Gerin, Isabelle; Hu, Chang-Deng; Hammer, Gary D.; Koenig, Ronald J.

    2009-01-01

    The nuclear receptor steroidogenic factor 1 (SF-1) is essential for adrenal development and steroidogenesis. The atypical orphan nuclear receptor Dax-1 binds to SF-1 and represses SF-1 target genes. Paradoxically, however, loss-of-function mutations of Dax-1 also cause adrenal hypoplasia, suggesting that Dax-1 may function as an SF-1 coactivator under some circumstances. Indeed, we found that Dax-1 can function as a dosage-dependent SF-1 coactivator. Both SF-1 and Dax-1 bind to steroid receptor RNA activator (SRA), a coactivator that functions as an RNA. The coactivator TIF2 also associates with Dax-1 and synergistically coactivates SF-1 target gene transcription. A naturally occurring Dax-1 mutation inhibits this transactivation, and the mutant Dax-1-TIF2 complex mislocalizes in living cells. Coactivation by Dax-1 is abolished by SRA knockdown. The expression of the steroidogenic gene products steroidogenic acute regulatory protein (StAR) and melanocortin 2 receptor is reduced in adrenal Y1 cells following the knockdown of endogenous SRA. Similarly, the knockdown of endogenous Dax-1 downregulates the expression of the steroidogenic gene products CYP11A1 and StAR in both H295R adrenal and MA-10 Leydig cells. These findings reveal novel functions of SRA and Dax-1 in steroidogenesis and adrenal biology. PMID:19188450

  19. A coactivator trap identifies NONO (p54nrb) as a component of the cAMP-signaling pathway.

    PubMed

    Amelio, Antonio L; Miraglia, Loren J; Conkright, Juliana J; Mercer, Becky A; Batalov, Serge; Cavett, Valerie; Orth, Anthony P; Busby, Jennifer; Hogenesch, John B; Conkright, Michael D

    2007-12-18

    Signal transduction pathways often use a transcriptional component to mediate adaptive cellular responses. Coactivator proteins function prominently in these pathways as the conduit to the basic transcriptional machinery. Here we present a high-throughput cell-based screening strategy, termed the "coactivator trap," to study the functional interactions of coactivators with transcription factors. We applied this strategy to the cAMP signaling pathway, which utilizes two families of coactivators, the cAMP response element binding protein (CREB) binding protein (CBP)/p300 family and the recently identified transducers of regulated CREB activity family (TORCs1-3). In addition to identifying numerous known interactions of these coactivators, this analysis identified NONO (p54(nrb)) as a TORC-interacting protein. RNA interference experiments demonstrate that NONO is necessary for cAMP-dependent activation of CREB target genes in vivo. Furthermore, TORC2 and NONO complex on cAMP-responsive promoters, and NONO acts as a bridge between the CREB/TORC complex and RNA polymerase II. These data demonstrate the utility of the coactivator trap by identification of a component of cAMP-mediated transcription.

  20. The Denial of Play.

    ERIC Educational Resources Information Center

    Sutton-Smith, Brian

    Well meaning parents and teachers often use children's play for the purposes of literacy and socialization. Yet, these attempts may deny play to children by subordinating play to some other concept. Evidence shows that even when parents play with their very young children they generally play games like shopping, cooking, and eating; whereas when…

  1. Children's Play and Television.

    ERIC Educational Resources Information Center

    Powell, Mark

    2001-01-01

    Discusses adverse effects of FCC deregulation of children's television programming on children's play behavior. Discusses the difference between play and imitation, the role of high quality dramatic play in healthy child development, the popularity of war play, and use of toys to increase dramatic play. Considers ways to help children gain control…

  2. Two people playing together: some thoughts on play, playing, and playfulness in psychoanalytic work.

    PubMed

    Vliegen, Nicole

    2009-01-01

    Children's play and the playfulness of adolescents and adults are important indicators of personal growth and development. When a child is not able to play, or an adolescent/adult is not able to be playful with thoughts and ideas, psychotherapy can help to find a more playful and creative stance. Elaborating Winnicott's (1968, p. 591) statement that "psychotherapy has to do with two people playing together," three perspectives on play in psychotherapy are discussed. In the first point of view, the child gets in touch with and can work through aspects of his or her inner world, while playing in the presence of the therapist. The power of play is then rooted in the playful communication with the self In a second perspective, in play the child is communicating aspects of his or her inner world to the therapist as a significant other. In a third view, in "playing together" child and therapist are coconstructing new meanings. These three perspectives on play are valid at different moments of a therapy process or for different children, depending on the complex vicissitudes of the child's constitution, life experiences, development, and psychic structure. Concerning these three perspectives, a parallel can be drawn between the therapist's attitude toward the child's play and the way the therapist responds to the verbal play of an adolescent or adult. We illustrate this with the case of Jacob, a late adolescent hardly able to play with ideas.

  3. The Play of Psychotherapy

    ERIC Educational Resources Information Center

    Marks-Tarlow, Terry

    2012-01-01

    The author reviews the role of play within psychotherapy. She does not discuss the formal play therapy especially popular for young children, nor play from the Jungian perspective that encourages the use of the sand tray with adults. Instead, she focuses on the informal use of play during psychotherapy as it is orchestrated intuitively. Because…

  4. Identification of SRC3/AIB1 as a Preferred Coactivator for Hormone-activated Androgen Receptor*♦

    PubMed Central

    Zhou, X. Edward; Suino-Powell, Kelly M.; Li, Jun; He, Yuanzheng; MacKeigan, Jeffrey P.; Melcher, Karsten; Yong, Eu-Leong; Xu, H. Eric

    2010-01-01

    Transcription activation by androgen receptor (AR), which depends on recruitment of coactivators, is required for the initiation and progression of prostate cancer, yet the mechanisms of how hormone-activated AR interacts with coactivators remain unclear. This is because AR, unlike any other nuclear receptor, prefers its own N-terminal FXXLF motif to the canonical LXXLL motifs of coactivators. Through biochemical and crystallographic studies, we identify that steroid receptor coactivator-3 (SRC3) (also named as amplified in breast cancer-1 or AIB1) interacts strongly with AR via synergistic binding of its first and third LXXLL motifs. Mutagenesis and functional studies confirm that SRC3 is a preferred coactivator for hormone-activated AR. Importantly, AR mutations found in prostate cancer patients correlate with their binding potency to SRC3, corroborating with the emerging role of SRC3 as a prostate cancer oncogene. These results provide a molecular mechanism for the selective utilization of SRC3 by hormone-activated AR, and they link the functional relationship between AR and SRC3 to the development and growth of prostate cancer. PMID:20086010

  5. Distinct roles of the steroid receptor coactivator 1 and of MED1 in retinoid-induced transcription and cellular differentiation.

    PubMed

    Flajollet, Sébastien; Lefebvre, Bruno; Rachez, Christophe; Lefebvre, Philippe

    2006-07-21

    Retinoic acid receptors (RARs) are the molecular relays of retinoid action on transcription, cellular differentiation and apoptosis. Transcriptional activation of retinoid-regulated promoters requires the dismissal of corepressors and the recruitment of coactivators to promoter-bound RAR. RARs recruit in vitro a plethora of coactivators whose actual contribution to retinoid-induced transcription is poorly characterized in vivo. Embryonal carcinoma P19 cells, which are highly sensitive to retinoids, were depleted from archetypical coactivators by RNAi. SRC1-deficient P19 cells showed severely compromised retinoid-induced responses, in agreement with the supposed role of SRC1 as a RAR coactivator. Unexpectedly, Med1/TRAP220/DRIP205-depleted cells exhibited an exacerbated response to retinoids, both in terms transcriptional responses and of cellular differentiation. Med1 depletion affected TFIIH and cdk9 detection at the prototypical retinoid-regulated RARbeta2 promoter, and favored a higher RNA polymerase II detection in transcribed regions of the RARbeta2 gene. Furthermore, the nature of the ligand impacted strongly on the ability of RARs to interact with a given coactivator and to activate transcription in intact cells. Thus RAR accomplishes transcriptional activation as a function of the ligand structure, by recruiting regulatory complexes which control distinct molecular events at retinoid-regulated promoters.

  6. Insights into Degron Recognition by APC/C Coactivators from the Structure of an Acm1-Cdh1 Complex

    PubMed Central

    He, Jun; Chao, William C.H.; Zhang, Ziguo; Yang, Jing; Cronin, Nora; Barford, David

    2013-01-01

    Summary The anaphase-promoting complex/cyclosome (APC/C) regulates sister chromatid segregation and the exit from mitosis. Selection of most APC/C substrates is controlled by coactivator subunits (either Cdc20 or Cdh1) that interact with substrate destruction motifs—predominantly the destruction (D) box and KEN box degrons. How coactivators recognize D box degrons and how this is inhibited by APC/C regulatory proteins is not defined at the atomic level. Here, from the crystal structure of S. cerevisiae Cdh1 in complex with its specific inhibitor Acm1, which incorporates D and KEN box pseudosubstrate motifs, we describe the molecular basis for D box recognition. Additional interactions between Acm1 and Cdh1 identify a third protein-binding site on Cdh1 that is likely to confer coactivator-specific protein functions including substrate association. We provide a structural rationalization for D box and KEN box recognition by coactivators and demonstrate that many noncanonical APC/C degrons bind APC/C coactivators at the D box coreceptor. PMID:23707760

  7. Validation of chemical compound library screening for transcriptional co-activator with PDZ-binding motif inhibitors using GFP-fused transcriptional co-activator with PDZ-binding motif.

    PubMed

    Nagashima, Shunta; Maruyama, Junichi; Kawano, Shodai; Iwasa, Hiroaki; Nakagawa, Kentaro; Ishigami-Yuasa, Mari; Kagechika, Hiroyuki; Nishina, Hiroshi; Hata, Yutaka

    2016-06-01

    Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in cell proliferation and differentiation. It is phosphorylated by large tumor suppressor kinases, the core kinases of the tumor-suppressive Hippo pathway. Phosphorylation induces the cytoplasmic accumulation of TAZ and its degradation. In human cancers, the deregulation of the Hippo pathway and gene amplification enhance TAZ activity. TAZ interacts with TEA domain family members (TEAD), and upregulates genes implicated in epithelial-mesenchymal transition. It also confers stemness to cancer cells. Thus, TAZ activation provides cancer cells with malignant properties and worsens the clinical prognosis. Therefore, TAZ attracts attention as a therapeutic target in cancer therapy. We applied 18 606 small chemical compounds to human osteosarcoma U2OS cells expressing GFP-fused TAZ (GFP-TAZ), monitored the subcellular localization of GFP-TAZ, and selected 33 compounds that shifted GFP-TAZ to the cytoplasm. Unexpectedly, only a limited number of compounds suppressed TAZ-mediated enhancement of TEAD-responsive reporter activity. Moreover, the compounds that weakened TEAD reporter activity did not necessarily decrease the unphosphorylated TAZ. In this study, we focused on three compounds that decreased both TEAD reporter activity and unphosphorylated TAZ, and treated several human cancer cells with these compounds. One compound did not show a remarkable effect, whereas the other two compounds compromised the cell viability in certain cancer cells. In conclusion, the GFP-TAZ-based assay can be used as the first screening for compounds that inhibit TAZ and show anticancer properties. To develop anticancer drugs, we need additional assays to select the compounds.

  8. Involvement of Steroid Receptor Coactivators/Ubiquitin Pathway Enzymes in Mammary Gland Tumorigenesis

    DTIC Science & Technology

    2005-06-01

    PRINCIPAL INVESTIGATOR: Xiuhua Gao, M.D., Ph.D. CONTRACTING ORGANIZATION: Baylor College of Medicine Houston, TX 77030 REPORT DATE: June 2005 TYPE OF REPORT...Summary 13 May 2002 - 12 May 2005 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Involvement of Steroid Receptor Coactivators/Ubiquitin Pathway 5b...Usell tc localization of MUcle ~s. Eý a, Eý Ca exaressiorn Crofile; E-p groffle; W1~’, API staining for nUcleUs. E6-AP DAMP -HI +E Figure 2: Effect of

  9. Targeting of the Nuclear Receptor Coactivator Isoform DELTA3AIB1 in Breast Cancer

    DTIC Science & Technology

    2007-03-01

    lab showed that the downregulation of overall levels of AIB1 plus ∆3AIB1, using a regulatable AIB1 directed ribozyme , resulted in reduced tumor...overall levels of AIB1 plus ∆3AIB1, using a regulatable AIB1 directed ribozyme , resulted in reduced tumor growth in vivo. Overall, these data indicate a...Reiter R, Powers C, Wellstein A, Riegel AT. Ribozyme targeting shows that the nuclear receptor coactivator AIB1 is a rate-limiting factor for estrogen

  10. Targeting of the Nuclear Receptor Coactivator Isoform Delta3Air in Breast Cancer

    DTIC Science & Technology

    2005-03-01

    Annabell Oh on a study in which siRNA directed at nucleotides 564-582 of AIBI to selectively reduce AIBI gene expression in the MCF-7 breast cancer...I mediates Insulin-like Growth Factor 1-Induced Phenotypic Changes in Human Breast Cancer Cells." Annabell Oh, Heinz Joachim List, Ronald Reiter...Receptor Coactivator AIB1 Mediates Insulin-like Growth Factor I-induced Phenotypic Changes in Human Breast Cancer Cells Annabell Oh,1 Heinz-Joachim List,1

  11. EGF Regulation of Nuclear Co-Activator AIB1 Function in Breast Cancer

    DTIC Science & Technology

    2005-04-01

    AD Award Number: DAMDl7-02-1-0394 TITLE: EGF Regulation of Nuclear Co-Activator AIBI Function in Breast Cancer PRINCIPAL INVESTIGATOR: Annabell S. Oh...Activator AIBI Function in DAMD17-02-1-0394 Breast Cancer 6. AUTHOR(S) Annabell S. Oh 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING...Factor-i Signaling in Human Breast Cancer. Doctoral dissertation of Annabell S. Oh, B.S. from the Department 14 of Tumor Biology, Georgetown

  12. Truncated Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α Splice Variant Is Severely Altered in Huntington's Disease

    PubMed Central

    Johri, Ashu; Starkov, Anatoly A.; Chandra, Abhishek; Hennessey, Thomas; Sharma, Abhijeet; Orobello, Sara; Squitieri, Ferdinando; Yang, Lichuan; Beal, M. Flint

    2011-01-01

    Background Reduced peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) gene expression has been observed in striatal cell lines, transgenic mouse models of Huntington's disease (HD), and brain tissue from HD patients. As this protein is a key transcription regulator of the expression of many mitochondrial proteins, these observations strongly support the role of aberrant mitochondrial function in the pathogenesis of HD. The PGC1α protein undergoes posttranslational modifications that affect its transcriptional activity. The N-truncated splice variant of PGC1α (NT-PGC1α) is produced in tissues, but the role of truncated splice variants of PGC1α in HD and in the regulation of mitochondrial gene expression has not been elucidated. Objective To examine the expression and modulation of expression of NT-PGC1α levels in HD. Methods and Results We found that the NT-PGC1α protein, a splice variant of ∼38 kDa, but not full-length PGC1α is severely and consistently altered in human HD brain, human HD myoblasts, mouse HD models, and HD striatal cells. NT-PGC1α levels were significantly upregulated in HD cells and mouse brown fat by physiologically relevant stimuli that are known to upregulate PGC1α gene expression. This resulted in an increase in mitochondrial gene expression and cytochrome c content. Conclusion Our data suggest that NT-PGC1α is an important component of the PGC1α transcriptional network, which plays a significant role in the pathogenesis of HD. Copyright © 2011 S. Karger AG, Basel PMID:21757867

  13. von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity.

    PubMed

    Panchenko, Maria V; Zhou, Mina I; Cohen, Herbert T

    2004-12-31

    Jade-1 was identified as a protein partner of the von Hippel-Lindau tumor suppressor pVHL. The interaction of Jade-1 and pVHL correlates with renal cancer risk. We have investigated the molecular function of Jade-1. Jade-1 has two zinc finger motifs called plant homeodomains (PHD). A line of evidence suggests that the PHD finger functions in chromatin remodeling and protein-protein interactions. We determined the cellular localization of Jade-1 and examined whether Jade-1 might have transcriptional and histone acetyltransferase (HAT) functions. Biochemical cell fractionation studies as well as confocal images of cells immunostained with a specific Jade-1 antibody revealed that endogenous Jade-1 is localized predominantly in the cell nucleus. Tethering of Gal4-Jade-1 fusion protein to Gal4-responsive promoters in co-transfection experiments activated transcription 5-6-fold, indicating that Jade-1 is a possible transcriptional activator. It was remarkable that overexpression of Jade-1 in cultured cells specifically increased levels of endogenous acetylated histone H4, but not histone H3, strongly suggesting that Jade-1 associates with HAT activity specific for histone H4. Deletion of the two PHD fingers completely abolished Jade-1 transcriptional and HAT activities, indicating that these domains are indispensable for Jade-1 nuclear functions. In addition, we demonstrated that TIP60, a known HAT with histone H4/H2A specificity, physically associates with Jade-1 and is able to augment Jade-1 HAT function in live cells, strongly suggesting that TIP60 might mediate Jade-1 HAT activity. Thus, Jade-1 is a novel candidate transcriptional co-activator associated with HAT activity and may play a key role in the pathogenesis of renal cancer and von Hippel-Lindau disease.

  14. PGC-1-related coactivator (PRC) negatively regulates endothelial adhesion of monocytes via inhibition of NF κB activity

    SciTech Connect

    Chengye, Zhan; Daixing, Zhou Qiang, Zhong; Shusheng, Li

    2013-09-13

    Highlights: •First time to display that LPS downregulate the expression of PRC. •First time to show that PRC inhibits the induction of VCAM-1 and E-selectin. •First time to show that PRC inhibit monocytes attachment to endothelial cells. •First time to display that PRC inhibits transcriptional activity of NF-κB. •PRC protects the respiration rate and suppresses the glycolysis rate against LPS. -- Abstract: PGC-1-related coactivator (PRC) is a growth-regulated transcriptional cofactor known to activate many of the nuclear genes specifying mitochondrial respiratory function. Endothelial dysfunction is a prominent feature found in many inflammatory diseases. Adhesion molecules, such as VCAM-1, mediate the attachment of monocytes to endothelial cells, thereby playing an important role in endothelial inflammation. The effects of PRC in regards to endothelial inflammation remain unknown. In this study, our findings show that PRC can be inhibited by the inflammatory cytokine LPS in cultured human umbilical vein endothelial cells (HUVECs). In the presence of LPS, the expression of endothelial cell adhesion molecular, such as VCAM1 and E-selectin, is found to be increased. These effects can be negated by overexpression of PRC. Importantly, monocyte adhesion to endothelial cells caused by LPS is significantly attenuated by PRC. In addition, overexpression of PRC protects mitochondrial metabolic function and suppresses the rate of glycolysis against LPS. It is also found that overexpression of PRC decreases the transcriptional activity of NF-κB. These findings suggest that PRC is a negative regulator of endothelial inflammation.

  15. AMP-activated protein kinase is required for exercise-induced peroxisome proliferator-activated receptor co-activator 1 translocation to subsarcolemmal mitochondria in skeletal muscle.

    PubMed

    Smith, Brennan K; Mukai, Kazutaka; Lally, James S; Maher, Amy C; Gurd, Brendon J; Heigenhauser, George J F; Spriet, Lawrence L; Holloway, Graham P

    2013-03-15

    In skeletal muscle, mitochondria exist as two subcellular populations known as subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS mitochondria preferentially respond to exercise training, suggesting divergent transcriptional control of the mitochondrial genomes. The transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and mitochondrial transcription factor A (Tfam) have been implicated in the direct regulation of the mitochondrial genome in mice, although SS and IMF differences may exist, and the potential signalling events regulating the mitochondrial content of these proteins have not been elucidated. Therefore, we examined the potential for PGC-1α and Tfam to translocate to SS and IMF mitochondria in human subjects, and performed experiments in rodents to identify signalling mechanisms regulating these translocation events. Acute exercise in humans and rats increased PGC-1α content in SS but not IMF mitochondria. Acute exposure to 5-aminoimidazole-4-carboxamide-1-β-ribofuranoside in rats recapitulated the exercise effect of increased PGC-1α protein within SS mitochondria only, suggesting that AMP-activated protein kinase (AMPK) signalling is involved. In addition, rendering AMPK inactive (AMPK kinase dead mice) prevented exercise-induced PGC-1α translocation to SS mitochondria, further suggesting that AMPK plays an integral role in these translocation events. In contrast to the conserved PGC-1α translocation to SS mitochondria across species (humans, rats and mice), acute exercise only increased mitochondrial Tfam in rats. Nevertheless, in rat resting muscle PGC-1α and Tfam co-immunoprecipate with α-tubulin, suggesting a common cytosolic localization. These data suggest that exercise causes translocation of PGC-1α preferentially to SS mitochondria in an AMPK-dependent manner.

  16. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

    PubMed Central

    Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

    2017-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

  17. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype?

    PubMed Central

    Wandschneider, Britta; Centeno, Maria; Vollmar, Christian; Symms, Mark; Thompson, Pamela J.; Duncan, John S.

    2014-01-01

    Juvenile myoclonic epilepsy is a heritable idiopathic generalized epilepsy syndrome, characterized by myoclonic jerks and frequently triggered by cognitive effort. Impairment of frontal lobe cognitive functions has been reported in patients with juvenile myoclonic epilepsy and their unaffected siblings. In a recent functional magnetic resonance imaging study we reported abnormal co-activation of the motor cortex and increased functional connectivity between the motor system and prefrontal cognitive networks during a working memory paradigm, providing an underlying mechanism for cognitively triggered jerks. In this study, we used the same task in 15 unaffected siblings (10 female; age range 18–65 years, median 40) of 11 of those patients with juvenile myoclonic epilepsy (six female; age range 22–54 years, median 35) and compared functional magnetic resonance imaging activations with 20 age- and gender-matched healthy control subjects (12 female; age range 23–46 years, median 30.5). Unaffected siblings showed abnormal primary motor cortex and supplementary motor area co-activation with increasing cognitive load, as well as increased task-related functional connectivity between motor and prefrontal cognitive networks, with a similar pattern to patients (P < 0.001 uncorrected; 20-voxel threshold extent). This finding in unaffected siblings suggests that altered motor system activation and functional connectivity is not medication- or seizure-related, but represents a potential underlying mechanism for impairment of frontal lobe functions in both patients and siblings, and so constitutes an endophenotype of juvenile myoclonic epilepsy. PMID:25001494

  18. Functional interaction of nuclear receptor coactivator 4 with aryl hydrocarbon receptor

    SciTech Connect

    Kollara, Alexandra; Brown, Theodore J. . E-mail: brown@mshri.on.ca

    2006-07-28

    Aryl hydrocarbon receptor (AhR) transcriptional activity is enhanced by interaction with p160 coactivators. We demonstrate here that NcoA4, a nuclear receptor coactivator, interacts with and amplifies AhR action. NcoA4-AhR and NcoA4-ARNT interactions were demonstrated by immunoprecipitation in T47D breast cancer and COS cells and was independent of ligand. Overexpression of NcoA4 enhanced AhR transcriptional activity 3.2-fold in the presence of dioxin, whereas overexpression of a splice variant, NcoA4{beta}, as well as a variant lacking the C-terminal region enhanced AhR transcriptional activity by only 1.6-fold. Enhanced AhR signaling by NcoA4 was independent of the LXXLL and FXXLF motifs or of the activation domain. NcoA4 protein localized to cytoplasm in the absence of dioxin and in both the cytoplasm and nucleus following dioxin treatment. NcoA4-facilitation of AhR activity was abolished by overexpression of androgen receptor, suggesting a potential competition of AhR and androgen receptor for NcoA4. These findings thus demonstrate a functional interaction between NcoA4 and AhR that may alter AhR activity to affect disease development and progression.

  19. Novel CARM1-Interacting Protein, DZIP3, Is a Transcriptional Coactivator of Estrogen Receptor-α

    PubMed Central

    Purcell, Daniel J.; Chauhan, Swati; Jimenez-Stinson, Diane; Elliott, Kathleen R.; Tsewang, Tenzin D.; Lee, Young-Ho; Marples, Brian

    2015-01-01

    Coactivator-associated arginine methyltransferase 1 (CARM1) is known to promote estrogen receptor (ER)α-mediated transcription in breast cancer cells. To further characterize the regulation of ERα-mediated transcription by CARM1, we screened CARM1-interacting proteins by yeast two-hybrid. Here, we have identified an E3 ubiquitin ligase, DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3), as a novel CARM1-binding protein. DZIP3-dependent ubiquitination of histone H2A has been associated with repression of transcription. However, ERα reporter gene assays demonstrated that DZIP3 enhanced ERα-mediated transcription and cooperated synergistically with CARM1. Interaction with CARM1 was observed with the E3 ligase RING domain of DZIP3. The methyltransferase activity of CARM1 partially contributed to the synergy with DZIP3 for transcription activation, but the E3 ubiquitin ligase activity of DZIP3 was dispensable. DZIP3 also interacted with the C-terminal activation domain 2 of glucocorticoid receptor-interacting protein 1 (GRIP1) and enhanced the interaction between GRIP1 and CARM1. Depletion of DZIP3 by small interfering RNA in MCF7 cells reduced estradiol-induced gene expression of ERα target genes, GREB1 and pS2, and DZIP3 was recruited to the estrogen response elements of the same ERα target genes. These results indicate that DZIP3 is a novel coactivator of ERα target gene expression. PMID:26505218

  20. Statins enhance peroxisome proliferator-activated receptor gamma coactivator-1alpha activity to regulate energy metabolism.

    PubMed

    Wang, Wenxian; Wong, Chi-Wai

    2010-03-01

    Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) serves as an inducible coactivator for a number of transcription factors to control energy metabolism. Insulin signaling through Akt kinase has been demonstrated to phosphorylate PGC-1alpha at serine 571 and downregulate its activity in the liver. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that reduce cholesterol synthesis in the liver. In this study, we found that statins reduced the active form of Akt and enhanced PGC-1alpha activity. Specifically, statins failed to activate an S571A mutant of PGC-1alpha. The activation of PGC-1alpha by statins selectively enhanced the expression of energy metabolizing enzymes and regulators including peroxisome proliferator-activated receptor alpha, acyl-CoA oxidase, carnitine palmitoyl transferase-1A, and pyruvate dehydrogenase kinase 4. Importantly, a constitutively active form of Akt partially reduced the statin-enhanced gene expression. Our study thus provides a plausible mechanistic explanation for the hypolipidemic effect of statin through elevating the rate of beta-oxidation and mitochondrial Kreb's cycle capacity to enhance fatty acid utilization while reducing the rate of glycolysis.

  1. The impact of language co-activation on L1 and L2 speech fluency.

    PubMed

    Bergmann, Christopher; Sprenger, Simone A; Schmid, Monika S

    2015-10-01

    Fluent speech depends on the availability of well-established linguistic knowledge and routines for speech planning and articulation. A lack of speech fluency in late second-language (L2) learners may point to a deficiency of these representations, due to incomplete acquisition. Experiments on bilingual language processing have shown, however, that there are strong reasons to believe that multilingual speakers experience co-activation of the languages they speak. We have studied to what degree language co-activation affects fluency in the speech of bilinguals, comparing a monolingual German control group with two bilingual groups: 1) first-language (L1) attriters, who have fully acquired German before emigrating to an L2 English environment, and 2) immersed L2 learners of German (L1: English). We have analysed the temporal fluency and the incidence of disfluency markers (pauses, repetitions and self-corrections) in spontaneous film retellings. Our findings show that learners to speak more slowly than controls and attriters. Also, on each count, the speech of at least one of the bilingual groups contains more disfluency markers than the retellings of the control group. Generally speaking, both bilingual groups-learners and attriters-are equally (dis)fluent and significantly more disfluent than the monolingual speakers. Given that the L1 attriters are unaffected by incomplete acquisition, we interpret these findings as evidence for language competition during speech production.

  2. Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer.

    PubMed

    Gregory, Christopher W; Fei, Xiaoyin; Ponguta, Liliana A; He, Bin; Bill, Heather M; French, Frank S; Wilson, Elizabeth M

    2004-02-20

    Growth of normal and neoplastic prostate is mediated by the androgen receptor (AR), a ligand-dependent transcription factor activated by high affinity androgen binding. The AR is highly expressed in recurrent prostate cancer cells that proliferate despite reduced circulating androgen. In this report, we show that epidermal growth factor (EGF) increases androgen-dependent AR transactivation in the recurrent prostate cancer cell line CWR-R1 through a mechanism that involves a post-transcriptional increase in the p160 coactivator transcriptional intermediary factor 2/glucocorticoid receptor interacting protein 1 (TIF2/GRIP1). Site-specific mutagenesis and selective MAPK inhibitors linked the EGF-induced increase in AR transactivation to phosphorylation of TIF2/GRIP1. EGF signaling increased the coimmunoprecipitation of TIF2 and AR. AR transactivation and its stimulation by EGF were reduced by small interfering RNA inhibition of TIF2/GRIP1 expression. The data indicate that EGF signaling through MAPK increases TIF2/GRIP1 coactivation of AR transactivation in recurrent prostate cancer.

  3. Defective co-activator recruitment in osteoclasts from microphthalmia-oak ridge mutant mice.

    PubMed

    Sharma, Sudarshana M; Sif, Said; Ostrowski, Michael C; Sankar, Uma

    2009-07-01

    The three basic DNA-binding domain mutations of the microphthalmia-associated transcription factor (Mitf), Mitf(mi/mi), Mitf(or/or), and Mitf(wh/wh) affect osteoclast differentiation with variable penetrance while completely impairing melanocyte development. Mitf(or/or) mice exhibit osteopetrosis that improves with age and their osteoclasts form functional multinuclear osteoclasts, raising the question as to why the Mitf(or/or) mutation results in osteopetrosis. Here we show that Mitf(or/or) osteoclasts express normal levels of acid phosphatase 5 (Acp5) mRNA and significantly lower levels of Cathepsin K (Ctsk) mRNA during receptor activator of nuclear factor kappa B (NFkappaB) ligand (RANKL)-mediated differentiation. Studies using chromatin immunoprecipitation (ChIP) analysis indicate that low levels of Mitf(or/or) protein are recruited to the Ctsk promoter. However, enrichment of Mitf-transcriptional co-activators PU.1 and Brahma-related gene 1 (Brg1) are severely impaired at the Ctsk promoter of Mitf(or/or) osteoclast precursors, indicating that defective recruitment of co-activators by the mutant Mitf(or/or) results in impaired Ctsk expression in osteoclasts. Cathepsin K may thus represent a unique class of Mitf-regulated osteoclast-specific genes that are important for osteoclast function.

  4. Expression of glucocorticoid receptor and coactivators in ependymal cells of male rats.

    PubMed

    Iwata, Kinuyo; Ozawa, Hitoshi

    2014-08-29

    Glucocorticoid receptor (GR) is a ligand-activated nuclear receptor which is widely distributed in the brain. Many types of neurons and glial cells are known to express GR, but the expression of GR in ependymal cells has yet to be identified. The present study therefore was undertaken to determine whether ependymal cells express GR and coactivators of GR, such as steroid receptor coactivator 1 (SRC-1) and p300. GR immunoreactivity was found in cells immunopositive to vimentin, a marker of ependymal cells, around the third ventricle (3V), the lateral ventricle (LV), the cerebral aqueduct and the fourth ventricle (4V), whereas the expression of GR in vimentin-immunoreactive (ir) cells was significantly reduced by adrenalectomy (ADX) in male rats. Vimentin-ir cells also expressed both SRC-1 and p300 at around 3V, LV, the cerebral aqueduct and 4V. ADX had no effect on the expression of SRC-1 or p300 in vimentin-ir cells. These results suggest that glucocorticoid may exert effects on ependymal cells through binding to GR followed by association with SRC-1 and p300 to maintain brain environment under stressful conditions.

  5. Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis.

    PubMed

    Dasgupta, Subhamoy; Putluri, Nagireddy; Long, Weiwen; Zhang, Bin; Wang, Jianghua; Kaushik, Akash K; Arnold, James M; Bhowmik, Salil K; Stashi, Erin; Brennan, Christine A; Rajapakshe, Kimal; Coarfa, Cristian; Mitsiades, Nicholas; Ittmann, Michael M; Chinnaiyan, Arul M; Sreekumar, Arun; O'Malley, Bert W

    2015-03-02

    Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2-driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer.

  6. The function of steroid receptor coactivator-1 in normal tissues and cancer.

    PubMed

    Walsh, Claire A; Qin, Li; Tien, Jean Ching-Yi; Young, Leonie S; Xu, Jianming

    2012-01-01

    In 1995, the steroid receptor coactivator-1 (SRC-1) was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.

  7. The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1.

    PubMed

    Han, Jinbo; Li, Erwei; Chen, Liqun; Zhang, Yuanyuan; Wei, Fangchao; Liu, Jieyuan; Deng, Haiteng; Wang, Yiguo

    2015-08-13

    Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.

  8. Playing It Right

    ERIC Educational Resources Information Center

    Tooley, Kay

    1973-01-01

    Described is one technique, referred to as "playing it right," to aid the therapist in the treatment of borderline children. "Playing it right" is based on the introduction of reality rules into the fantasy world of the borderline child. (CS)

  9. Role-Playing Mitosis.

    ERIC Educational Resources Information Center

    Wyn, Mark A.; Stegink, Steven J.

    2000-01-01

    Introduces a role playing activity that actively engages students in the learning process of mitosis. Students play either chromosomes carrying information, or cells in the cell membrane. (Contains 11 references.) (Author/YDS)

  10. Outdoor Creative Play Areas.

    ERIC Educational Resources Information Center

    Miller, Peggy L.

    Guidelines are given for the development of outdoor play areas on school sites to provide children with natural areas and simple facilities for creative play. Site selection, analysis, and development are discussed. Natural, topographical features of the environment and natural play equipment are suggested. Illustrations are also presented to aid…

  11. The Excellence of Play.

    ERIC Educational Resources Information Center

    Moyles, Janet R., Ed.

    Recognizing that for young children, play is a tool for learning, this book compiles contributions by different authors, reflecting both up-to-date research and current classroom practice as they relate to children's play. Part 1 of the book explores the value of play as a cross-cultural concept as well as one rooted in the Western world. Gender…

  12. Play Is the Way

    ERIC Educational Resources Information Center

    Gross, Steve; Sanderson, Rebecca Cornelli

    2012-01-01

    Historically, play has been viewed as a frivolous break from important endeavors like working and learning when, in fact, a child's ability to fully and freely engage in play is essential to their learning, productivity, and overall development. A natural drive to play is universal across all young mammals. Children from every society on earth…

  13. Life! Through Play.

    ERIC Educational Resources Information Center

    Van Anne, Nancy

    This speech presents a review of research concerning the nature of play. Some of the formal characteristics of play are: (a) it is distinct from ordinary life in its "temporariness" and its limitless location; (b) there is an element of tension in play that leads to uncertainty concerning the outcome but at the same time provides the opportunity…

  14. The Pedagogy of Play

    ERIC Educational Resources Information Center

    Giesbrecht, Sheila

    2012-01-01

    Play is important. Environmental educators Sobel and Louv write about the relationship between children and outside play and suggest that early transcendental experiences within nature allow children to develop empathetic orientations towards the natural world. Children who play out-of-doors develop an appreciation for the environment and…

  15. A Transcription Factor-Binding Domain of the Coactivator CBP Is Essential for Long-Term Memory and the Expression of Specific Target Genes

    ERIC Educational Resources Information Center

    Oliveira, Ana M. M.; Brindle, Paul K.; Abel, Ted; Wood, Marcelo A.; Attner, Michelle A.

    2006-01-01

    Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with…

  16. Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis: a study in healthy volunteers.

    PubMed

    Jacobs, G E; Hulskotte, E G J; de Kam, M L; Zha, G; Jiang, J; Hu, P; Zhao, Q; van Pelt, J; Goekoop, J G; Zitman, F G; van Gerven, J M A

    2010-12-01

    The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

  17. African oil plays

    SciTech Connect

    Clifford, A.J. )

    1989-09-01

    The vast continent of Africa hosts over eight sedimentary basins, covering approximately half its total area. Of these basins, only 82% have entered a mature exploration phase, 9% have had little or no exploration at all. Since oil was first discovered in Africa during the mid-1950s, old play concepts continue to bear fruit, for example in Egypt and Nigeria, while new play concepts promise to become more important, such as in Algeria, Angola, Chad, Egypt, Gabon, and Sudan. The most exciting developments of recent years in African oil exploration are: (1) the Gamba/Dentale play, onshore Gabon; (2) the Pinda play, offshore Angola; (3) the Lucula/Toca play, offshore Cabinda; (4) the Metlaoui play, offshore Libya/Tunisia; (5) the mid-Cretaceous sand play, Chad/Sudan; and (6) the TAG-I/F6 play, onshore Algeria. Examples of these plays are illustrated along with some of the more traditional oil plays. Where are the future oil plays likely to develop No doubt, the Saharan basins of Algeria and Libya will feature strongly, also the presalt of Equatorial West Africa, the Central African Rift System and, more speculatively, offshore Ethiopia and Namibia, and onshore Madagascar, Mozambique, and Tanzania.

  18. Lysine 246 of the vitamin D receptor is crucial for ligand-dependent interaction with coactivators and transcriptional activity.

    PubMed

    Jiménez-Lara, A M; Aranda, A

    1999-05-07

    Mutant K246A in the predicted helix 3 of the ligand-binding domain, as well as mutants L417S and E420Q in helix 12, which contains the core ligand-dependent transcriptional activation domain (AF-2), were generated to examine AF-2 activity of the vitamin D receptor (VDR). These mutations abolished vitamin D-dependent transactivation. In addition, VDR mediates a ligand-dependent repression of the response of the retinoic acid receptor beta2 promoter to retinoic acid, and the helix 3 and helix 12 mutants were unable to mediate transrepression. Furthermore, the VDR mutants, but not the native receptor, enhanced phorbol ester induction of the activator protein-1-containing collagenase promoter. The helix 3 and helix 12 mutations strikingly reduced the ability of VDR to interact with the coactivators steroid receptor coactivator-1, ACTR, and the CREB-binding protein. As a consequence, overexpression of steroid receptor coactivator-1 increased vitamin D-dependent transactivation by VDR but not by the K246A mutant. These results indicate that the lysine 246 participates, together with residues in helix 12, in the recruitment of coactivators and that AF-2 activity is involved both in ligand-dependent transactivation and in transrepression by VDR.

  19. Ash2 acts as an ecdysone receptor coactivator by stabilizing the histone methyltransferase Trr

    PubMed Central

    Carbonell, Albert; Mazo, Alexander; Serras, Florenci; Corominas, Montserrat

    2013-01-01

    The molting hormone ecdysone triggers chromatin changes via histone modifications that are important for gene regulation. On hormone activation, the ecdysone receptor (EcR) binds to the SET domain–containing histone H3 methyltransferase trithorax-related protein (Trr). Methylation of histone H3 at lysine 4 (H3K4me), which is associated with transcriptional activation, requires several cofactors, including Ash2. We find that ash2 mutants have severe defects in pupariation and metamorphosis due to a lack of activation of ecdysone-responsive genes. This transcriptional defect is caused by the absence of the H3K4me3 marks set by Trr in these genes. We present evidence that Ash2 interacts with Trr and is required for its stabilization. Thus we propose that Ash2 functions together with Trr as an ecdysone receptor coactivator. PMID:23197473

  20. Normal and Cancer-Related Functions of the p160 Steroid Receptor Coactivator (SRC) Family

    PubMed Central

    Xu, Jianming; Wu, Ray-Chang; O’Malley, Bert W.

    2010-01-01

    The three homologous members of the p160 SRC family (SRC-1, SRC-2 and SRC-3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all transcriptional coactivators. Recent work has indicated that the SRC genes are subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression along with the mechanisms by which SRCs promote breast and prostate cancer cell proliferation and survival have been identified, as have the specific contributions of individual SRC family members in spontaneous breast and prostate carcinogenesis in genetically manipulated mouse models. These studies have identified new challenges for cancer research and therapy. PMID:19701241

  1. Human transcriptional coactivator PC4 stimulates DNA end joining and activates DSB repair activity.

    PubMed

    Batta, Kiran; Yokokawa, Masatoshi; Takeyasu, Kunio; Kundu, Tapas K

    2009-01-23

    Human transcriptional coactivator PC4 is a highly abundant nuclear protein that is involved in diverse cellular processes ranging from transcription to chromatin organization. Earlier, we have shown that PC4, a positive activator of p53, overexpresses upon genotoxic insult in a p53-dependent manner. In the present study, we show that PC4 stimulates ligase-mediated DNA end joining irrespective of the source of DNA ligase. Pull-down assays reveal that PC4 helps in the association of DNA ends through its C-terminal domain. In vitro nonhomologous end-joining assays with cell-free extracts show that PC4 enhances the joining of noncomplementary DNA ends. Interestingly, we found that PC4 activates double-strand break (DSB) repair activity through stimulation of DSB rejoining in vivo. Together, these findings demonstrate PC4 as an activator of nonhomologous end joining and DSB repair activity.

  2. Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

    PubMed Central

    Wu, Mei-Yi; Fu, Junjiang; Xu, Jianming; O'Malley, Bert W; Wu, Ray-Chang

    2012-01-01

    SRC-3/AIB1 (steroid receptor coactivator 3/amplified in breast cancer 1) is an authentic oncogene that contributes to the development of drug resistance and poor disease-free survival in cancer patients. Autophagy is also an important cell death mechanism that has tumor suppressor function. In this study, we identified macrophage migration inhibitory factor (MIF) as a novel target gene of SRC-3 and demonstrated its importance in cell survival. Specifically, we showed that MIF is a strong suppressor of autophagic cell death. We further showed that suppression of MIF, in turn, induced autophagic cell death, enhanced chemosensitivity and inhibited tumorigenesis in a xenograft mouse tumorigenesis model. Our study demonstrated that regulation of MIF expression and suppression of autophagic cell death is a potent mechanism by which SRC-3 contributes to increased chemoresistance and tumorigenicity. PMID:22430150

  3. The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis.

    PubMed

    Aghajanova, Lusine; Velarde, Michael C; Giudice, Linda C

    2009-08-01

    Endometriosis is an estrogen-dependent disorder primarily associated with pelvic pain and infertility in up to 10% of women of reproductive age. Recent studies suggest that resistance to progesterone action may contribute to the development and pathophysiology of this disorder. In this study we examined the in vivo and in vitro expression and function of one progesterone receptor (PR) coactivator, Hic-5, in human endometrium and endometrial stromal fibroblasts (hESFs) from 29 women with and 30 (control) women without endometriosis. Hic-5 was highly expressed in stromal, but not epithelial, cells in women without endometriosis, in a cycle-dependent manner. In contrast, Hic-5 expression was not regulated during the menstrual cycle in hESFs from women with endometriosis and was significantly reduced in hESFs from women with vs. without disease. Hic-5 mRNA expression throughout the cycle in endometrium from control women, but not those with endometriosis, correlated with expression of PR. Hic-5 mRNA in hESFs was significantly up-regulated in control but not endometriosis hESFs after treatment in vitro with 8-bromoadenosine-cAMP for 96 h but only modestly after 14 d of progesterone treatment. Hic-5 silencing did not influence cAMP-regulated gene expression but affected genes regulated solely by progesterone (e.g. DKK1 and calcitonin). Together the data suggest that the proposed progesterone resistance in endometrium from women with endometriosis derives, in part, from impaired expression of the PR coactivator, Hic-5, in endometrial tissue and cultured endometrial stromal fibroblasts.

  4. DuOx2 Promoter Regulation by Hormones, Transcriptional Factors and the Coactivator TAZ.

    PubMed

    Cardoso-Weide, L C; Cardoso-Penha, R C; Costa, M W; Ferreira, A C F; Carvalho, D P; Santisteban, P S

    2015-03-01

    The production of H2O2, which is essential to thyroid hormone synthesis, involves two NADPH oxidases: dual oxidases 1 and 2 (DuOx1 and DuOx2). A functional study with human DuOx genes and their 5'-flanking regions showed that DuOx1 and -2 promoters are different from thyroid-specific gene promoters. Furthermore, their transcriptional activities are not restricted to thyroid cells. While regulation of Tg (thyroglobulin) and TPO (thyroperoxidase) expression have been extensively studied, DuOx2 promoter regulation by hormones and transcriptional factors need to be more explored. Herein we investigated the role of TSH, insulin and insulin-like growth factor 1 (IGF-1), as well as the cAMP effect on DuOx2 promoter (ptx41) activity in transfected rat thyroid cell lines (PCCL3). We also assessed DuOx2 promoter activity in the presence of transcriptional factors crucial to thyroid development such as TTF-1 (thyroid transcription factor 1), PAX8, CREB, DREAM, Nkx2.5 and the coactivator TAZ in HeLa and HEK 293T-transfected cells. Our results show that TSH and forskolin, which increase cAMP in thyroid cells, stimulated DuOx2 promoter activity. IGF-1 led to pronounced stimulation, while insulin induction was not statistically different from DuOx2 promoter basal activity. All transcriptional factors selected for this work and coactivator TAZ, except DREAM, stimulated DuOx2 promoter activity. Moreover, Nkx2.5 and TAZ synergistically increased DuOx2 promoter activity. In conclusion, we show that DuOx2 expression is regulated by hormones and transcription factors involved in thyroid organogenesis and carcinogenesis, reinforcing the importance of the control of H2O2 generation in the thyroid.

  5. DuOx2 Promoter Regulation by Hormones, Transcriptional Factors and the Coactivator TAZ

    PubMed Central

    Cardoso-Weide, L.C.; Cardoso-Penha, R.C.; Costa, M.W.; Ferreira, A.C.F.; Carvalho, D.P.; Santisteban, P.S.

    2015-01-01

    The production of H2O2, which is essential to thyroid hormone synthesis, involves two NADPH oxidases: dual oxidases 1 and 2 (DuOx1 and DuOx2). A functional study with human DuOx genes and their 5′-flanking regions showed that DuOx1 and −2 promoters are different from thyroid-specific gene promoters. Furthermore, their transcriptional activities are not restricted to thyroid cells. While regulation of Tg (thyroglobulin) and TPO (thyroperoxidase) expression have been extensively studied, DuOx2 promoter regulation by hormones and transcriptional factors need to be more explored. Herein we investigated the role of TSH, insulin and insulin-like growth factor 1 (IGF-1), as well as the cAMP effect on DuOx2 promoter (ptx41) activity in transfected rat thyroid cell lines (PCCL3). We also assessed DuOx2 promoter activity in the presence of transcriptional factors crucial to thyroid development such as TTF-1 (thyroid transcription factor 1), PAX8, CREB, DREAM, Nkx2.5 and the coactivator TAZ in HeLa and HEK 293T-transfected cells. Our results show that TSH and forskolin, which increase cAMP in thyroid cells, stimulated DuOx2 promoter activity. IGF-1 led to pronounced stimulation, while insulin induction was not statistically different from DuOx2 promoter basal activity. All transcriptional factors selected for this work and coactivator TAZ, except DREAM, stimulated DuOx2 promoter activity. Moreover, Nkx2.5 and TAZ synergistically increased DuOx2 promoter activity. In conclusion, we show that DuOx2 expression is regulated by hormones and transcription factors involved in thyroid organogenesis and carcinogenesis, reinforcing the importance of the control of H2O2 generation in the thyroid. PMID:25960956

  6. Adr1 and Cat8 Mediate Coactivator Recruitment and Chromatin Remodeling at Glucose-Regulated Genes

    PubMed Central

    Biddick, Rhiannon K.; Law, G. Lynn; Young, Elton T.

    2008-01-01

    Background Adr1 and Cat8 co-regulate numerous glucose-repressed genes in S. cerevisiae, presenting a unique opportunity to explore their individual roles in coactivator recruitment, chromatin remodeling, and transcription. Methodology/Principal Findings We determined the individual contributions of Cat8 and Adr1 on the expression of a cohort of glucose-repressed genes and found three broad categories: genes that need both activators for full derepression, genes that rely mostly on Cat8 and genes that require only Adr1. Through combined expression and recruitment data, along with analysis of chromatin remodeling at two of these genes, ADH2 and FBP1, we clarified how these activators achieve this wide range of co-regulation. We find that Adr1 and Cat8 are not intrinsically different in their abilities to recruit coactivators but rather, promoter context appears to dictate which activator is responsible for recruitment to specific genes. These promoter-specific contributions are also apparent in the chromatin remodeling that accompanies derepression: ADH2 requires both Adr1 and Cat8, whereas, at FBP1, significant remodeling occurs with Cat8 alone. Although over-expression of Adr1 can compensate for loss of Cat8 at many genes in terms of both activation and chromatin remodeling, this over-expression cannot complement all of the cat8Δ phenotypes. Conclusions/Significance Thus, at many of the glucose-repressed genes, Cat8 and Adr1 appear to have interchangeable roles and promoter architecture may dictate the roles of these activators. PMID:18197247

  7. Fatigue-induced adjustment in antagonist coactivation by old adults during a steadiness task.

    PubMed

    Arellano, Christopher J; Caha, David; Hennessey, Joseph E; Amiridis, Ioannis G; Baudry, Stéphane; Enoka, Roger M

    2016-05-01

    The purpose of this study was to determine the adjustments in the level of coactivation during a steadiness task performed by young and old adults after the torque-generating capacity of the antagonist muscles was reduced by a fatiguing contraction. Torque steadiness (coefficient of variation) and electromyographic activity of the extensor and flexor carpi radialis muscles were measured as participants matched a wrist extensor target torque (10% maximum) before and after sustaining an isometric contraction (30% maximum) with wrist flexors to task failure. Time to failure was similar (P = 0.631) for young (417 ± 121 s) and old (452 ± 174 s) adults. The reduction in maximal voluntary contraction torque (%initial) for the wrist flexors after the fatiguing contraction was greater (P = 0.006) for young (32.5 ± 13.7%) than old (21.8 ± 6.6%) adults. Moreover, maximal voluntary contraction torque for the wrist extensors declined for old (-13.7 ± 12.7%; P = 0.030), but not young (-5.4 ± 13.8%; P = 0.167), adults. Torque steadiness during the matching task with the wrist extensors was similar before and after the fatiguing contraction for both groups, but the level of coactivation increased after the fatiguing contraction for old (P = 0.049) but not young (P = 0.137) adults and was twice the amplitude for old adults (P = 0.002). These data reveal that old adults are able to adjust the amount of antagonist muscle activity independent of the agonist muscle during steady submaximal contractions.

  8. Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter

    SciTech Connect

    Matsui, Keiji; Oda, Kasumi; Mizuta, Shumpei; Ishino, Ruri; Urahama, Norinaga; Hasegawa, Natsumi; Roeder, Robert G.; Ito, Mitsuhiro

    2013-10-11

    Highlights: •MED1 is a bona fide T3-dependent coactivator on TSHB promoter. •Mice with LxxLL-mutant MED1 have attenuated TSHβ mRNA and thyroid hormone levels. •MED1 activates TSHB promoter T3-dependently in cultured cells. •T3-dependent MED1 action is enhanced when SRC1/SRC2 or HDAC2 is downregulated. •MED1 is also a T3-independent GATA2/Pit1 coactivator on TSHB promoter. -- Abstract: The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor β (TRβ) on the TSHβ gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHβ gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHβ gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHβ gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSHβ gene promoter.

  9. Identification of polyproline II regions derived from the proline-rich nuclear receptor coactivators PNRC and PNRC2: new insights for ERα coactivator interactions.

    PubMed

    Byrne, C; Miclet, E; Broutin, I; Gallo, D; Pelekanou, V; Kampa, M; Castanas, E; Leclercq, G; Jacquot, Y

    2013-10-01

    Protein-protein interactions are crucial for signal transductions required for cell differentiation and proliferation. Their modulation is therefore key to the development of therapeutic alternatives, particularly in the context of cancer. According to literature data, the polyproline-rich nuclear receptor coactivators PNRC and PNRC2 interact with estrogen receptor (ERα) through their PxxP SH3-binding motifs. In a search to identify the molecular features governing this interaction, we explored using electronic circular dichroism (ECD) spectroscopy and molecular dynamics (MD) calculations, the capacity of a range of putative biologically active peptides derived from these proteins and containing this PxxP motif(s) to form polyproline II (PPII) domains. An additional more exhaustive structural study on a lead PPII peptide was also performed using 2D nuclear magnetic resonance (NMR) spectroscopy. With the exception of one of all the investigated peptides (PNRC-D), binding assays failed to detect any affinity for Grb2 SH3 domains, suggesting that PPII motifs issued from Grb2 antagonists have a binding mode distinct from those derived from Grb2 agonists. Instead, the peptides revealed a competitive binding ability against a synthetic peptide (ERα17p) with a putative PPII-cognate domain located within a coregulator recruitment region of ERα (AF-2 site). Our work, which constitutes the first structure-related interaction study concerning PNRC and PNRC2, supports not only the existence of PxxP-induced PPII sequences in these coregulators, but also confirms the presence of a PPII recognition site in the AF-2 of the steroid receptor ERα, a region important for transcription regulation.

  10. Return to Play

    ERIC Educational Resources Information Center

    Mangan, Marianne

    2013-01-01

    Call it physical activity, call it games, or call it play. Whatever its name, it's a place we all need to return to. In the physical education, recreation, and dance professions, we need to redesign programs to address the need for and want of play that is inherent in all of us.

  11. The Fear of Play

    ERIC Educational Resources Information Center

    Almon, Joan

    2009-01-01

    Real play--play that is initiated and directed by children and that bubbles up from within the child rather than being imposed by adults--has largely disappeared from the landscape of childhood in the United States. There are many reasons for this, such as the long hours spent in front of screens each day or in activities organized by adults. In…

  12. Clinical Intuition at Play

    ERIC Educational Resources Information Center

    Marks-Tarlow, Terry

    2014-01-01

    A clinical psychologist and consulting psychotherapist discusses how elements of play, inherent in the intuition required in analysis, can provide a cornerstone for serious therapeutic work. She argues that many aspects of play--its key roles in human development, individual growth, and personal creativity, among others--can help therapists and…

  13. Play, Policy & Practice.

    ERIC Educational Resources Information Center

    Klugman, Edgar, Ed.

    In 1992, the U.S.-Israel Binational Science Foundation (BSF), in conjunction with Wheelock College (Boston), sponsored its second workshop on children's play, entitled "Play and Cognitive Ability: The Cultural Context." This volume reflects the presentations and discussions held at the workshop, offering perspectives on children's play…

  14. An Invitation to Play.

    ERIC Educational Resources Information Center

    Lange, Jenny; Zieher, Connie

    The manual is intended to provide suggestions for play to parents of young children with exceptional educational needs. Nineteen types of activities are described and pictured, including make believe with boxes, dress-up activities, kitchen play, bubbles, small motor activities using beans and buttons, use of throw-away materials, painting,…

  15. Role Playing and Skits

    ERIC Educational Resources Information Center

    Letwin, Robert, Ed.

    1975-01-01

    Explores non-scripted role playing, dialogue role playing, sociodrama, and skits as variations of simulation techniques. Provides step-by-step guidelines for conducting such sessions. Successful Meetings, Bill Communications, Inc., 1422 Chestnut Street, Philadelphia, Pa. 19102. Subscription Rates: yearly (US, Canada, Mexico) $14.00; elsewhere,…

  16. Growing Up with Play

    ERIC Educational Resources Information Center

    Katch, Jane

    2008-01-01

    Many adults are afraid of boys' play today, believing that the aggression that is so common in boys' fantasies is dangerous and might make them become violent men. This personal reflection describes the importance of multiage play in showing little boys how to become big boys while encouraging empathy and emotional growth in older boys. The author…

  17. Theories of Play.

    ERIC Educational Resources Information Center

    Peller, Lili E.

    1996-01-01

    Discusses several theories of play advanced before the development of psychoanalysis, including the theories of surplus energy, recreation, and practice. Examines the psychoanalytical view advanced by Freud and others, which focuses on the emotional release of play and its role in discovery and learning. (MDM)

  18. Play and Digital Media

    ERIC Educational Resources Information Center

    Johnson, James E.; Christie, James F.

    2009-01-01

    This article examines how play is affected by computers and digital toys. Research indicates that when computer software targeted at children is problem-solving oriented and open-ended, children tend to engage in creative play and interact with peers in a positive manner. On the other hand, drill-and-practice programs can be quite boring and limit…

  19. Let's Just Play

    ERIC Educational Resources Information Center

    Schmidt, Janet

    2003-01-01

    Children have a right to play. The idea is so simple it seems self-evident. But a stroll through any toy superstore, or any half-hour of so-called "children's" programming on commercial TV, makes it clear that violence, not play, dominates what's being sold. In this article, the author discusses how teachers and parents share the responsibility in…

  20. Play, Toys and Television.

    ERIC Educational Resources Information Center

    Brougere, Gilles

    In Western societies, television has transformed the life, culture, and points of reference of the child. Its particular sphere of influence is the child's play culture. This play culture is not hermetic: it is very oriented toward manipulation; has a symbolic role as a representational medium; evolves along with the child; has a certain amount of…

  1. Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-κB activation and caspase inhibition

    SciTech Connect

    Liu, Changjiang; Yang, Jixin; Fu, Wenjuan; Qi, Suqin; Wang, Chenmin; Quan, Chao; Yang, Kedi

    2014-06-15

    Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague–Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32 mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10 μM) for 24 h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposure to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity. - Highlights: • PCB153 led to hepatotoxicity through NF-κB activation and caspase inhibition. • The PI3K/Akt and ERK pathways were coactivated in vivo and in vitro by PCB153. • The ERK pathway regulated levels of phospho-NF-κB and caspase-9. • The PI3K/Akt pathway regulated levels of caspase-3, -8 and -9.

  2. The Scottish Play.

    ERIC Educational Resources Information Center

    Wheat, Chris

    1999-01-01

    Recounts an episode when, as young schoolboys, Prince Charles and classmates presented "Macbeth" as an end-of-term-play. Traces the events at school that took on different meanings when viewed from maturity. (NH)

  3. Taiman acts as a coactivator of Yorkie in the Hippo pathway to promote tissue growth and intestinal regeneration

    PubMed Central

    Wang, Chao; Yin, Meng-Xin; Wu, Wei; Dong, Liang; Wang, Shimin; Lu, Yi; Xu, Jinjin; Wu, Wenqing; Li, Sheng; Zhao, Yun; Zhang, Lei

    2016-01-01

    The Hippo signaling pathway regulates tissue growth and organ size through controlling cell growth, proliferation and apoptosis. During these processes, the coactivator Yorkie partners with the transcription factor Scalloped to mediate Hippo pathway-regulated cellular functions. Here, we demonstrate that Taiman facilitates the activity of Yorkie. First, Taiman overexpression upregulates Hippo pathway-responsive genes and induces tissue overgrowth. Second, the loss of tai downregulates the expression of Hippo pathway target genes and reduces organ size as well as tissue overgrowth caused by Yorkie overexpression. Furthermore, we provide evidence that Taiman binds to Yorkie and facilitates the activity of Yorkie-Scalloped to activate the transcription of several Hippo pathway target genes. Moreover, we found that the C-terminus of Taiman is indispensable for the function of Taiman in Hippo signaling. Finally, we demonstrate that Taiman is also required in intestinal stem cell proliferation. Our findings suggest Taiman is an essential coactivator of Yorkie. PMID:27462453

  4. Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes.

    PubMed

    Dhanasekaran, Karthigeyan; Kumari, Sujata; Boopathi, Ramachandran; Shima, Hiroki; Swaminathan, Amrutha; Bachu, Mahesh; Ranga, Udaykumar; Igarashi, Kazuhiko; Kundu, Tapas K

    2016-03-01

    Positive coactivator 4 (PC4), a human transcriptional coactivator, is involved in diverse processes like chromatin organization and transcription regulation. It is hyperphosphorylated during mitosis, with unknown significance. For the first time, we demonstrate the function of PC4 outside the nucleus upon nuclear envelope breakdown. A fraction of PC4 associates with Aurora A and Aurora B and undergoes phosphorylation, following which PC4 activates both Aurora A and B to sustain optimal kinase activity to maintain the phosphorylation gradient for the proper functioning of the mitotic machinery. This mitotic role is evident in PC4 knockdown cells where the defects are rescued only by the catalytically active Aurora kinases, but not the kinase-dead mutants. Similarly, the PC4 phosphodeficient mutant failed to rescue such defects. Hence, our observations establish a novel mitotic function of PC4 that might be dependent on Aurora kinase-mediated phosphorylation.

  5. Bifurcation analysis and potential landscapes of the p53-Mdm2 module regulated by the co-activator programmed cell death 5

    NASA Astrophysics Data System (ADS)

    Bi, Yuanhong; Yang, Zhuoqin; Zhuge, Changjing; Lei, Jinzhi

    2015-11-01

    The dynamics of p53 play important roles in the regulation of cell fate decisions in response to various stresses, and programmed cell death 5 (PDCD5) functions as a co-activator of p53 that modulates p53 dynamics. In the present paper, we investigated how p53 dynamics are modulated by PDCD5 during the deoxyribose nucleic acid damage response using methods of bifurcation analysis and potential landscape. Our results revealed that p53 activities display rich dynamics under different PDCD5 levels, including monostability, bistability with two stable steady states, oscillations, and the coexistence of a stable steady state (or two states) and an oscillatory state. The physical properties of the p53 oscillations were further demonstrated by the potential landscape in which the potential force attracts the system state to the limit cycle attractor, and the curl flux force drives coherent oscillation along the cyclic trajectory. We also investigated the efficiency with which PDCD5 induced p53 oscillations. We show that Hopf bifurcation can be induced by increasing the PDCD5 efficiency and that the system dynamics exhibited clear transition features in both barrier height and energy dissipation when the efficiency was close to the bifurcation point.

  6. Bifurcation analysis and potential landscapes of the p53-Mdm2 module regulated by the co-activator programmed cell death 5.

    PubMed

    Bi, Yuanhong; Yang, Zhuoqin; Zhuge, Changjing; Lei, Jinzhi

    2015-11-01

    The dynamics of p53 play important roles in the regulation of cell fate decisions in response to various stresses, and programmed cell death 5 (PDCD5) functions as a co-activator of p53 that modulates p53 dynamics. In the present paper, we investigated how p53 dynamics are modulated by PDCD5 during the deoxyribose nucleic acid damage response using methods of bifurcation analysis and potential landscape. Our results revealed that p53 activities display rich dynamics under different PDCD5 levels, including monostability, bistability with two stable steady states, oscillations, and the coexistence of a stable steady state (or two states) and an oscillatory state. The physical properties of the p53 oscillations were further demonstrated by the potential landscape in which the potential force attracts the system state to the limit cycle attractor, and the curl flux force drives coherent oscillation along the cyclic trajectory. We also investigated the efficiency with which PDCD5 induced p53 oscillations. We show that Hopf bifurcation can be induced by increasing the PDCD5 efficiency and that the system dynamics exhibited clear transition features in both barrier height and energy dissipation when the efficiency was close to the bifurcation point.

  7. Correspondent Functional Topography of the Human Left Inferior Parietal Lobule at Rest and Under Task Revealed Using Resting-State fMRI and Coactivation Based Parcellation.

    PubMed

    Wang, Jiaojian; Xie, Sangma; Guo, Xin; Becker, Benjamin; Fox, Peter T; Eickhoff, Simon B; Jiang, Tianzi

    2017-03-01

    The human left inferior parietal lobule (LIPL) plays a pivotal role in many cognitive functions and is an important node in the default mode network (DMN). Although many previous studies have proposed different parcellation schemes for the LIPL, the detailed functional organization of the LIPL and the exact correspondence between the DMN and LIPL subregions remain unclear. Mounting evidence indicates that spontaneous fluctuations in the brain are strongly associated with cognitive performance at the behavioral level. However, whether a consistent functional topographic organization of the LIPL during rest and under task can be revealed remains unknown. Here, they used resting-state functional connectivity (RSFC) and task-related coactivation patterns separately to parcellate the LIPL and identified seven subregions. Four subregions were located in the supramarginal gyrus (SMG) and three subregions were located in the angular gyrus (AG). The subregion-specific networks and functional characterization revealed that the four anterior subregions were found to be primarily involved in sensorimotor processing, movement imagination and inhibitory control, audition perception and speech processing, and social cognition, whereas the three posterior subregions were mainly involved in episodic memory, semantic processing, and spatial cognition. The results revealed a detailed functional organization of the LIPL and suggested that the LIPL is a functionally heterogeneous area. In addition, the present study demonstrated that the functional architecture of the LIPL during rest corresponds with that found in task processing. Hum Brain Mapp 38:1659-1675, 2017. © 2017 Wiley Periodicals, Inc.

  8. Looking into Children's Play Communities

    ERIC Educational Resources Information Center

    Mabry, Mark; Fucigna, Carolee

    2009-01-01

    Play, particularly children's sociodramatic play, is the cornerstone of early childhood classrooms in the United States. Early childhood educators learn and expound mantras of "the value of play," "play-based programs," "children learning through play," and "play as child's work." They strive to promote the importance of making a place for play in…

  9. Creative Outdoor Play Areas.

    ERIC Educational Resources Information Center

    Miller, Peggy L.

    Considering the creation of proper play areas for children (school sites, municipal and mini parks, private homes and backyards, shopping centers, apartment complexes, recreational areas, roadside parks, nursery schools, churches, summer camps, and drive-in theaters) as one of today's major challenges, the author recommends that professional…

  10. Play's Importance in School

    ERIC Educational Resources Information Center

    Sandberg, Anette; Heden, Rebecca

    2011-01-01

    The purpose of this study is to contribute knowledge on and gain an understanding of elementary school teachers' perspectives on the function of play in children's learning processes. The study is qualitative with a hermeneutical approach and has George Herbert Mead as a theoretical frame of reference. Interviews have been carried out with seven…

  11. Playing with Science

    ERIC Educational Resources Information Center

    Vieyra, Rebecca; Edwards, Teon; Rowe, Elizabeth; Asbell-Clarke, Jodi

    2015-01-01

    Gaming is becoming an effective form of learning and assessment and shouldn't be overlooked in an increasingly technological world. The games described in this article ("Impulse," "Quantum Spectre," and "Ravenous"), entertaining enough to be played by the general public, are also appropriate and useful in a classroom…

  12. "Playing" with Science

    ERIC Educational Resources Information Center

    Allen, Dave

    2012-01-01

    When faced with a multitude of tasks, any opportunity to "kill two birds with one stone" is welcome. Drama has always excited the author: as a child performing in plays, later as a student and now as a teacher directing performances and improvising within lessons. The author was lucky enough to have inspirational teachers during his…

  13. Integrated Play Groups

    ERIC Educational Resources Information Center

    Glovak, Sandra

    2007-01-01

    As an occupational therapist running social play groups with sensory integration for children on the autism spectrum, the author frequently doubted the wisdom of combining several children on the spectrum into a group. In fact, as the owner of a clinic she said, "No more!" The groups seemed like a waste of parents' time and money, and she refused…

  14. Abstraction through Game Play

    ERIC Educational Resources Information Center

    Avraamidou, Antri; Monaghan, John; Walker, Aisha

    2012-01-01

    This paper examines the computer game play of an 11-year-old boy. In the course of building a virtual house he developed and used, without assistance, an artefact and an accompanying strategy to ensure that his house was symmetric. We argue that the creation and use of this artefact-strategy is a mathematical abstraction. The discussion…

  15. One Play a Day

    ERIC Educational Resources Information Center

    Blankenship, Mark

    2007-01-01

    Undergraduate theater students rarely get the chance to work on a major world premiere, but this year hundreds of them will. Currently, more than 70 colleges and universities are participating in "365 Days/365 Plays," an ambitious project from Pulitzer Prize-winning playwright Suzan-Lori Parks. Every week, as they mount their portion of this epic…

  16. Yeast transcription co-activator Sub1 and its human homolog PC4 preferentially bind to G-quadruplex DNA

    PubMed Central

    Gao, Jun; Zybailov, Boris L.; Byrd, Alicia K.; Griffin, Wezley C.; Chib, Shubeena; Mackintosh, Samuel G.; Tackett, Alan J.; Raney, Kevin D.

    2015-01-01

    Using a G-quadruplex bait, we identified the transcription co-activator Sub1 as a G-quadruplex binding protein by quantitative LC-MS/MS and demonstrated in vivo G-quadruplex binding by ChIP. In vitro, Sub1, and its human homolog PC4, bind preferentially to G-quadruplexes. This provides a possible mechanism by which G-quadruplexes can influence gene transcription. PMID:25813861

  17. Modeling violations of the race model inequality in bimodal paradigms: co-activation from decision and non-decision components.

    PubMed

    Zehetleitner, Michael; Ratko-Dehnert, Emil; Müller, Hermann J

    2015-01-01

    The redundant-signals paradigm (RSP) is designed to investigate response behavior in perceptual tasks in which response-relevant targets are defined by either one or two features, or modalities. The common finding is that responses are speeded for redundantly compared to singly defined targets. This redundant-signals effect (RSE) can be accounted for by race models if the response times do not violate the race model inequality (RMI). When there are violations of the RMI, race models are effectively excluded as a viable account of the RSE. The common alternative is provided by co-activation accounts, which assume that redundant target signals are integrated at some processing stage. However, "co-activation" has mostly been only indirectly inferred and the accounts have only rarely been explicitly modeled; if they were modeled, the RSE has typically been assumed to have a decisional locus. Yet, there are also indications in the literature that the RSE might originate, at least in part, at a non-decisional or motor stage. In the present study, using a distribution analysis of sequential-sampling models (ex-Wald and Ratcliff Diffusion model), the locus of the RSE was investigated for two bimodal (audio-visual) detection tasks that strongly violated the RMI, indicative of substantial co-activation. Three model variants assuming different loci of the RSE were fitted to the quantile reaction time proportions: a decision, a non-decision, and a combined variant both to vincentized group as well as individual data. The results suggest that for the two bimodal detection tasks, co-activation has a shared decisional and non-decisional locus. These findings point to the possibility that the mechanisms underlying the RSE depend on the specifics (task, stimulus, conditions, etc.) of the experimental paradigm.

  18. The High Mobility Group Protein 1 Is a Coactivator of Herpes Simplex Virus ICP4 In Vitro

    PubMed Central

    Carrozza, Michael J.; DeLuca, Neal

    1998-01-01

    ICP4 is an activator of herpes simplex virus early and late gene transcription during infection and in vitro can efficiently activate the transcription of a core promoter template containing only a TATA box and an initiator element. In this study, we noted that the extent of activation by ICP4 in vitro was highly dependent on the purity of TFIID when recombinant TFIIB, TFIIE, and TFIIF were used as sources of these factors. ICP4 efficiently activated transcription with a crude TFIID fraction. However, when immunoaffinity-purified TFIID was used in place of the less pure TFIID, ICP4 activated transcription to a significantly lesser extent. This finding indicated that the crude TFIID fraction may contain additional factors that serve as coactivators of ICP4. To test this hypothesis, the crude TFIID preparation was further fractionated by gel filtration chromatography. The TFIID that eluted from the column lacked the hypothesized coactivator activity. A fraction well separated from TFIID contained an activity that when added with the TFIID fraction resulted in higher levels of transcription in the presence ICP4. Further purification of the coactivator-containing fraction resulted in the isolation of a single 30-kDa polypeptide (p30). p30 was also shown to serve as a coactivator of ICP4 with immunoaffinity-purified TFIID; however, p30 had no effect on basal transcription. Amino acid sequence analysis revealed that p30 was the high mobility group protein 1, which has been shown to facilitate the formation of higher-order DNA-protein complexes. PMID:9658123

  19. [RAC3 nuclear receptor co-activator has a protective role in the apoptosis induced by different stimuli].

    PubMed

    Coló, Georgina P; Rubio, María F; Alvarado, Cecilia V; Costas, Mónica A

    2007-01-01

    RAC3 belongs to the family of p160 nuclear receptors coactivators and it is over-expressed in several tumors. We have previously shown that RAC3 is a NF-kappaB coactivator. In this paper, we investigated the role of RAC3 in cell-sensitivity to apoptosis, using H2O2 in the human embryonic kidney cell line (HEK293), and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in a human chronic myeloid leukemia cell line (K562) naturally resistant to TRAIL. We observed that the tumoral K562 cells have high levels of RAC3 if compared with the non-tumoral HEK293 cells. The normal or transfected coactivator over-expression inhibits apoptosis through a diminished caspase activity and AIF nuclear translocation, increased NF-kappaB, AKT and p38, and decreased ERK activities. In contrast, inhibition of RAC3 by siRNA induced sensitivity of K562 to TRAIL-induced apoptosis. Such results suggest that over-expression of RAC3 contributes to tumor development through molecular mechanisms that do not depend strictly on acetylation and/or steroid hormones, which control cell death. This could be a possible target for future tumor therapies.

  20. Training through gametherapy promotes coactivation of the pelvic floor and abdominal muscles in young women, nulliparous and continents

    PubMed Central

    Silva, Valeria Regina; Riccetto, Cássio; Martinho, Natalia Miguel; Marques, Joseane; Carvalho, Leonardo Cesar; Botelho, Simone

    2016-01-01

    ABSTRACT Introduction and objectives: Several studies have been investigated co-activation can enhance the effectveness of PFM training protocols allowing preventive and therapeutic goals in pelvic floor dysfunctions. The objective of the present study was to investigate if an abdominal-pelvic protocol of training (APT) using gametherapy would allow co-activation of PFM and transversus abdominis/oblique internal (TrA/OI) muscles. Patients and methods: Twenty-five nulliparous, continent, young females, with median age 24.76 (±3.76) years were evaluated using digital palpation (DP) of PFM and surface electromyography of PFM and TrA/OI simultaneously, during maximal voluntary contraction (MVC), alternating PFM and TrA/OI contraction requests. All women participated on a supervised program of APT using gametherapy, that included exercises of pelvic mobilization associated to contraction of TrA/OI muscles oriented by virtual games, for 30 minutes, three times a week, in a total of 10 sessions. Electromyographic data were processed and analyzed by ANOVA - analysis of variance. Results: When MVC of TrA/OI was solicited, it was observed simultaneous increase of electromyographic activity of PFM (p=0.001) following ATP. However, EMG activity did not change significantly during MVC of PFM. Conclusion: Training using gametherapy allowed better co-activation of pelvic floor muscles in response to contraction of TrA, in young nulliparous and continent women. PMID:27564290

  1. Structural basis of coactivation of liver receptor homolog-1 by β-catenin

    PubMed Central

    Yumoto, Fumiaki; Nguyen, Phuong; Sablin, Elena P.; Baxter, John D.; Webb, Paul; Fletterick, Robert J.

    2012-01-01

    We report the three-dimensional structure of a β-catenin armadillo repeat in complex with the liver receptor homolog-1 (LRH-1) ligand binding domain at 2.8 Å resolution as the first structure of β-catenin in complex with any nuclear receptor. The surface of β-catenin that binds LRH-1 partly overlaps defined contact sites for peptide segments of β-catenin partners, including T-cell factor-4. The surface of LRH-1 that engages β-catenin is comprised of helices 1, 9, and 10 and is distinct from known interaction surfaces of LRH-1, including corepressor and coactivator binding sites. Targeted mutagenesis of amino acids forming both sides of the LRH-1/β-catenin interface reveals that they are essential for stable interactions between these proteins in solution. The LRH-1 binding site in β-catenin is also required for association with androgen receptor, providing evidence that the observed LRH-1/β-catenin interaction may be prototypic. PMID:22187462

  2. The tomato mosaic tobamovirus movement protein interacts with a putative transcriptional coactivator KELP.

    PubMed

    Matsushita, Y; Deguchi, M; Youda, M; Nishiguchi, M; Nyunoya, H

    2001-08-31

    Viral movement through plasmodesmata in host plants likely depends on the interaction between virus-encoded movement protein (MP) and host proteins. In order to search for MP-interacting protein (MIP), we carried out far-western screening of a Brassica campestris cDNA library using a recombinant MP of tomato mosaic tobamovirus (ToMV) as a probe. One of the positive clones, designated MIP102, was found to be a putative orthologue for a transcriptional coactivator KELP of Arabidopsis thaliana. In vitro analysis with recombinant proteins revealed that ToMV MP could bind to KELP proteins that are derived from different plant species. At least 31 amino acids from the carboxyl-terminus of ToMV MP were dispensable for the interaction with KELP. Other MPs, derived from crucifer tobamovirus CTMV-W and cucumber mosaic cucumovirus, also exhibited comparable binding abilities. This suggests that these MPs could commonly interact with KELP, possibly to modulate the host gene expression.

  3. Interaction proteome of human Hippo signaling: modular control of the co-activator YAP1.

    PubMed

    Hauri, Simon; Wepf, Alexander; van Drogen, Audrey; Varjosalo, Markku; Tapon, Nic; Aebersold, Ruedi; Gstaiger, Matthias

    2013-01-01

    Tissue homeostasis is controlled by signaling systems that coordinate cell proliferation, cell growth and cell shape upon changes in the cellular environment. Deregulation of these processes is associated with human cancer and can occur at multiple levels of the underlying signaling systems. To gain an integrated view on signaling modules controlling tissue growth, we analyzed the interaction proteome of the human Hippo pathway, an established growth regulatory signaling system. The resulting high-resolution network model of 480 protein-protein interactions among 270 network components suggests participation of Hippo pathway components in three distinct modules that all converge on the transcriptional co-activator YAP1. One of the modules corresponds to the canonical Hippo kinase cassette whereas the other two both contain Hippo components in complexes with cell polarity proteins. Quantitative proteomic data suggests that complex formation with cell polarity proteins is dynamic and depends on the integrity of cell-cell contacts. Collectively, our systematic analysis greatly enhances our insights into the biochemical landscape underlying human Hippo signaling and emphasizes multifaceted roles of cell polarity complexes in Hippo-mediated tissue growth control.

  4. A C-Terminal Acidic Domain Regulates Degradation of the Transcriptional Coactivator Bob1

    PubMed Central

    Wong, Christina S. F.; Möller, Andreas

    2013-01-01

    Bob1 (Obf-1 or OCA-B) is a 34-kDa transcriptional coactivator encoded by the Pou2af1 gene that is essential for normal B-cell development and immune responses in mice. During lymphocyte activation, Bob1 protein levels dramatically increase independently of mRNA levels, suggesting that the stability of Bob1 is regulated. We used a fluorescent protein-based reporter system to analyze protein stability in response to genetic and physiological perturbations and show that, while Bob1 degradation is proteasome mediated, it does not require ubiquitination of Bob1. Furthermore, degradation of Bob1 in B cells appears to be largely independent of the E3 ubiquitin ligase Siah. We propose a novel mechanism of Bob1 turnover in B cells, whereby an acidic region in the C terminus of Bob1 regulates the activity of degron signals elsewhere in the protein. Changes that make the C terminus more acidic, including tyrosine phosphorylation-mimetic mutations, stabilize the instable murine Bob1 protein, indicating that B cells may regulate Bob1 stability and activity via signaling pathways. Finally, we show that expressing a stable Bob1 mutant in B cells suppresses cell proliferation and induces changes in surface marker expression commonly seen during B-cell differentiation. PMID:24061476

  5. Creb coactivators direct anabolic responses and enhance performance of skeletal muscle

    PubMed Central

    Bruno, Nelson E; Kelly, Kimberly A; Hawkins, Richard; Bramah-Lawani, Mariam; Amelio, Antonio L; Nwachukwu, Jerome C; Nettles, Kendall W; Conkright, Michael D

    2014-01-01

    During the stress response to intense exercise, the sympathetic nervous system (SNS) induces rapid catabolism of energy reserves through the release of catecholamines and subsequent activation of protein kinase A (PKA). Paradoxically, chronic administration of sympathomimetic drugs (β-agonists) leads to anabolic adaptations in skeletal muscle, suggesting that sympathetic outflow also regulates myofiber remodeling. Here, we show that β-agonists or catecholamines released during intense exercise induce Creb-mediated transcriptional programs through activation of its obligate coactivators Crtc2 and Crtc3. In contrast to the catabolic activity normally associated with SNS function, activation of the Crtc/Creb transcriptional complex by conditional overexpression of Crtc2 in the skeletal muscle of transgenic mice fostered an anabolic state of energy and protein balance. Crtc2-overexpressing mice have increased myofiber cross-sectional area, greater intramuscular triglycerides and glycogen content. Moreover, maximal exercise capacity was enhanced after induction of Crtc2 expression in transgenic mice. Collectively these findings demonstrate that the SNS-adrenergic signaling cascade coordinates a transient catabolic stress response during high-intensity exercise, which is followed by transcriptional reprogramming that directs anabolic changes for recovery and that augments subsequent exercise performance. PMID:24674967

  6. Body Dissatisfaction in Early Adolescence: The Coactive Roles of Cognitive and Sociocultural Factors.

    PubMed

    Saunders, Jessica F; Frazier, Leslie D

    2016-09-12

    The sociocultural influences of the media, friends, and family on body dissatisfaction in young girls are well documented, yet further increasing our comprehension of the coaction of cognitive processes with sociocultural factors is crucial to understanding the dynamic emergence of body dissatisfaction in early adolescence. The current study examined the roles of appearance related messages and expectations from friends and family and selective attention biases in the development of body dissatisfaction. An ethnically and racially diverse sample of girls (72 % Hispanic White, 17.8 % African-American, 8.5 % non-Hispanic White, and 1.7 % Asian-American) between the ages of 9 and 13 (N = 118) completed multiple measures of attention, sociocultural attitudes toward weight and shape, and body dissatisfaction. The data from these measures were examined using path analysis. The final model fit well, and demonstrated the coactive effect of selective attention and sociocultural factors on body dissatisfaction. These findings will be instrumental in designing future body dissatisfaction intervention and prevention programs that incorporate cognitive factors, augmenting the existing sociocultural and psycho-educational frameworks.

  7. Remodeling the clock: coactivators and signal transduction in the circadian clockworks

    NASA Astrophysics Data System (ADS)

    Weber, Frank

    2009-03-01

    Most organisms on earth such as cyanobacteria, fungi, plants, insects, animals, and humans synchronize their physiological and behavioral activities with the environmental cycles of day and night. Significant progress has been made in unraveling the genetic components that constitute a molecular circadian clock, which facilitates the temporal control of physiology and behavior. Clock genes assemble interlocked transcriptional/translational feedback loops that underlie the circadian oscillations. Recent investigations revealed that posttranslational regulation of clock proteins is crucial for functioning of the molecular oscillator and for precise temporal control of circadian transcription. This review provides an overview of the homologous clockworks in Drosophila and mammals, with a special focus on recent insights in the posttranslational regulation of clock proteins as well as the role of coactivators, repressors, and signal transduction for circadian controlled genome-wide transcription. The emerging mechanisms of clock gene regulation provide an understanding of the temporal control of transcription in general and the circadian orchestration of physiology and behavior in particular.

  8. Remodeling the clock: coactivators and signal transduction in the circadian clockworks.

    PubMed

    Weber, Frank

    2009-03-01

    Most organisms on earth such as cyanobacteria, fungi, plants, insects, animals, and humans synchronize their physiological and behavioral activities with the environmental cycles of day and night. Significant progress has been made in unraveling the genetic components that constitute a molecular circadian clock, which facilitates the temporal control of physiology and behavior. Clock genes assemble interlocked transcriptional/translational feedback loops that underlie the circadian oscillations. Recent investigations revealed that posttranslational regulation of clock proteins is crucial for functioning of the molecular oscillator and for precise temporal control of circadian transcription. This review provides an overview of the homologous clockworks in Drosophila and mammals, with a special focus on recent insights in the posttranslational regulation of clock proteins as well as the role of coactivators, repressors, and signal transduction for circadian controlled genome-wide transcription. The emerging mechanisms of clock gene regulation provide an understanding of the temporal control of transcription in general and the circadian orchestration of physiology and behavior in particular.

  9. Functional interaction between the HIV transactivator Tat and the transcriptional coactivator PC4 in T cells.

    PubMed

    Holloway, A F; Occhiodoro, F; Mittler, G; Meisterernst, M; Shannon, M F

    2000-07-14

    The human immunodeficiency virus (HIV) transactivator Tat is a potent activator of transcription from the HIV long terminal repeat and is essential for efficient viral gene expression and replication. Tat has been shown to interact with components of the basal transcription machinery and transcriptional activators. Here we identify the cellular coactivator PC4 as a Tat-interacting protein using the yeast two-hybrid system and confirmed this interaction both in vitro and in vivo by coimmunoprecipitation. We found that this interaction has a functional outcome in that PC4 overexpression enhanced activation of the HIV long terminal repeat in transient transfection studies in a Tat-dependent manner. The domains of PC4 and Tat required for the interaction were mapped. In vitro binding studies showed that the basic transactivation-responsive binding domain of Tat is required for the interaction with PC4. The minimum region of PC4 required for Tat binding was amino acids 22-91, whereas mutation of the lysine-rich domain between amino acids 22 and 43 prevented interaction with Tat. Tat-PC4 interactions may be controlled by phosphorylation, because phosphorylation of PC4 by casein kinase II inhibited interactions with Tat both in vivo and in vitro. We propose that PC4 may be involved in linking Tat to the basal transcription machinery.

  10. Androgen Receptor Coactivator ARID4B Is Required for the Function of Sertoli Cells in Spermatogenesis.

    PubMed

    Wu, Ray-Chang; Zeng, Yang; Pan, I-Wen; Wu, Mei-Yi

    2015-09-01

    Defects in spermatogenesis, a process that produces spermatozoa inside seminiferous tubules of the testis, result in male infertility. Spermatogenic progression is highly dependent on a microenvironment provided by Sertoli cells, the only somatic cells and epithelium of seminiferous tubules. However, genes that regulate such an important activity of Sertoli cells are poorly understood. Here, we found that AT-rich interactive domain 4B (ARID4B), is essential for the function of Sertoli cells to regulate spermatogenesis. Specifically, we generated Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice, and showed that the Arid4bSCKO male mice were completely infertile with impaired testis development and significantly reduced testis size. Importantly, severe structural defects accompanied by loss of germ cells and Sertoli cell-only phenotype were found in many seminiferous tubules of the Arid4bSCKO testes. In addition, maturation of Sertoli cells was significantly delayed in the Arid4bSCKO mice, associated with delayed onset of spermatogenesis. Spermatogenic progression was also defective, showing an arrest at the round spermatid stage in the Arid4bSCKO testes. Interestingly, we showed that ARID4B functions as a "coactivator" of androgen receptor and is required for optimal transcriptional activation of reproductive homeobox 5, an androgen receptor target gene specifically expressed in Sertoli cells and critical for spermatogenesis. Together, our study identified ARID4B to be a key regulator of Sertoli cell function important for male germ cell development.

  11. Introducing co-activation pattern metrics to quantify spontaneous brain network dynamics.

    PubMed

    Chen, Jingyuan E; Chang, Catie; Greicius, Michael D; Glover, Gary H

    2015-05-01

    Recently, fMRI researchers have begun to realize that the brain's intrinsic network patterns may undergo substantial changes during a single resting state (RS) scan. However, despite the growing interest in brain dynamics, metrics that can quantify the variability of network patterns are still quite limited. Here, we first introduce various quantification metrics based on the extension of co-activation pattern (CAP) analysis, a recently proposed point-process analysis that tracks state alternations at each individual time frame and relies on very few assumptions; then apply these proposed metrics to quantify changes of brain dynamics during a sustained 2-back working memory (WM) task compared to rest. We focus on the functional connectivity of two prominent RS networks, the default-mode network (DMN) and executive control network (ECN). We first demonstrate less variability of global Pearson correlations with respect to the two chosen networks using a sliding-window approach during WM task compared to rest; then we show that the macroscopic decrease in variations in correlations during a WM task is also well characterized by the combined effect of a reduced number of dominant CAPs, increased spatial consistency across CAPs, and increased fractional contributions of a few dominant CAPs. These CAP metrics may provide alternative and more straightforward quantitative means of characterizing brain network dynamics than time-windowed correlation analyses.

  12. Mitochondrial Fusion Is Increased by the Nuclear Coactivator PGC-1β

    PubMed Central

    Liesa, Marc; Borda-d'Água, Bárbara; Medina-Gómez, Gema; Lelliott, Christopher J.; Paz, José Carlos; Rojo, Manuel; Palacín, Manuel; Vidal-Puig, Antonio; Zorzano, Antonio

    2008-01-01

    Background There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression. Methodology/Principal Findings Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1β is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1β increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1β-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1β increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor α (ERRα). Conclusions/Significance Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1β in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2. PMID:18974884

  13. Structural Basis for the Recognition Between HIV-1 Integrase and Transcriptional Coactivator p75

    SciTech Connect

    Cherepanov,P.; Ambrosio, A.; Rahman, S.; Ellenberger, T.; Engelman, A.

    2005-01-01

    Integrase (IN) is an essential retroviral enzyme, and human transcriptional coactivator p75, which is also referred to as lens epithelium-derived growth factor (LEDGF), is the dominant cellular binding partner of HIV-1 IN. Here, we report the crystal structure of the dimeric catalytic core domain of HIV-1 IN complexed to the IN-binding domain of LEDGF. Previously identified LEDGF hotspot residues anchor the protein to both monomers at the IN dimer interface. The principal structural features of IN that are recognized by the host factor are the backbone conformation of residues 168-171 from one monomer and a hydrophobic patch that is primarily comprised of {alpha}-helices 1 and 3 of the second IN monomer. Inspection of diverse retroviral primary and secondary sequence elements helps to explain the apparent lentiviral tropism of the LEDGF-IN interaction. Because the lethal phenotypes of HIV-1 mutant viruses unable to interact with LEDGF indicate that IN function is highly sensitive to perturbations of the structure around the LEDGF-binding site, we propose that small molecule inhibitors of the protein-protein interaction might similarly disrupt HIV-1 replication.

  14. Prediction of missing flow records using multilayer perceptron and coactive neurofuzzy inference system.

    PubMed

    Tfwala, Samkele S; Wang, Yu-Min; Lin, Yu-Chieh

    2013-01-01

    Hydrological data are often missing due to natural disasters, improper operation, limited equipment life, and other factors, which limit hydrological analysis. Therefore, missing data recovery is an essential process in hydrology. This paper investigates the accuracy of artificial neural networks (ANN) in estimating missing flow records. The purpose is to develop and apply neural networks models to estimate missing flow records in a station when data from adjacent stations is available. Multilayer perceptron neural networks model (MLP) and coactive neurofuzzy inference system model (CANFISM) are used to estimate daily flow records for Li-Lin station using daily flow data for the period 1997 to 2009 from three adjacent stations (Nan-Feng, Lao-Nung and San-Lin) in southern Taiwan. The performance of MLP is slightly better than CANFISM, having R (2) of 0.98 and 0.97, respectively. We conclude that accurate estimations of missing flow records under the complex hydrological conditions of Taiwan could be attained by intelligent methods such as MLP and CANFISM.

  15. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2

    PubMed Central

    Pan, Huize; Guan, Di; Liu, Xiaomeng; Li, Jingyi; Wang, Lixia; Wu, Jun; Zhou, Junzhi; Zhang, Weizhou; Ren, Ruotong; Zhang, Weiqi; Li, Ying; Yang, Jiping; Hao, Ying; Yuan, Tingting; Yuan, Guohong; Wang, Hu; Ju, Zhenyu; Mao, Zhiyong; Li, Jian; Qu, Jing; Tang, Fuchou; Liu, Guang-Hui

    2016-01-01

    SIRT6 belongs to the mammalian homologs of Sir2 histone NAD+-dependent deacylase family. In rodents, SIRT6 deficiency leads to aging-associated degeneration of mesodermal tissues. It remains unknown whether human SIRT6 has a direct role in maintaining the homeostasis of mesodermal tissues. To this end, we generated SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated functional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs were predominately characterized by dysregulated redox metabolism and increased sensitivity to the oxidative stress. In addition, we found SIRT6 in a protein complex with both nuclear factor erythroid 2-related factor 2 (NRF2) and RNA polymerase II, which was required for the transactivation of NRF2-regulated antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6-null hMSCs rescued premature cellular attrition. Our study uncovers a novel function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents a new layer of regulation of oxidative stress-associated stem cell decay. PMID:26768768

  16. The Insulin-Regulated CREB Coactivator TORC Promotes Stress Resistance in Drosophila

    PubMed Central

    Wang, Biao; Goode, Jason; Best, Jennifer; Meltzer, Jodi; Schilman, Pablo E.; Chen, Jian; Garza, Dan; Thomas, John B.; Montminy, Marc

    2013-01-01

    SUMMARY In fasted mammals, glucose homeostasis is maintained through induction of the cAMP response element-binding protein (CREB) coactivator transducer of regulated CREB activity 2 (TORC2), which stimulates the gluconeogenic program in concert with the forkhead factor FOXO1. Here we show that starvation also triggers TORC activation in Drosophila, where it maintains energy balance through induction of CREB target genes in the brain. TORC mutant flies have reduced glycogen and lipid stores and are sensitive to starvation and oxidative stress. Neuronal TORC expression rescued stress sensitivity as well as CREB target gene expression in TORC mutants. During refeeding, increases in insulin signaling inhibited TORC activity through the salt-inducible kinase 2 (SIK2)-mediated phosphorylation and subsequent degradation of TORC. Depletion of neuronal SIK2 increased TORC activity and enhanced stress resistance. As disruption of insulin signaling also augmented TORC activity in adult flies, our results illustrate the importance of an insulin-regulated pathway that functions in the brain to maintain energy balance. PMID:18460334

  17. Playing tricks to ions

    NASA Astrophysics Data System (ADS)

    Leibfried, Dietrich

    2017-01-01

    Ted Hänsch's career is defined by breaking new ground in experimental physics. Curiosity, vivid imagination, deep understanding, patience and tenacity are part of the winning formula, but perhaps an equally important ingredient may be Ted's favorite past-time of exploring new tricks in his "Spiellabor" (play-lab), that often resurfaced as key ingredients in rather serious experiments later. On the occasion of Ted's 75th birthday, a few past and potential future experiments with trapped ions are playfully surveyed here. Some of these tricks are already part of the trade, some are currently emerging and a few are mostly speculation today. Maybe some of the latter will be realized and even prove useful in the future.

  18. Viewpoints: The High School Play.

    ERIC Educational Resources Information Center

    Harbison, Lawrence; And Others

    1981-01-01

    Presents opinions of professionals on the current state of the high school play. Participants include a playwright, play supplier, high school theater instructor, workshop leader, and play publisher. Discusses selection, production, and performance of plays. (JMF)

  19. The Novel SLIK Histone Acetyltransferase Complex Functions in the Yeast Retrograde Response Pathway

    PubMed Central

    Pray-Grant, Marilyn G.; Schieltz, David; McMahon, Stacey J.; Wood, Jennifer M.; Kennedy, Erin L.; Cook, Richard G.; Workman, Jerry L.; Yates III, John R.; Grant, Patrick A.

    2002-01-01

    The SAGA complex is a conserved histone acetyltransferase-coactivator that regulates gene expression in Saccharomyces cerevisiae. SAGA contains a number of subunits known to function in transcription including Spt and Ada proteins, the Gcn5 acetyltransferase, a subset of TATA-binding-protein-associated factors (TAFIIs), and Tra1. Here we report the identification of SLIK (SAGA-like), a complex related in composition to SAGA. Notably SLIK uniquely contains the protein Rtg2, linking the function of SLIK to the retrograde response pathway. Yeast harboring mutations in both SAGA and SLIK complexes displays synthetic phenotypes more severe than those of yeast with mutation of either complex alone. We present data indicating that distinct forms of the SAGA complex may regulate specific subsets of genes and that SAGA and SLIK have multiple partly overlapping activities, which play a critical role in transcription by RNA polymerase II. PMID:12446794

  20. Play in Practice: Case Studies in Young Children's Play.

    ERIC Educational Resources Information Center

    Brown, Cheryl Render, Ed.; Marchant, Catherine, Ed.

    This book uses a collection of stories, or "cases," as a basis for reflection, discussion, and learning about the many roles "play" has in children's lives. Each of the 12 cases addresses an issue of play from one of three categories--the role of adults in play, the cultural meanings of play, and the issues related to play in…

  1. Crx activates opsin transcription by recruiting HAT-containing co-activators and promoting histone acetylation

    PubMed Central

    Peng, Guang-Hua; Chen, Shiming

    2008-01-01

    The homeodomain transcription factor Crx is required for expression of many photoreceptor genes in the mammalian retina. The mechanism by which Crx activates transcription remains to be determined. Using protein–protein interaction assays, Crx was found to interact with three co-activator proteins (complexes): STAGA, Cbp and p300, all of which possess histone acetyl-transferase (HAT) activity. To determine the role of Crx–HAT interactions in target gene chromatin modification and transcriptional activation, quantitative RT–PCR and chromatin immunoprecipitation were performed on Crx target genes, rod and cone opsins, in developing mouse retina. Although cone opsins are transcribed earlier than rhodopsin during development, the transcription of each gene is preceded by the same sequence of events in their promoter and enhancer regions: (i) binding of Crx, followed by (ii) binding of HATs, (iii) the acetylation of histone H3, then (iv) binding of other photoreceptor transcription factors (Nrl and Nr2e3) and RNA polymerase II. In Crx knockout mice (Crx−/−), the association of HATs and AcH3 with target promoter/enhancer regions was significantly decreased, which correlates with aberrant opsin transcription and photoreceptor dysfunction in these mice. Similar changes to the opsin chromatin were seen in Y79 retinoblastoma cells, where opsin genes are barely transcribed. These defects in Y79 cells can be reversed by expressing a recombinant Crx or applying histone deacetylase inhibitors. Altogether, these results suggest that one mechanism for Crx-mediated transcriptional activation is to recruit HATs to photoreceptor gene chromatin for histone acetylation, thereby inducing and maintaining appropriate chromatin configurations for transcription. PMID:17656371

  2. Control of Amino Acid Homeostasis by a Ubiquitin Ligase-Coactivator Protein Complex.

    PubMed

    Guerra, Damian; Chapiro, Sonia M; Pratelli, Réjane; Yu, Shi; Jia, Weitao; Leary, Julie; Pilot, Guillaume; Callis, Judy

    2017-03-03

    Intercellular amino acid transport is essential for the growth of all multicellular organisms, and its dysregulation is implicated in developmental disorders. By an unknown mechanism, amino acid efflux is stimulated in plants by overexpression of a membrane-localized protein (GLUTAMINE DUMPER 1 (GDU1)) that requires a ubiquitin ligase (LOSS OF GDU 2 (LOG2). Here we further explore the physiological consequences of the interaction between these two proteins. LOG2 ubiquitin ligase activity is necessary for GDU1-dependent tolerance to exogenous amino acids, and LOG2 self-ubiquitination was markedly stimulated by the GDU1 cytosolic domain, suggesting that GDU1 functions as an adaptor or coactivator of amino acid exporter(s). However, other consequences more typical of a ligase-substrate relationship are observed: disruption of the LOG2 gene increased the in vivo half-life of GDU1, mass spectrometry confirmed that LOG2 ubiquitinates GDU1 at cytosolic lysines, and GDU1 protein levels decreased upon co-expression with active, but not enzymatically inactive LOG2. Altogether these data indicate LOG2 negatively regulates GDU1 protein accumulation by a mechanism dependent upon cytosolic GDU1 lysines. Although GDU1-lysine substituted protein exhibited diminished in vivo ubiquitination, overexpression of GDU1 lysine mutants still conferred amino acid tolerance in a LOG2-dependent manner, consistent with GDU1 being both a substrate and facilitator of LOG2 function. From these data, we offer a model in which GDU1 activates LOG2 to stimulate amino acid export, a process that could be negatively regulated by GDU1 ubiquitination and LOG2 self-ubiquitination.

  3. NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors.

    PubMed

    Zhou, X; Hollern, D; Liao, J; Andrechek, E; Wang, H

    2013-03-28

    N-methyl-D-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration. The current prevailing theory suggests that synaptic and extrasynaptic NMDAR (syn- and ex-NMDAR) impose counteracting effects on cell fate, and neuronal cell death is mainly mediated by the activation of ex-NMDAR. However, several lines of evidence implicate the limitation of this theory. Here, we demonstrate that activation of NMDAR bi-directionally regulated cell fate through stimulating pro-survival or pro-death signaling. While low-dose NMDA preferentially activated syn-NMDAR and stimulated the extracellular signal-regulated kinase ½-cAMP responsive element-binding protein-brain-derived neurotrophic factor pro-survival signaling, higher doses progressively activated increasing amount of ex-NMDAR along with syn-NMDAR and triggered cell death program. Interestingly, the activation of syn- or ex-NMDAR alone did not cause measurable cell death. Consistently, activation of syn- or ex-NMDAR alone stimulated pro-survival but not pro-death signaling. Next, we found that memantine, which was previously identified as an ex-NMDAR blocker, inhibited intracellular signaling mediated by syn- or ex-NMDAR. Simultaneous blockade of syn- and ex-NMDAR by memantine dose-dependently attenuated NMDAR-mediated death. Moreover, long- but not short-term treatment with high-dose NMDA or oxygen-glucose deprivation triggered cell death and suppressed pro-survival signaling. These data implicate that activation of syn- or ex-NMDAR alone is not neurotoxic. The degree of excitotoxicity depends on the magnitude and duration of syn- and ex-NMDAR coactivation. Finally, genome-wide examination demonstrated that the activation of syn- and ex-NMDAR lead to significant overlapping rather than counteracting transcriptional responses.

  4. Towards an automated selection of spontaneous co-activity maps in functional magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Sourty, Marion; Thoraval, Laurent; Roquet, Daniel; Armspach, Jean-Paul; Foucher, Jack

    2015-03-01

    Functional magnetic resonance imaging allows to assess large scale functional integration of the brain. One of the leading techniques to extract functionally relevant networks is spatial independent component analysis (ICA). Spatial ICA separates independent spatial sources, many of whom are noise or imaging artifacts, whereas some do correspond to functionally relevant Spontaneous co-Activity Maps (SAMs). For research purposes, ICA is generally performed on group data. This strategy is well adapted to uncover commonly shared networks, e.g. resting-state networks, but fails to capture idiosyncratic functional networks which may be related to pathological activity, e.g. epilepsy, hallucinations. To capture these subject specific networks, ICA has to be applied to single subjects using a large number of components, from which a tenth are SAMs. Up to now, SAMs have to be selected manually by an expert based on predefined criteria. We aim to semi-automate the selection process in order to save time. To this end, some approaches have been proposed but none with the near 100 % sensitivity required for clinical purposes. In this paper, we propose a computerized version of the SAM's criteria used by experts, based on frequential and spatial characteristics of functional networks. Here we present a pre-selection method and its results at different resolutions, with different scanners or imaging sequences. While preserving a near 100 % sensitivity, it allows an average of 70 % reduction of components to be classified which save 55% of experts' time. In comparison, group ICA fails to detect about 25% of the SAMs.

  5. Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition.

    PubMed

    Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C; Renthal, Nora E; Johnston, John M; Mitsche, Matthew A; Chambon, Pierre; Xu, Jianming; O'Malley, Bert W; Mendelson, Carole R

    2015-07-01

    The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A-deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2-deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2-deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2-deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2-dependent production of SP-A and PAF is crucial for this process.

  6. Autoimmune regulator is acetylated by transcription coactivator CBP/p300

    SciTech Connect

    Saare, Mario; Rebane, Ana; Rajashekar, Balaji; Vilo, Jaak; Peterson, Paert

    2012-08-15

    The Autoimmune Regulator (AIRE) is a regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes. -- Highlights: Black-Right-Pointing-Pointer AIRE is acetylated by the acetyltransferases p300 and CBP. Black-Right-Pointing-Pointer Acetylation occurs between CARD and SAND domains and within the SAND domain. Black-Right-Pointing-Pointer Acetylation increases the size of AIRE nuclear dots. Black-Right-Pointing-Pointer Acetylation increases AIRE protein stability. Black-Right-Pointing-Pointer AIRE acetylation mimic regulates a different set of AIRE

  7. Farm Hall: The Play

    NASA Astrophysics Data System (ADS)

    Cassidy, David C.

    2013-03-01

    It's July 1945. Germany is in defeat and the atomic bombs are on their way to Japan. Under the direction of Samuel Goudsmit, the Allies are holding some of the top German nuclear scientists-among them Heisenberg, Hahn, and Gerlach-captive in Farm Hall, an English country manor near Cambridge, England. As secret microphones record their conversations, the scientists are unaware of why they are being held or for how long. Thinking themselves far ahead of the Allies, how will they react to the news of the atomic bombs? How will these famous scientists explain to themselves and to the world their failure to achieve even a chain reaction? How will they come to terms with the horror of the Third Reich, their work for such a regime, and their behavior during that period? This one-act play is based upon the transcripts of their conversations as well as the author's historical work on the subject.

  8. A Distinct Mechanism for Coactivator versus Corepressor Function by Histone Methyltransferase G9a in Transcriptional Regulation*

    PubMed Central

    Purcell, Daniel J.; Jeong, Kwang Won; Bittencourt, Danielle; Gerke, Daniel S.; Stallcup, Michael R.

    2011-01-01

    Histone methyltransferase G9a has been understood primarily as a corepressor of gene expression, but we showed previously that G9a positively regulates nuclear receptor-mediated transcription in reporter gene assays. Here, we show that endogenous G9a contributes to the estradiol (E2)-dependent induction of some endogenous target genes of estrogen receptor (ER)α in MCF-7 breast cancer cells while simultaneously limiting the E2-induced expression of other ERα target genes. Thus, G9a has a dual and selective role as a coregulator for ERα target genes. The ERα binding regions associated with the pS2 gene, which requires G9a for E2-induced expression, are transiently occupied by G9a at 15 min after beginning E2 treatment, suggesting that G9a coactivator function is by direct interaction with ERα target genes. Transient reporter gene assays with deletion mutants of G9a demonstrated that domains previously associated with the corepressor functions of G9a (C-terminal methyltransferase domain, ankyrin repeat domain, and cysteine-rich domain) were unnecessary for G9a coactivator function in ERα-mediated transcription. In contrast, the N-terminal domain of G9a was necessary and sufficient for enhancement of ERα-mediated transcription and for E2-induced occupancy of G9a on ERα binding sites associated with endogenous target genes of ERα. In addition to a previously identified activation domain, this region contains a previously uncharacterized ligand-dependent ERα binding function, indicating how G9a is recruited to the target genes. Therefore, the coactivator and corepressor functions of G9a involve different G9a domains and different molecular mechanisms. PMID:21984853

  9. Modeling violations of the race model inequality in bimodal paradigms: co-activation from decision and non-decision components

    PubMed Central

    Zehetleitner, Michael; Ratko-Dehnert, Emil; Müller, Hermann J.

    2015-01-01

    The redundant-signals paradigm (RSP) is designed to investigate response behavior in perceptual tasks in which response-relevant targets are defined by either one or two features, or modalities. The common finding is that responses are speeded for redundantly compared to singly defined targets. This redundant-signals effect (RSE) can be accounted for by race models if the response times do not violate the race model inequality (RMI). When there are violations of the RMI, race models are effectively excluded as a viable account of the RSE. The common alternative is provided by co-activation accounts, which assume that redundant target signals are integrated at some processing stage. However, “co-activation” has mostly been only indirectly inferred and the accounts have only rarely been explicitly modeled; if they were modeled, the RSE has typically been assumed to have a decisional locus. Yet, there are also indications in the literature that the RSE might originate, at least in part, at a non-decisional or motor stage. In the present study, using a distribution analysis of sequential-sampling models (ex-Wald and Ratcliff Diffusion model), the locus of the RSE was investigated for two bimodal (audio-visual) detection tasks that strongly violated the RMI, indicative of substantial co-activation. Three model variants assuming different loci of the RSE were fitted to the quantile reaction time proportions: a decision, a non-decision, and a combined variant both to vincentized group as well as individual data. The results suggest that for the two bimodal detection tasks, co-activation has a shared decisional and non-decisional locus. These findings point to the possibility that the mechanisms underlying the RSE depend on the specifics (task, stimulus, conditions, etc.) of the experimental paradigm. PMID:25805987

  10. Runx1 Regulation of Pu.1 Corepressor/Coactivator Exchange Identifies Specific Molecular Targets for Leukemia Differentiation Therapy*

    PubMed Central

    Gu, Xiaorong; Hu, Zhenbo; Ebrahem, Quteba; Crabb, John S.; Mahfouz, Reda Z.; Radivoyevitch, Tomas; Crabb, John W.; Saunthararajah, Yogen

    2014-01-01

    Gene activation requires cooperative assembly of multiprotein transcription factor-coregulator complexes. Disruption to cooperative assemblage could underlie repression of tumor suppressor genes in leukemia cells. Mechanisms of cooperation and its disruption were therefore examined for PU.1 and RUNX1, transcription factors that cooperate to activate hematopoietic differentiation genes. PU.1 is highly expressed in leukemia cells, whereas RUNX1 is frequently inactivated by mutation or translocation. Thus, coregulator interactions of Pu.1 were examined by immunoprecipitation coupled with tandem mass spectrometry/Western blot in wild-type and Runx1-deficient hematopoietic cells. In wild-type cells, the NuAT and Baf families of coactivators coimmunoprecipitated with Pu.1. Runx1 deficiency produced a striking switch to Pu.1 interaction with the Dnmt1, Sin3A, Nurd, CoRest, and B-Wich corepressor families. Corepressors of the Polycomb family, which are frequently inactivated by mutation or deletion in myeloid leukemia, did not interact with Pu.1. The most significant gene ontology association of Runx1-Pu.1 co-bound genes was with macrophages, therefore, functional consequences of altered corepressor/coactivator exchange were examined at Mcsfr, a key macrophage differentiation gene. In chromatin immunoprecipitation analyses, high level Pu.1 binding to the Mcsfr promoter was not decreased by Runx1 deficiency. However, the Pu.1-driven shift from histone repression to activation marks at this locus, and terminal macrophage differentiation, were substantially diminished. DNMT1 inhibition, but not Polycomb inhibition, in RUNX1-translocated leukemia cells induced terminal differentiation. Thus, RUNX1 and PU.1 cooperate to exchange corepressors for coactivators, and the specific corepressors recruited to PU.1 as a consequence of RUNX1 deficiency could be rational targets for leukemia differentiation therapy. PMID:24695740

  11. Imagination, Playfulness, and Creativity in Children's Play with Different Toys

    ERIC Educational Resources Information Center

    Mo????ller, Signe?? Juhl?

    2015-01-01

    Based on a four-month experimental study of preschool children's play with creative-construction and social-fantasy toys, the author examines the in?uence of both types of toys on the play of preschool children. Her comparative analysis considers the impact of transformative play on the development of imagination during play activities and…

  12. Playing My Heart Out: Original Play as Adventure.

    ERIC Educational Resources Information Center

    Donaldson, O. Fred

    1999-01-01

    "Original" play denotes play that is pre-cultural--before conceptualizations and learned responses. Four anecdotes about play with an infant with Down's syndrome, a child with leukemia, a lioness, and a dying woman illustrate the connections between beings and between the ordinary and the sacred during trusting, fearless, playful encounters. (SV)

  13. Child's Play: Revisiting Play in Early Childhood Settings.

    ERIC Educational Resources Information Center

    Dau, Elizabeth, Ed.; Jones, Elizabeth, Ed.

    Noting that play is an essential aspect of learning for young children, this book presents a collection of articles on children's play in Australia. Part 1, "Play, Development, and Learning," contains the following chapters: (1) "The Role of Play in Development and Learning" (Ann Glover); (2) "Stop, Look, and Listen:…

  14. Transcriptional Regulation in Saccharomyces cerevisiae: Transcription Factor Regulation and Function, Mechanisms of Initiation, and Roles of Activators and Coactivators

    PubMed Central

    Hahn, Steven; Young, Elton T.

    2011-01-01

    Here we review recent advances in understanding the regulation of mRNA synthesis in Saccharomyces cerevisiae. Many fundamental gene regulatory mechanisms have been conserved in all eukaryotes, and budding yeast has been at the forefront in the discovery and dissection of these conserved mechanisms. Topics covered include upstream activation sequence and promoter structure, transcription factor classification, and examples of regulated transcription factor activity. We also examine advances in understanding the RNA polymerase II transcription machinery, conserved coactivator complexes, transcription activation domains, and the cooperation of these factors in gene regulatory mechanisms. PMID:22084422

  15. Synergistic Co-activation Increases the Extent of Mechanical Interaction between Rat Ankle Plantar-Flexors

    PubMed Central

    Tijs, Chris; van Dieën, Jaap H.; Baan, Guus C.; Maas, Huub

    2016-01-01

    Force transmission between rat ankle plantar-flexors has been found for physiological muscle lengths and relative positions, but only with all muscles maximally activated. The aims of this study were to assess intermuscular mechanical interactions between ankle plantar-flexors during (i) fully passive conditions, (ii) excitation of soleus (SO), (iii) excitation of lateral gastrocnemius (LG), and (iv) during co-activation of SO, and LG (SO&LG). We assessed effects of proximal lengthening of LG and plantaris (PL) muscles (i.e., simulating knee extension) on forces exerted at the distal SO tendon (FSO) and on the force difference between the proximal and distal LG+PL tendons (ΔFLG+PL) of the rat. LG+PL lengthening increased FSO to a larger extent (p = 0.017) during LG excitation (0.0026 N/mm) than during fully passive conditions (0.0009 N/mm). Changes in FSO in response to LG+PL lengthening were lower (p = 0.002) during SO only excitation (0.0056 N/mm) than during SO&LG excitation (0.0101 N/mm). LG+PL lengthening changed ΔFLG+PL to a larger extent (p = 0.007) during SO excitation (0.0211 N/mm) than during fully passive conditions (0.0157 N/mm). In contrast, changes in ΔFLG+PL in response to LG+PL lengthening during LG excitation (0.0331 N/mm) were similar (p = 0.161) to that during SO&LG excitation (0.0370 N/mm). In all conditions, changes of FSO were lower than those of ΔFLG+PL. This indicates that muscle forces were transmitted not only between LG+PL and SO, but also between LG+PL and other surrounding structures. In addition, epimuscular myofascial force transmission between rat ankle plantar-flexors was enhanced by muscle activation. However, the magnitude of this interaction was limited. PMID:27708589

  16. Renal Proximal Tubule Na,K-ATPase is Controlled by CREB Regulated Transcriptional CoActivators as well as Salt Inducible Kinase 1

    PubMed Central

    Taub, Mary; Garamella, Sudha; Kim, Dongwook; Rajkhowa, Trivikram; Cutuli, Facundo

    2015-01-01

    Sodium reabsorption by the kidney is regulated by locally produced natriuretic and anti-natriuretic factors, including dopamine and norepinephrine, respectively. Previous studies indicated that signaling events initiated by these natriuretic and anti-natriuretic factors achieve their effects by altering the phosphorylation of Na,K-ATPase in the renal proximal tubule, and that Protein Kinase A (PKA) and Calcium mediated signaling pathways are involved. The same signaling pathways also control the transcription of the Na,K-ATPase β subunit gene atp1b1 in renal proximal tubule cells. In this report, evidence is presented that 1) both the recently discovered cAMP-Regulated Transcriptional Coactivators (CRTCs), and Salt Inducible Kinase 1 (SIK1) contribute to the transcriptional regulation of atp1b1 in renal proximal tubule (RPT) cells, and 2) that renal effectors including norepinephrine, dopamine, prostaglandins and sodium play a role. Exogenously expressed CRTCs stimulate atp1b1 transcription. Evidence for a role of endogenous CRTCs includes the loss of transcriptional regulation of atp1b1 by a dominant negative CRTC, as well as by a CREB mutant, with an altered CRTC binding site. In a number of experimental systems, SIK phosphorylates CRTCs, which are then sequestered in the cytoplasm, preventing their nuclear effects. Consistent with such a role of SIK in primary RPT cells, atp1b1 transcription increased in the presence of a dominant negative SIK1, and in addition, regulation by dopamine, norepinephrine and monensin was disrupted by a dominant negative SIK1. These latter observations can be explained, if SIK1 is phosphorylated and inactivated in the presence of these renal effectors. Our results support the hypothesis that Na,K-ATPase in the renal proximal tubule is regulated at the transcriptional level via SIK1 and CRTCs by renal effectors, in addition to the previously reported control of the phosphorylation of Na,K-ATPase. PMID:26432356

  17. A preliminary investigation of the role of the transcription co-activators YAP/TAZ of the Hippo signalling pathway in canine and feline mammary tumours.

    PubMed

    Beffagna, G; Sacchetto, R; Cavicchioli, L; Sammarco, A; Mainenti, M; Ferro, S; Trez, D; Zulpo, M; Michieletto, S; Cecchinato, A; Goldschmidt, M; Zappulli, V

    2016-01-01

    Breast cancer is the most common cancer in women worldwide. Cancer metastases are responsible for the high mortality rate. A small but distinct subset of cells, cancer stem cells (CSCs), have the capacity to self-renew, initiate tumour formation, and develop metastases. The CSC content in human breast cancer correlates with the Hippo tumour suppressor signalling pathway. Specifically, the activity of YAP/TAZ, transcription co-activators of the Hippo pathway, sustains the self-renewal and tumour-initiation capacities of CSCs. Little is known about YAP/TAZ in canine and feline mammary tumours, which are very common tumours. The preliminary aim of the study was to investigate the expression of YAP/TAZ in canine and feline mammary tumours by Western blot and immunohistochemistry. Increased cytoplasmic and nuclear expression of YAP/TAZ was observed in all carcinomas compared to normal tissues, indicating neoplastic deregulation of the Hippo pathway. Nuclear expression significantly increased in grade III (high grade carcinomas) compared to grade I (low grade carcinomas) tumours, suggesting that YAP/TAZ play a role in the increased aggressiveness of these tumours. Moreover, different scoring systems for immunohistochemical analyses were compared and the H index and the Allred scores were the most significant. In conclusion, YAP/TAZ are expressed in aggressive canine and feline mammary tumours as reported in some human cancers. Further studies might better elucidate the role of the Hippo pathway in prognosis and as a target for new therapies. In addition, tumours in dogs and cats may be a useful model to study this pathway.

  18. Play and Positive Group Dynamics

    ERIC Educational Resources Information Center

    Thompson, Pam; White, Samantha

    2010-01-01

    Play is an important part of a child's life and essential to learning and development (Vygotsky, 1978). It is vital that students participate in play and that play be conducted in a restorative manner. Play allows a variety of group dynamics to emerge. Irvin Yalom (1995) identifies 11 curative factors of the group experience. These factors include…

  19. Playful Learning and Montessori Education

    ERIC Educational Resources Information Center

    Lillard, Angeline S.

    2013-01-01

    Although Montessori education is often considered a form of playful learning, Maria Montessori herself spoke negatively about a major component of playful learning--pretend play, or fantasy--for young children. In this essay, the author discusses this apparent contradiction: how and why Montessori education includes elements of playful learning…

  20. Play: Children's Context for Development.

    ERIC Educational Resources Information Center

    Klein, Tovah P.; Wirth, Daniele; Linas, Keri

    2003-01-01

    Defines the elements of play, illuminating its central role in young children's learning and development. Focuses on how play experiences contribute to children's independence in negotiating, its role in keeping children involved, and the play-reality distinction. Offers suggestions to teachers for facilitating and supporting children's play,…

  1. Rough and Tumble Play 101

    ERIC Educational Resources Information Center

    Carlson, Frances

    2009-01-01

    Many people fear that play-fighting or rough and tumble play is the same as real fighting. There is also a fear that this rough play will become real fighting if allowed to continue. Most of all, parents and teachers fear that during the course of rough and tumble play a child may be hurt. To provide for and allow children to play rough without…

  2. Rifampicin-Independent Interactions between the Pregnane X Receptor Ligand Binding Domain and Peptide Fragments of Coactivator and Corepressor Proteins

    PubMed Central

    Navaratnarajah, Punya; Steele, Bridgett L.; Redinbo, Matthew R.; Thompson, Nancy L.

    2015-01-01

    The pregnane X receptor (PXR), a member of the nuclear receptor superfamily, regulates the expression of drug-metabolizing enzymes in a ligand-dependent manner. The conventional view of nuclear receptor action is that ligand binding enhances the receptor’s affinity for coactivator proteins, while decreasing its affinity for corepressors. To date, however, no known rigorous biophysical studies have been conducted to investigate the interaction among PXR, its coregulators, and ligands. In this work, steady-state total internal reflection fluorescence microscopy (TIRFM) and total internal reflection with fluorescence recovery after photobleaching were used to measure the thermodynamics and kinetics of the interaction between the PXR ligand binding domain and a peptide fragment of the steroid receptor coactivator-1 (SRC-1) in the presence and absence of the established PXR agonist, rifampicin. Equilibrium dissociation and dissociation rate constants of ~5 μM and ~2 s−1, respectively, were obtained in the presence and absence of rifampicin, indicating that the ligand does not enhance the affinity of the PXR and SRC-1 fragments. Additionally, TIRFM was used to examine the interaction between PXR and a peptide fragment of the corepressor protein, the silencing mediator for retinoid and thyroid receptors (SMRT). An equilibrium dissociation constant of ~70 μM was obtained for SMRT in the presence and absence of rifampicin. These results strongly suggest that the mechanism of ligand-dependent activation in PXR differs significantly from that seen in many other nuclear receptors. PMID:22185585

  3. Downregulation of Steroid Receptor Coactivator-2 Modulates Estrogen-Responsive Genes and Stimulates Proliferation of MCF-7 Breast Cancer Cells

    PubMed Central

    Fenne, Ingvild S.; Helland, Thomas; Flågeng, Marianne H.; Dankel, Simon N.; Mellgren, Gunnar; Sagen, Jørn V.

    2013-01-01

    The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERα) activity. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERα and changed expression of the ERα target gene, pS2. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells. PMID:23936147

  4. Jab1 is a T2-dependent coactivator or a T3-dependent corepressor of TRB1-mediated gene regulation.

    PubMed

    Hernández-Puga, Gabriela; Mendoza, Arturo; León-Del-Río, Alfonso; Orozco, Aurea

    2017-03-01

    Thyroid hormones (THs) induce pleiotropic effects in vertebrates, mainly through the activation or repression of gene expression. These mechanisms involve thyroid hormone binding to thyroid hormone receptors, an event that is followed by the sequential recruitment of coactivator or corepressor proteins, which in turn modify the rate of transcription. In the present study, we looked for specific coregulators recruited by the long isoform of the teleostean thyroid hormone receptor beta 1 (L-Trb1) when bound to the bioactive TH, 3,5-T2 (T2). We found that jun activation domain-binding protein1 (Jab1) interacts with L-Trb1 + T2 complex. Using both the teleostean and human TRB1 isoforms, we characterized the Jab1-TRB1 by yeast two-hybrid, pull-down and transactivation assays. Our results showed that the TRB1-Jab1 interaction was ligand dependent and involved the single Jab1 nuclear receptor box, as well as the ligand-binding and N-terminal domains of TRB1. We also provide evidence of ligand-dependent, dual coregulatory properties of Jab1. Indeed, when T2 is bound to L-Trb1 or hTRB1, Jab1 acts as a coactivator of transcription, whereas it has corepressor activity when interacting with the T3-bound S-Trb1 or hTRB1. These mechanisms could explain some of the pleiotropic actions exerted by THs to regulate diverse biological processes.

  5. The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo

    SciTech Connect

    Eisele, Petra Sabine; Furrer, Regula; Beer, Markus

    2015-08-28

    The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is abundantly expressed in trained muscles and regulates muscle adaptation to endurance exercise. Inversely, mice lacking a functional PGC-1α allele in muscle exhibit reduced muscle functionality and increased inflammation. In isolated muscle cells, PGC-1α and the related PGC-1β counteract the induction of inflammation by reducing the activity of the nuclear factor κB (NFκB). We now tested the effects of these metabolic regulators on inflammatory reactions in muscle tissue of control and muscle-specific PGC-1α/-1β transgenic mice in vivo in the basal state as well as after an acute inflammatory insult. Surprisingly, we observed a PGC-1-dependent alteration of the cytokine profile characterized by an increase in anti-inflammatory factors and a strong suppression of the pro-inflammatory interleukin 12 (IL-12). In conclusion, the anti-inflammatory environment in muscle that is promoted by the PGC-1s might contribute to the beneficial effects of these coactivators on muscle function and provides a molecular link underlying the tight mutual regulation of metabolism and inflammation. - Highlights: • Muscle PGC-1s are insufficient to prevent acute systemic inflammation. • The muscle PGC-1s however promote a local anti-inflammatory environment. • This anti-inflammatory environment could contribute to the therapeutic effect of the PGC-1s.

  6. Pain as a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems.

    PubMed

    Benedetti, Fabrizio; Thoen, Wilma; Blanchard, Catherine; Vighetti, Sergio; Arduino, Claudia

    2013-03-01

    Pain is a negative emotional experience that is modulated by a variety of psychological factors through different inhibitory systems. For example, endogenous opioids and cannabinoids have been found to be involved in stress and placebo analgesia. Here we show that when the meaning of the pain experience is changed from negative to positive through verbal suggestions, the opioid and cannabinoid systems are co-activated and these, in turn, increase pain tolerance. We induced ischemic arm pain in healthy volunteers, who had to tolerate the pain as long as possible. One group was informed about the aversive nature of the task, as done in any pain study. Conversely, a second group was told that the ischemia would be beneficial to the muscles, thus emphasizing the usefulness of the pain endurance task. We found that in the second group pain tolerance was significantly higher compared to the first one, and that this effect was partially blocked by the opioid antagonist naltrexone alone and by the cannabinoid antagonist rimonabant alone. However, the combined administration of naltrexone and rimonabant antagonized the increased tolerance completely. Our results indicate that a positive approach to pain reduces the global pain experience through the co-activation of the opioid and cannabinoid systems. These findings may have a profound impact on clinical practice. For example, postoperative pain, which means healing, can be perceived as less unpleasant than cancer pain, which means death. Therefore, the behavioral and/or pharmacological manipulation of the meaning of pain can represent an effective approach to pain management.

  7. The transcriptional co-activator LEDGF/p75 displays a dynamic scan-and-lock mechanism for chromatin tethering

    PubMed Central

    Hendrix, Jelle; Gijsbers, Rik; De Rijck, Jan; Voet, Arnout; Hotta, Jun-ichi; McNeely, Melissa; Hofkens, Johan; Debyser, Zeger; Engelborghs, Yves

    2011-01-01

    Nearly all cellular and disease related functions of the transcriptional co-activator lens epithelium-derived growth factor (LEDGF/p75) involve tethering of interaction partners to chromatin via its conserved integrase binding domain (IBD), but little is known about the mechanism of in vivo chromatin binding and tethering. In this work we studied LEDGF/p75 in real-time in living HeLa cells combining different quantitative fluorescence techniques: spot fluorescence recovery after photobleaching (sFRAP) and half-nucleus fluorescence recovery after photobleaching (hnFRAP), continuous photobleaching, fluorescence correlation spectroscopy (FCS) and an improved FCS method to study diffusion dependence of chromatin binding, tunable focus FCS. LEDGF/p75 moves about in nuclei of living cells in a chromatin hopping/scanning mode typical for transcription factors. The PWWP domain of LEDGF/p75 is necessary, but not sufficient for in vivo chromatin binding. After interaction with HIV-1 integrase via its IBD, a general protein–protein interaction motif, kinetics of LEDGF/p75 shift to 75-fold larger affinity for chromatin. The PWWP is crucial for locking the complex on chromatin. We propose a scan-and-lock model for LEDGF/p75, unifying paradoxical notions of transcriptional co-activation and lentiviral integration targeting. PMID:20974633

  8. Co-activation of NR2A and NR2B subunits induces resistance to fear extinction.

    PubMed

    Leaderbrand, Katherine; Corcoran, Kevin A; Radulovic, Jelena

    2014-09-01

    Unpredictable stress is known to profoundly enhance susceptibility to fear and anxiety while reducing the ability to extinguish fear when threat is no longer present. Accordingly, partial aversive reinforcement, via random exposure to footshocks, induces fear that is resistant to extinction. Here we sought to determine the hippocampal mechanisms underlying susceptibility versus resistance to context fear extinction as a result of continuous (CR) and partial (PR) reinforcement, respectively. We focused on N-methyl-D-aspartate receptor (NMDAR) subunits 2A and B (NR2A and NR2B) as well as their downstream signaling effector, extracellular signal-regulated kinase (ERK), based on their critical role in the acquisition and extinction of fear. Pharmacological inactivation of NR2A, but not NR2B, blocked extinction after CR, whereas inactivation of NR2A, NR2B, or both subunits facilitated extinction after PR. The latter finding suggests that co-activation of NR2A and NR2B contributes to persistent fear following PR. In contrast to CR, PR increased membrane levels of ERK and NR2 subunits after the conditioning and extinction sessions, respectively. In parallel, nuclear activation of ERK was significantly reduced after the extinction session. Thus, co-activation and increased surface expression of NR2A and NR2B, possibly mediated by ERK, may cause persistent fear. These findings suggest that patients with post-traumatic stress disorder (PTSD) may benefit from antagonism of specific NR2 subunits.

  9. Fast skeletal muscle troponin I is a co-activator of estrogen receptor-related receptor {alpha}

    SciTech Connect

    Li Yuping; Chen Bin; Chen Jian; Lou Guiyu; Chen Shiuan; Zhou Dujin

    2008-05-16

    ERR{alpha} (estrogen receptor-related receptor {alpha}) is a member of the nuclear receptor superfamily. To further our understanding of the detailed molecular mechanism of transcriptional regulation by ERR{alpha}, we searched for ERR{alpha}-interacting proteins using a yeast two-hybrid system by screening a human mammary gland cDNA expression library with the ligand-binding domain (LBD) of ERR{alpha} as the 'bait'. Fast skeletal muscle troponin I (TNNI2), along with several known nuclear receptor co-activators, were isolated. We demonstrated that TNNI2 localizes to the cell nucleus and interacts with ERR{alpha} in co-immunoprecipitation experiments. GST pull-down assays also revealed that TNNI2 interacts directly with ERR{alpha}. Through luciferase reporter gene assays, TNNI2 was found to enhance the transactivity of ERR{alpha}. Combining mutagenesis and yeast two-hybrid assays, we mapped the ERR{alpha}-interacting domain on TNNI2 to a region encompassing amino acids 1-128. These findings reveal a new function for TNNI2 as a co-activator of ERR{alpha}.

  10. DCA1 Acts as a Transcriptional Co-activator of DST and Contributes to Drought and Salt Tolerance in Rice.

    PubMed

    Cui, Long-Gang; Shan, Jun-Xiang; Shi, Min; Gao, Ji-Ping; Lin, Hong-Xuan

    2015-10-01

    Natural disasters, including drought and salt stress, seriously threaten food security. In previous work we cloned a key zinc finger transcription factor gene, Drought and Salt Tolerance (DST), a negative regulator of drought and salt tolerance that controls stomatal aperture in rice. However, the exact mechanism by which DST regulates the expression of target genes remains unknown. In the present study, we demonstrated that DST Co-activator 1 (DCA1), a previously unknown CHY zinc finger protein, acts as an interacting co-activator of DST. DST was found to physically interact with itself and to form a heterologous tetramer with DCA1. This transcriptional complex appears to regulate the expression of peroxidase 24 precursor (Prx 24), a gene encoding an H2O2 scavenger that is more highly expressed in guard cells. Downregulation of DCA1 significantly enhanced drought and salt tolerance in rice, and overexpression of DCA1 increased sensitivity to stress treatment. These phenotypes were mainly influenced by DCA1 and negatively regulated stomatal closure through the direct modulation of genes associated with H2O2 homeostasis. Our findings establish a framework for plant drought and salt stress tolerance through the DCA1-DST-Prx24 pathway. Moreover, due to the evolutionary and functional conservation of DCA1 and DST in plants, engineering of this pathway has the potential to improve tolerance to abiotic stress in other important crop species.

  11. Separate regions of glucocorticoid receptor, coactivator TIF2, and comodulator STAMP modify different parameters of glucocorticoid-mediated gene induction.

    PubMed

    Awasthi, Smita; Simons, S Stoney

    2012-05-15

    Increased specificity in steroid-regulated gene expression is a long-sought goal of endocrinologists. Considerable progress has resulted from the discovery of coactivators, corepressors, and comodulators that adjust the total activity (A(max)) of gene induction. Two less frequently quantitated, but equally potent, means of improving specificity are the concentration of agonist steroid required for half-maximal activity (EC(50)) and the residual or partial agonist activity displayed by most antisteroids (PAA). It is usually assumed that the modulatory activity of transcriptional cofactors coordinately regulates A(max), EC(50), and PAA. Here we examine the hypothesis that these three parameters can be independently modified by separate protein domains. The test system involves three differently sized fragments of each of three factors (glucocorticoid receptor [GR], coactivator TIF2, and comodulator STAMP), which are shown to form a ternary complex and similarly affect the induction properties of transfected and endogenous genes. Twenty-five different fragment combinations of the ternary complex are examined for their ability to modulate the A(max), EC(50), and PAA of a transiently transfected synthetic reporter gene. Different combinations selectively alter one, two, or all three parameters. These results clearly demonstrate that A(max), EC(50), and PAA can be independently regulated under some conditions by different pathways or molecular interactions. This new mechanistic insight suggests that selected activities of individual transcription factors are attractive targets for small molecules, which would have obvious clinical applications for increasing the specificity of steroids during endocrine therapies.

  12. Solar Power at Play

    NASA Astrophysics Data System (ADS)

    2007-03-01

    For the very first time, astronomers have witnessed the speeding up of an asteroid's rotation, and have shown that it is due to a theoretical effect predicted but never seen before. The international team of scientists used an armada of telescopes to discover that the asteroid's rotation period currently decreases by 1 millisecond every year, as a consequence of the heating of the asteroid's surface by the Sun. Eventually it may spin faster than any known asteroid in the solar system and even break apart. ESO PR Photo 11a/07 ESO PR Photo 11a/07 Asteroid 2000 PH5 "The Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) effect is believed to alter the way small bodies in the Solar System rotate," said Stephen Lowry (Queens University Belfast, UK), lead-author of one of the two companion papers in which this work is reported [1, 2]. "The warming caused by sunlight hitting the surfaces of asteroids and meteoroids leads to a gentle recoil effect as the heat is released," he added. "By analogy, if one were to shine light on a propeller over a long enough period, it would start spinning." Although this is an almost immeasurably weak force, its effect over millions of years is far from negligible. Astronomers believe the YORP effect may be responsible for spinning some asteroids up so fast that they break apart, perhaps leading to the formation of double asteroids. Others may be slowed down so that they take many days to complete a full turn. The YORP effect also plays an important role in changing the orbits of asteroids between Mars and Jupiter, including their delivery to planet-crossing orbits, such as those of near-Earth asteroids. Despite its importance, the effect has never been seen acting on a solar system body, until now. Using extensive optical and radar imaging from powerful Earth-based observatories, astronomers have directly observed the YORP effect in action on a small near-Earth asteroid, known as (54509) 2000 PH5. Shortly after its discovery in 2000, it was

  13. Play technique in psychodynamic psychotherapy.

    PubMed

    Yanof, Judith A

    2013-04-01

    Imaginary play is often a child's best way of communicating affects, fantasies, and internal states. In play children are freer to express their forbidden and conflicted thoughts. Consequently, one of the best ways for the therapist to enter the child's world is to do so from within the displacement of the play process. For children who cannot play, the therapist's goal is to teach the child to use play as a means of communication and to create meaning. This article present clinical examples to illustrate how the author uses play in the clinical situation.

  14. GENERAL CONTROL NONREPRESSED PROTEIN5-Mediated Histone Acetylation of FERRIC REDUCTASE DEFECTIVE3 Contributes to Iron Homeostasis in Arabidopsis1

    PubMed Central

    Wang, Tianya; Liu, Zhenshan; Xu, Jianqin; Yao, Yingyin; Peng, Huiru; Xin, Mingming; Ni, Zhongfu

    2015-01-01

    Iron homeostasis is essential for plant growth and development. Here, we report that a mutation in GENERAL CONTROL NONREPRESSED PROTEIN5 (GCN5) impaired iron translocation from the root to the shoot in Arabidopsis (Arabidopsis thaliana). Illumina high-throughput sequencing revealed 879 GCN5-regulated candidate genes potentially involved in iron homeostasis. Chromatin immunoprecipitation assays indicated that five genes (At3G08040, At2G01530, At2G39380, At2G47160, and At4G05200) are direct targets of GCN5 in iron homeostasis regulation. Notably, GCN5-mediated acetylation of histone 3 lysine 9 and histone 3 lysine 14 of FERRIC REDUCTASE DEFECTIVE3 (FRD3) determined the dynamic expression of FRD3. Consistent with the function of FRD3 as a citrate efflux protein, the iron retention defect in gcn5 was rescued and fertility was partly restored by overexpressing FRD3. Moreover, iron retention in gcn5 roots was significantly reduced by the exogenous application of citrate. Collectively, these data suggest that GCN5 plays a critical role in FRD3-mediated iron homeostasis. Our results provide novel insight into the chromatin-based regulation of iron homeostasis in Arabidopsis. PMID:26002909

  15. Problematic game play: the diagnostic value of playing motives, passion, and playing time in men.

    PubMed

    Kneer, Julia; Rieger, Diana

    2015-04-30

    Internet gaming disorder is currently listed in the DSM-not in order to diagnose such a disorder but to encourage research to investigate this phenomenon. Even whether it is still questionable if Internet Gaming Disorder exists and can be judged as a form of addiction, problematic game play is already very well researched to cause problems in daily life. Approaches trying to predict problematic tendencies in digital game play have mainly focused on playing time as a diagnostic criterion. However, motives to engage in digital game play and obsessive passion for game play have also been found to predict problematic game play but have not yet been investigated together. The present study aims at (1) analyzing if obsessive passion can be distinguished from problematic game play as separate concepts, and (2) testing motives of game play, passion, and playing time for their predictive values for problematic tendencies. We found (N = 99 males, Age: M = 22.80, SD = 3.81) that obsessive passion can be conceptually separated from problematic game play. In addition, the results suggest that compared to solely playing time immersion as playing motive and obsessive passion have added predictive value for problematic game play. The implications focus on broadening the criteria in order to diagnose problematic playing.

  16. Problematic Game Play: The Diagnostic Value of Playing Motives, Passion, and Playing Time in Men

    PubMed Central

    Kneer, Julia; Rieger, Diana

    2015-01-01

    Internet gaming disorder is currently listed in the DSM—not in order to diagnose such a disorder but to encourage research to investigate this phenomenon. Even whether it is still questionable if Internet Gaming Disorder exists and can be judged as a form of addiction, problematic game play is already very well researched to cause problems in daily life. Approaches trying to predict problematic tendencies in digital game play have mainly focused on playing time as a diagnostic criterion. However, motives to engage in digital game play and obsessive passion for game play have also been found to predict problematic game play but have not yet been investigated together. The present study aims at (1) analyzing if obsessive passion can be distinguished from problematic game play as separate concepts, and (2) testing motives of game play, passion, and playing time for their predictive values for problematic tendencies. We found (N = 99 males, Age: M = 22.80, SD = 3.81) that obsessive passion can be conceptually separated from problematic game play. In addition, the results suggest that compared to solely playing time immersion as playing motive and obsessive passion have added predictive value for problematic game play. The implications focus on broadening the criteria in order to diagnose problematic playing. PMID:25942516

  17. Pretend Play and Creative Processes

    ERIC Educational Resources Information Center

    Russ, Sandra W.; Wallace, Claire E.

    2013-01-01

    The authors contend that many cognitive abilities and affective processes important in creativity also occur in pretend play and that pretend play in childhood affects the development of creativity in adulthood. They discuss a variety of theories and observations that attempt to explain the importance of pretend play to creativity. They argue that…

  18. Play Memories and Place Identity.

    ERIC Educational Resources Information Center

    Sandberg, Anette

    2003-01-01

    This retrospective study examined play memories from childhood to adulthood of 478 university students between ages 20 and 62 as exhibited in drawings of play memories and questionnaire responses. The study focused on the role of the physical environment and place identity in play memories and individual identity development. Findings showed that…

  19. Play in Evolution and Development

    ERIC Educational Resources Information Center

    Pellegrini, Anthony D.; Dupuis, Danielle; Smith, Peter K.

    2007-01-01

    In this paper we examine the role of play in human ontogeny and phylogeny, following Surplus Resource Theory. We consider how juveniles use play to sample their environment in order to develop adaptive behaviors. We speculate about how innovative behaviors developed in play in response to environmental novelty may influence subsequent evolutionary…

  20. The Values of Outdoor Play

    ERIC Educational Resources Information Center

    Elkind, David

    2006-01-01

    This article describes outdoor play as a solid foundation and a central vehicle of knowledge about the real world. Outdoor play is important to all age levels, but particularly in early childhood and the elementary years. Children's outdoor play is not a luxury. It is critical in children's ability to learn about the world, others, and themselves.…

  1. Piaget, Play and Cognition, Revisited.

    ERIC Educational Resources Information Center

    Sutton-Smith, Brian

    Piaget's early contribution to theorizing about play is discussed critically with reference to three major interrelated problems. These are: (1) that despite their equipotentiality in Piaget's theory of intelligence, imitation and play are not conceptualized as making an equal contribution to cognition, play taking a subordinate role; (2) that…

  2. Meanings of Play among Children

    ERIC Educational Resources Information Center

    Glenn, Nicole M.; Knight, Camilla J.; Holt, Nicholas L.; Spence, John C.

    2013-01-01

    The purpose of this study was to examine meanings of play among children. Thirty-eight students aged 7-9 years from a suburban public school in Western Canada participated in focus groups. Data analysis revealed participants saw almost anything as an opportunity for play and would play almost anywhere with anyone. However, they perceived parents…

  3. Play Therapy in School Counseling

    ERIC Educational Resources Information Center

    Trice-Black, Shannon; Bailey, Carrie Lynn; Kiper Riechel, Morgan E.

    2013-01-01

    Play therapy is an empirically supported intervention used to address a number of developmental issues faced in childhood. Through the natural language of play, children and adolescents communicate feelings, thoughts, and experiences. Schools provide an ideal setting for play therapy in many ways; however, several challenges exist in implementing…

  4. Co-Activity during Maximum Voluntary Contraction: A Study of Four Lower-Extremity Muscles in Children with and without Cerebral Palsy

    ERIC Educational Resources Information Center

    Tedroff, Kristina; Knutson, Loretta M.; Soderberg, Gary L.

    2008-01-01

    This study was designed to determine whether children with cerebral palsy (CP) showed more co-activity than comparison children in non-prime mover muscles with regard to the prime mover during maximum voluntary isometric contraction (MVIC) of four lower-extremity muscles. Fourteen children with spastic diplegic CP (10 males, four females; age…

  5. MicroRNA-22 and microRNA-140 suppress NF-{kappa}B activity by regulating the expression of NF-{kappa}B coactivators

    SciTech Connect

    Takata, Akemi; Otsuka, Motoyuki; Kojima, Kentaro; Yoshikawa, Takeshi; Kishikawa, Takahiro; Yoshida, Haruhiko; Koike, Kazuhiko

    2011-08-12

    Highlights: {yields} miRNAs were screened for their ability to regulate NF-{kappa}B activity. {yields} miRNA-22 and miRNA-140-3p suppress NF-{kappa}B activity by regulating coactivators. {yields} miRNA-22 targets nuclear receptor coactivator 1 (NCOA1). {yields} miRNA-140-3p targets nuclear receptor-interacting protein 1 (NRIP1). -- Abstract: Nuclear factor {kappa}B (NF-{kappa}B) is a transcription factor that regulates a set of genes that are critical to many biological phenomena, including liver tumorigenesis. To identify microRNAs (miRNAs) that regulate NF-{kappa}B activity in the liver, we screened 60 miRNAs expressed in hepatocytes for their ability to modulate NF-{kappa}B activity. We found that miRNA-22 and miRNA-140-3p significantly suppressed NF-{kappa}B activity by regulating the expression of nuclear receptor coactivator 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1), both of which are NF-{kappa}B coactivators. Our results provide new information about the roles of miRNAs in the regulation of NF-{kappa}B activity.

  6. Thinking about Children's Play: Play Is Not Work, Nor Is Work Play.

    ERIC Educational Resources Information Center

    Elkind, David

    2001-01-01

    Addresses the concept of "play as a child's work," from the viewpoints of Montessori, Freud, and Piaget. Contends that children's play: (1) like adult play, may be individual or social; (2) has immediate value for the child as a way of expressing feelings; and (3) is a healthy counterpoise to work. (SD)

  7. Identification of Small-Molecule Enhancers of Arginine Methylation Catalyzed by Coactivator-Associated Arginine Methyltransferase 1

    PubMed Central

    Castellano, Sabrina; Spannhoff, Astrid; Milite, Ciro; Dal Piaz, Fabrizio; Cheng, Donghang; Tosco, Alessandra; Viviano, Monica; Yamani, Abdellah; Cianciulli, Agostino; Sala, Marina; Cura, Vincent; Cavarelli, Jean; Novellino, Ettore; Mai, Antonello; Bedford, Mark T.; Sbardella, Gianluca

    2012-01-01

    Arginine methylation is a common post-translational modification that is crucial in modulating gene expression at multiple critical levels. The arginine methyltransferases (PRMTs) are envisaged as promising druggable targets but their role in physiological and pathological pathways is far from being clear, due to the limited number of modulators reported to date. In this effort, enzyme activators can be invaluable tools useful as gain-of-function reagents to interrogate the biological roles in cells and in vivo of PRMTs. Yet the identification of such molecules is rarely pursued. Herein we describe a series of aryl ureido acetamido indole carboxylates (dubbed “uracandolates”), able to increase the methylation of histone- (H3) or non-histone (polyadenylate-binding protein 1, PABP1) substrates induced by coactivator-associated arginine methyltransferase 1 (CARM1), both in in vitro and cellular settings. To the best of our knowledge, this is the first report of compounds acting as CARM1 activators. PMID:23095008

  8. Identification of Novel Inhibitors against Coactivator Associated Arginine Methyltransferase 1 Based on Virtual Screening and Biological Assays

    PubMed Central

    Xie, Yiqian; Luo, Cheng

    2016-01-01

    Overexpression of coactivator associated arginine methyltransferase 1 (CARM1), a protein arginine N-methyltransferase (PRMT) family enzyme, is associated with various diseases including cancers. Consequently, the development of small-molecule inhibitors targeting PRMTs has significant value for both research and therapeutic purposes. In this study, together with structure-based virtual screening with biochemical assays, two compounds DC_C11 and DC_C66 were identified as novel inhibitors of CARM1. Cellular studies revealed that the two inhibitors are cell membrane permeable and effectively blocked proliferation of cancer cells including HELA, K562, and MCF7. We further predicted the binding mode of these inhibitors through molecular docking analysis, which indicated that the inhibitors competitively occupied the binding site of the substrate and destroyed the protein-protein interactions between CARM1 and its substrates. Overall, this study has shed light on the development of small-molecule CARM1 inhibitors with novel scaffolds. PMID:27872854

  9. Cytoarchitectonic mapping of the human brain cerebellar nuclei in stereotaxic space and delineation of their co-activation patterns.

    PubMed

    Tellmann, Stefanie; Bludau, Sebastian; Eickhoff, Simon; Mohlberg, Hartmut; Minnerop, Martina; Amunts, Katrin

    2015-01-01

    The cerebellar nuclei are involved in several brain functions, including the modulation of motor and cognitive performance. To differentiate their participation in these functions, and to analyze their changes in neurodegenerative and other diseases as revealed by neuroimaging, stereotaxic maps are necessary. These maps reflect the complex spatial structure of cerebellar nuclei with adequate spatial resolution and detail. Here we report on the cytoarchitecture of the dentate, interposed (emboliform and globose) and fastigial nuclei, and introduce 3D probability maps in stereotaxic MNI-Colin27 space as a prerequisite for subsequent meta-analysis of their functional involvement. Histological sections of 10 human post mortem brains were therefore examined. Differences in cell density were measured and used to distinguish a dorsal from a ventral part of the dentate nucleus. Probabilistic maps were calculated, which indicate the position and extent of the nuclei in 3D-space, while considering their intersubject variability. The maps of the interposed and the dentate nuclei differed with respect to their interaction patterns and functions based on meta-analytic connectivity modeling and quantitative functional decoding, respectively. For the dentate nucleus, significant (p < 0.05) co-activations were observed with thalamus, supplementary motor area (SMA), putamen, BA 44 of Broca's region, areas of superior and inferior parietal cortex, and the superior frontal gyrus (SFG). In contrast, the interposed nucleus showed more limited co-activations with SMA, area 44, putamen, and SFG. Thus, the new stereotaxic maps contribute to analyze structure and function of the cerebellum. These maps can be used for anatomically reliable and precise identification of degenerative alteration in MRI-data of patients who suffer from various cerebellar diseases.

  10. The Elongation Complex Components BRD4 and MLLT3/AF9 Are Transcriptional Coactivators of Nuclear Retinoid Receptors

    PubMed Central

    Flajollet, Sébastien; Rachez, Christophe; Ploton, Maheul; Schulz, Céline; Gallais, Rozenn; Métivier, Raphaël; Pawlak, Michal; Leray, Aymeric; Issulahi, Al Amine; Héliot, Laurent; Staels, Bart; Salbert, Gilles; Lefebvre, Philippe

    2013-01-01

    Nuclear all-trans retinoic acid receptors (RARs) initiate early transcriptional events which engage pluripotent cells to differentiate into specific lineages. RAR-controlled transactivation depends mostly on agonist-induced structural transitions in RAR C-terminus (AF-2), thus bridging coactivators or corepressors to chromatin, hence controlling preinitiation complex assembly. However, the contribution of other domains of RAR to its overall transcriptional activity remains poorly defined. A proteomic characterization of nuclear proteins interacting with RAR regions distinct from the AF-2 revealed unsuspected functional properties of the RAR N-terminus. Indeed, mass spectrometry fingerprinting identified the Bromodomain-containing protein 4 (BRD4) and ALL1-fused gene from chromosome 9 (AF9/MLLT3), known to associate with and regulates the activity of Positive Transcription Elongation Factor b (P-TEFb), as novel RAR coactivators. In addition to promoter sequences, RAR binds to genomic, transcribed regions of retinoid-regulated genes, in association with RNA polymerase II and as a function of P-TEFb activity. Knockdown of either AF9 or BRD4 expression affected differentially the neural differentiation of stem cell-like P19 cells. Clusters of retinoid-regulated genes were selectively dependent on BRD4 and/or AF9 expression, which correlated with RAR association to transcribed regions. Thus RAR establishes physical and functional links with components of the elongation complex, enabling the rapid retinoid-induced induction of genes required for neuronal differentiation. Our data thereby extends the previously known RAR interactome from classical transcriptional modulators to components of the elongation machinery, and unravel a functional role of RAR in transcriptional elongation. PMID:23762261

  11. Coactivator PGC-1{alpha} regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes

    SciTech Connect

    Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki; Viitala, Pirkko; Lang, Matti A.; Pelkonen, Olavi; Hakkola, Jukka

    2008-10-01

    The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1{alpha} and CYP2A5 mRNAs in murine primary hepatocytes. Furthermore, the elevation of the PGC-1{alpha} expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1{alpha} expression vector demonstrated that PGC-1{alpha} is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4{alpha} response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1{alpha} binds, together with HNF-4{alpha}, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1{alpha} mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4{alpha}. This strongly suggests that PGC-1{alpha} is the major factor mediating the fasting response of CYP2A5.

  12. T cells coactivated with immobilized anti-CD3 and anti-CD28 as potential immunotherapy for cancer.

    PubMed

    Garlie, N K; LeFever, A V; Siebenlist, R E; Levine, B L; June, C H; Lum, L G

    1999-07-01

    This report describes the generation of T cells with characteristics that may prove useful for the immunotherapy of cancer. Peripheral blood mononuclear cells obtained from healthy donors were cultured in the presence of anti-CD3/anti-CD28 mAb-coated beads (3/28 beads) at a 3:1 bead to cell ratio. The 3/28 beads were removed after 14 days of culture. Optimal growth conditions for CD3/CD28 coactivated T cells (COACTS) were determined to be X-VIVO 15 containing 5% human AB serum and 100 IU/ml of interleukin-2. The median fold expansion after 14 days was 84-fold. Flow cytometric analyses demonstrated that all cultures were > 90% CD3+ with an increase in the proportion of CD8+ cells. CD28 expression was maintained at very high levels on CD4+ cells and augmented on CD8+ cells. COACTS were induced to secrete high levels of Th1-type cytokines (IFN-gamma and TNF-alpha) after a 24-h restimulation with fresh 3/28 beads and displayed nonmajor histocompatibility complex-restricted lytic activity against a variety of human tumor cell lines in standard 51Cr-release assays. Bead removal from COACT cultures before day 14 greatly enhanced the cell growth and cytokine production without significantly affecting the lytic potential. In summary, large numbers of T cells can be generated by coactivation with anti-CD3/anti-CD28-coated beads for 14 days. This method may provide an advantage over current forms of cellular immunotherapy for cancer because of the ability of COACTS to secrete tumoricidal cytokines and generate antitumor cytotoxicity.

  13. Muscle co-activity tuning in Parkinsonian hand movement: disease-specific changes at behavioral and cerebral level

    PubMed Central

    van der Stouwe, A. M. M.; Toxopeus, C. M.; de Jong, B. M.; Yavuz, P.; Valsan, G.; Conway, B. A.; Leenders, K. L.; Maurits, N. M.

    2015-01-01

    We investigated simple directional hand movements based on different degrees of muscle co-activity, at behavioral and cerebral level in healthy subjects and Parkinson's disease (PD) patients. We compared “singular” movements, dominated by the activity of one agonist muscle, to “composite” movements, requiring conjoint activity of multiple muscles, in a center-out (right hand) step-tracking task. Behavioral parameters were obtained by EMG and kinematic recordings. fMRI was used to investigate differences in underlying brain activations between PD patients (N = 12) and healthy (age-matched) subjects (N = 18). In healthy subjects, composite movements recruited the striatum and cortical areas comprising bilaterally the supplementary motor area and premotor cortex, contralateral medial prefrontal cortex, primary motor cortex, primary visual cortex, and ipsilateral superior parietal cortex. Contrarily, the ipsilateral cerebellum was more involved in singular movements. This striking dichotomy between striatal and cortical recruitment vs. cerebellar involvement was considered to reflect the complementary roles of these areas in motor control, in which the basal ganglia are involved in movement selection and the cerebellum in movement optimization. Compared to healthy subjects, PD patients showed decreased activation of the striatum and cortical areas in composite movement, while performing worse at behavioral level. This implies that PD patients are especially impaired on tasks requiring highly tuned muscle co-activity. Singular movement, on the other hand, was characterized by a combination of increased activation of the ipsilateral parietal cortex and left cerebellum. As singular movement performance was only slightly compromised, we interpret this as a reflection of increased visuospatial processing, possibly as a compensational mechanism. PMID:26300761

  14. Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1*

    PubMed Central

    Amazit, Larbi; Le Billan, Florian; Kolkhof, Peter; Lamribet, Khadija; Viengchareun, Say; Fay, Michel R.; Khan, Junaid A.; Hillisch, Alexander; Lombès, Marc; Rafestin-Oblin, Marie-Edith; Fagart, Jérôme

    2015-01-01

    Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads todeleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist. PMID:26203193

  15. Behavioral approaches to promoting play.

    PubMed

    Stahmer, Aubyn C; Ingersoll, Brooke; Carter, Cynthia

    2003-12-01

    A variety of techniques grounded in behavioral psychology, and more specifically in applied behavior analysis, have been established to increase and improve play skills in children with autistic spectrum disorders. This article introduces a set of efficacious methods, which range from highly structured techniques to more naturalistic strategies. It focuses on object play as other authors in the issue discuss social play in greater depth. Behavioral techniques that are reviewed include: discrete trial training, use of stereotyped behaviors to increase play skills, pivotal response training, reciprocal imitation training, differential reinforcement of appropriate behavior, in vivo modeling and play scripts, and video modeling. A discussion of expanding behavior techniques to teach more complex play as well as training in varied environments is also presented. References are provided to allow the reader to obtain more in-depth information about each technique.

  16. Let's Play: Teaching Play Skills to Young Children with Autism

    ERIC Educational Resources Information Center

    Boutot, E. Amanda; Guenther, Tracee; Crozier, Shannon

    2005-01-01

    Watch any young child and you will likely see him or her engaged in some form of play. Play is an integral part of early childhood development in which typically developing children learn social and language skills, as well as appropriate behaviors, problem solving, and a variety of other cognitive skills. By its very definition, autism is a…

  17. The Influence of Play Material on Discourse during Play.

    ERIC Educational Resources Information Center

    Burroughs, Elizabeth I.; Murray, Sharon E.

    1992-01-01

    Evaluation of the conversational behavior of 36 children (ages 48-59 months) playing in dyads with 3 different materials (modeling dough, a farm set, and animal puppets) found that each toy elicited the same amount of talking, though there were differences in discourse structure attributable to play materials. (DB)

  18. The Importance of Play: Why Children Need to Play

    ERIC Educational Resources Information Center

    Bodrova, Elena; Leong, Deborah J.

    2005-01-01

    In this article, the authors discuss the important role of dramatic ("pretend") play in early childhood with increasing emphasis at school on developing academic skills in children at younger and younger ages. Play is especially beneficial to children's learning when it reaches a certain degree of sophistication. In other words, "unproductive"…

  19. Playing with the Multiple Intelligences: How Play Helps Them Grow

    ERIC Educational Resources Information Center

    Eberle, Scott G.

    2011-01-01

    Howard Gardner first posited a list of "multiple intelligences" as a liberating alternative to the assumptions underlying traditional IQ testing in his widely read study "Frames of Mind" (1983). Play has appeared only in passing in Gardner's thinking about intelligence, however, even though play instructs and trains the verbal, interpersonal,…

  20. Well Played: The Origins and Future of Playfulness

    ERIC Educational Resources Information Center

    Gordon, Gwen

    2014-01-01

    In this article, the author synthesizes research from several disciplines to shed light on play's central role in healthy development. Gordon builds on research in attachment theory that correlates secure attachment in infancy with adult well-being to demonstrate how playfulness might be a lifelong outcome of secure attachment and a primary…

  1. Symbolic play and language development.

    PubMed

    Orr, Edna; Geva, Ronny

    2015-02-01

    Symbolic play and language are known to be highly interrelated, but the developmental process involved in this relationship is not clear. Three hypothetical paths were postulated to explore how play and language drive each other: (1) direct paths, whereby initiation of basic forms in symbolic action or babbling, will be directly related to all later emerging language and motor outputs; (2) an indirect interactive path, whereby basic forms in symbolic action will be associated with more complex forms in symbolic play, as well as with babbling, and babbling mediates the relationship between symbolic play and speech; and (3) a dual path, whereby basic forms in symbolic play will be associated with basic forms of language, and complex forms of symbolic play will be associated with complex forms of language. We micro-coded 288 symbolic vignettes gathered during a yearlong prospective bi-weekly examination (N=14; from 6 to 18 months of age). Results showed that the age of initiation of single-object symbolic play correlates strongly with the age of initiation of later-emerging symbolic and vocal outputs; its frequency at initiation is correlated with frequency at initiation of babbling, later-emerging speech, and multi-object play in initiation. Results support the notion that a single-object play relates to the development of other symbolic forms via a direct relationship and an indirect relationship, rather than a dual-path hypothesis.

  2. Young Children and War Play.

    ERIC Educational Resources Information Center

    Carlsson-Paige, Nancy; Levin, Diane E.

    1988-01-01

    In a recent survey of parents and early childhood professionals the prevalence of war play among children and an increase in the amount of violence in children's play was noted. Outlines how the deregulation of children's television during the Reagan administration has affected children's exposure to violence in children's television programming.…

  3. Playing To Get Smart. Viewpoint.

    ERIC Educational Resources Information Center

    Jones, Elizabeth

    2003-01-01

    Asserts that it is through play with materials and relationships, invention of classification systems, and solving problems in dialogue with others that young children develop the basic skills they will need to become effective contributors to the health of a changing world. Offers suggestions for teaching children play skills by providing…

  4. A Place for Block Play.

    ERIC Educational Resources Information Center

    Moore, Gary T.

    1997-01-01

    Discusses the importance of block play--including its contributions to perceptual, fine motor, and cognitive development--and components of a good preschool block play area. Recommends unit blocks complemented by stacking blocks, toys, beads, cubes, and Brio wooden toys. Makes recommendations for space, size, locations and connections to other…

  5. Invention at Play. Educators' Manual.

    ERIC Educational Resources Information Center

    Judd, Michael; Lacasse, Jane; Smith, Monica; Reilly, Katie

    A Smithsonian exhibition was developed that looked at invention in an innovative way. It aimed to encourage visitors to make connections between their own lives and abilities and those of inventors. The role of play in the invention process was examined. Play is a universal and familiar activity and can help people find the link between their own…

  6. Empowering Groups that Enable Play

    ERIC Educational Resources Information Center

    Wilson, David Sloan; Marshall, Danielle; Iserhott, Hindi

    2011-01-01

    Creating play environments for children usually requires groups of adults working together. An extensive scientific literature describes how groups function to achieve shared goals in general terms, and groups attempting to empower play may find this literature useful. Design principles for managing natural resources, identified by Elinor Ostrom…

  7. The Fractal Self at Play

    ERIC Educational Resources Information Center

    Marks-Tarlow, Terry

    2010-01-01

    In this article, the author draws on contemporary science to illuminate the relationship between early play experiences, processes of self-development, and the later emergence of the fractal self. She argues that orientation within social space is a primary function of early play and developmentally a two-step process. With other people and with…

  8. The Social Competence of Play.

    ERIC Educational Resources Information Center

    Fein, Greta G.

    This is a study of how young children gain social competence through pretend play or role playing. Subjects were 38 Caucasian children (19 females, 19 males) who were observed at four ages: 12, 18, 24 and 30 months. The same set of toys, which included a doll, a saucepan, doll bottles, coffee mug, teacup, teaspoon, doll crib, blanket, toy phone…

  9. Sand and Water Table Play

    ERIC Educational Resources Information Center

    Wallace, Ann H.; White, Mary J.; Stone, Ryan

    2010-01-01

    The authors observed preschoolers engaged at the sand and water table to determine if math could be found within their play. Wanting to understand how children interact with provided materials and what kinds of math ideas they explore during these interactions, the authors offer practical examples of how such play can promote mathematical…

  10. Teaching Literature to Adolescents: Plays.

    ERIC Educational Resources Information Center

    Howes, Alan B.

    In this book designed for the high school drama teacher, several commonly-taught plays are used to illustrate (1) ways to use the adolescents' experience with TV to increase their appreciation of other forms of drama, (2) practical means for removing some of the barriers to understanding plays and producing an active response to the world of the…

  11. Engaging Families through Artful Play

    ERIC Educational Resources Information Center

    Brown, Robert

    2015-01-01

    This paper explores how aligned arts and play experiences can extend child and family engagement in a public outdoor space. The importance of outdoor play for children is strongly advocated and in response local governments provide playgrounds and recreational open spaces. To extend further the experiences afforded in such spaces some local…

  12. The Child's Right To Play.

    ERIC Educational Resources Information Center

    Guddemi, Marcy

    Several factors are eroding children's right to play. The first is continuing poverty throughout the world. This factor is evident in underdeveloped countries and the inner cities of industrialized countries. Changing cultural values are a second factor in developed societies where indifference toward the importance of play is prevalent. The many…

  13. Principles of Play for Soccer

    ERIC Educational Resources Information Center

    Ouellette, John

    2004-01-01

    Soccer coaches must understand the principles of play if they want to succeed. The principles of play are the rules of action that support the basic objectives of soccer and the foundation of a soccer coaching strategy. They serve as a set of permanent criteria that coaches can use to evaluate the efforts of their team. In this article, the author…

  14. The Play of Socratic Dialogue

    ERIC Educational Resources Information Center

    Smith, Richard

    2011-01-01

    Proponents of philosophy for children generally see themselves as heirs to the "Socratic" tradition. They often claim too that children's aptitude for play leads them naturally to play with abstract, philosophical ideas. However in Plato's dialogues we find in the mouth of "Socrates" many warnings against philosophising with the young. Those…

  15. Outdoor Play: Combating Sedentary Lifestyles

    ERIC Educational Resources Information Center

    Thigpen, Betsy

    2007-01-01

    Increasingly sedentary lifestyles are contributing to overweight and other health concerns as children spend less and less time outside engaged in active play. Outdoor play provides important opportunities to explore the natural world, interact with peers, engage in vigorous physical activity, and learn about our environment. However, outdoor…

  16. Transmedia Play: Literacy across Media

    ERIC Educational Resources Information Center

    Alper, Meryl; Herr-Stephenson, Rebecca

    2013-01-01

    Transmedia play is a new way to understand how children develop critical media literacy and new media literacies through their interactions with contemporary media that links stories and structures across platforms. This essay highlights five characteristics of transmedia play that make it particularly useful for learning:…

  17. Making Play Work for Education

    ERIC Educational Resources Information Center

    Weisberg, Deena Skolnick; Kittredge, Audrey K.; Hirsh-Pasek, Kathy; Golinkoff, Roberta Michnick; Klahr, David

    2015-01-01

    Children, especially in the preschool years, learn a tremendous amount through play. Research on guided play demonstrates how schools can couple a curriculum-centered preschool program with a developmentally appropriate pedagogical approach to classroom teaching. However, to fully test this claim, we need a clear definition of the term…

  18. Playground Play: Educational and Inclusive

    ERIC Educational Resources Information Center

    Moore, Lisa

    2011-01-01

    It is easy to understand that fun is one of the key ingredients to any playground activity. But what one may not realize is that play systems--including slides, tunnels, activity panels, and more--encourage a lot more than just fun: there is learning at work in playground play, as well as the opportunity to include children of all abilities in…

  19. Playful biometrics: controversial technology through the lens of play.

    PubMed

    Ellerbrok, Ariane

    2011-01-01

    This article considers the role of play in the context of technological emergence and expansion, particularly as it relates to recently emerging surveillance technologies. As a case study, I consider the trajectory of automated face recognition—a biometric technology of numerous applications, from its more controversial manifestations under the rubric of national security to a clearly emerging orientation toward play. This shift toward “playful” biometrics—or from a technology traditionally coded as “hard” to one now increasingly coded as “soft”—is critical insofar as it renders problematic the traditional modes of critique that have, up until this point, challenged the expansion of biometric systems into increasingly ubiquitous realms of everyday life. In response to this dynamic, I propose theorizing the expansion of face recognition specifically in relation to “play,” a step that allows us to broaden the critical space around newly emerging playful biometrics, as well as playful surveillance more generally. In addition, play may also have relevance for theorizing other forms of controversial technology, particularly given its potential role in processes of obfuscation, normalization, and marginalization.

  20. Learning, Play, and Your Newborn

    MedlinePlus

    ... the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to ... Month-Old About the Play & Learn Center Your Child's Development: Newborn Your Child’s Development: 3-5 Days Contact ...

  1. Discussion of "interpretation and play".

    PubMed

    Pick, Irma Brenman

    2011-01-01

    This discussion addresses the conflict in technique between play versus interpretation. It further considers how the nature of the interpretation may be affected by a consideration of what is being projected into the analyst.

  2. A multiverse play divides opinion

    NASA Astrophysics Data System (ADS)

    Crease, Robert P.

    2015-03-01

    The stage lights rise. A man and woman meet in a cute way - "Do you know why it's impossible to lick the tips of your elbows?" she asks - they chat momentarily, and separate. The play is Constellations by Nick Payne.

  3. The Many Faces of Play.

    ERIC Educational Resources Information Center

    Werth, Louise H.

    1984-01-01

    Presents descriptions of play reflecting recent theories, including the psychoanalytic works of Freud, Erikson, and Peller; Piaget's developmental theory (with discussion of Sutton-Smith); and the views of Smilansky and Parten. (AS)

  4. Digital Play: A New Classification

    ERIC Educational Resources Information Center

    Marsh, Jackie; Plowman, Lydia; Yamada-Rice, Dylan; Bishop, Julia; Scott, Fiona

    2016-01-01

    This paper draws on an ESRC-funded study of play and creativity in preschool-aged children's use of apps in the UK. The main objectives of the study were to collect information about access to and use of apps in the home, establish the most popular apps and identify the features of those apps that are successful in promoting play and creativity. A…

  5. Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β) Protein Attenuates Vascular Lesion Formation by Inhibition of Chromatin Loading of Minichromosome Maintenance Complex in Smooth Muscle Cells*

    PubMed Central

    Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Chang, Lin; Lin, Jiandie D.; Chen, Y. Eugene

    2013-01-01

    Proliferation of vascular smooth muscle cells (VSMCs) in response to vascular injury plays a critical role in vascular lesion formation. Emerging data suggest that peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) is a key regulator of energy metabolism and other biological processes. However, the physiological role of PGC-1β in VSMCs remains unknown. A decrease in PGC-1β expression was observed in balloon-injured rat carotid arteries. PGC-1β overexpression substantially inhibited neointima formation in vivo and markedly inhibited VSMC proliferation and induced cell cycle arrest at the G1/S transition phase in vitro. Accordingly, overexpression of PGC-1β decreased the expression of minichromosome maintenance 4 (MCM4), which leads to a decreased loading of the MCM complex onto chromatin at the replication origins and decreased cyclin D1 levels, whereas PGC-1β loss of function by adenovirus containing PGC-1β shRNA resulted in the opposite effect. The transcription factor AP-1 was involved in the down-regulation of MCM4 expression. Furthermore, PGC-1β is up-regulated by metformin, and metformin-associated anti-proliferative activity in VSMCs is at least partially dependent on PGC-1β. Our data show that PGC-1β is a critical component in regulating DNA replication, VSMC proliferation, and vascular lesion formation, suggesting that PGC-1β may emerge as a novel therapeutic target for control of proliferative vascular diseases. PMID:23264620

  6. Up-regulation of the Sirtuin 1 (Sirt1) and Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α) Genes in White Adipose Tissue of Id1 Protein-deficient Mice

    PubMed Central

    Zhao, Ying; Ling, Flora; Griffin, Timothy M.; He, Ting; Towner, Rheal; Ruan, Hong; Sun, Xiao-Hong

    2014-01-01

    Id1, a helix-loop-helix (HLH) protein that inhibits the function of basic HLH E protein transcription factors in lymphoid cells, has been implicated in diet- and age-induced obesity by unknown mechanisms. Here we show that Id1-deficient mice are resistant to a high fat diet- and age-induced obesity, as revealed by reduced weight gain and body fat, increased lipid oxidation, attenuated hepatosteatosis, lower levels of lipid droplets in brown adipose tissue, and smaller white adipocytes after a high fat diet feeding or in aged animals. Id1 deficiency improves glucose tolerance, lowers serum insulin levels, and reduces TNFα gene expression in white adipose tissue. Id1 deficiency also increased expression of Sirtuin 1 and peroxisome proliferator-activated receptor γ coactivator 1α, regulators of mitochondrial biogenesis and energy expenditure, in the white adipose tissue. This effect was accompanied by the elevation of several genes encoding proteins involved in oxidative phosphorylation and fatty acid oxidation, such as cytochrome c, medium-chain acyl-CoA dehydrogenase, and adipocyte protein 2. Moreover, the phenotype for Id1 deficiency was similar to that of mice expressing an E protein dominant-positive construct, ET2, suggesting that the balance between Id and E proteins plays a role in regulating lipid metabolism and insulin sensitivity. PMID:25190816

  7. Critical roles of co-activation receptor DNAX accessory molecule-1 in natural killer cell immunity

    PubMed Central

    Xiong, Peng; Sang, Hai-Wei; Zhu, Min

    2015-01-01

    Natural killer (NK) cells, which can exert early and powerful anti-tumour and anti-viral responses, are important components of the innate immune system. DNAX accessory molecule-1 (DNAM-1) is an activating receptor molecule expressed on the surface of NK cells. Recent findings suggest that DNAM-1 is a critical regulator of NK cell biology. DNAM-1 is involved in NK cell education and differentiation, and also plays a pivotal role in the development of cancer, viral infections and immune-related diseases. However, tumours and viruses have developed multiple mechanisms to evade the immune system. They are able to impair DNAM-1 activity by targeting the DNAM-1 receptor–ligand system. We have reviewed the roles of DNAM-1, and its biological functions, with respect to NK cell biology and DNAM-1 chimeric antigen receptor-based immunotherapy. PMID:26235210

  8. The B cell coactivator Bob1 shows DNA sequence-dependent complex formation with Oct-1/Oct-2 factors, leading to differential promoter activation.

    PubMed

    Gstaiger, M; Georgiev, O; van Leeuwen, H; van der Vliet, P; Schaffner, W

    1996-06-03

    We have shown previously that both octamer binding transcription factors, namely the ubiquitous Oct-1 and the B cell-specific Oct-2A protein, can be enhanced in transcriptional activity by their association with the B cell-specific coactivator protein Bob1, also called OBF-1 or OCA-B. Here we study the structural requirements for ternary complex formation of DNA-Oct-Bob1 and coactivation function of Bob1. In analogy to DNA-bound transcription factors, Bob1 has a modular structure that includes an interaction domain (amino acids 1-65) and a C-terminal domain (amino acids 65-256), both important for transcriptional activation. A mutational analysis has resolved a region of seven amino acids (amino acids 26-32) in the N-terminus of Bob1 that are important for contacting the DNA binding POU domain of Oct-1 or Oct-2. In contrast to the viral coactivator VP16 (vmw65), which interacts with Oct-1 via the POU homeosubdomain, Bob1 association with Oct factors requires residues located in the POU-specific subdomain. Because the same residues are also involved in DNA recognition, we surmised that this association would affect the DNA binding specificity of the Oct-Bob1 complex compared with free Oct factors. While Oct-1 or Oct-2 bind to a large variety of octamer sequences, Bob1 ternary complex formation is indeed highly selective and occurs only in a subset of these sequences, leading to the differential coactivation of octamer-containing promoters. The results uncover a new level in selectivity that furthers our understanding in the regulation of cell type-specific gene expression.

  9. EXERCISES THAT FACILITATE OPTIMAL HAMSTRING AND QUADRICEPS CO-ACTIVATION TO HELP DECREASE ACL INJURY RISK IN HEALTHY FEMALES: A SYSTEMATIC REVIEW OF THE LITERATURE.

    PubMed Central

    Dedinsky, Rachel; Baker, Lindsey; Imbus, Samuel; Bowman, Melissa

    2017-01-01

    Background Anterior cruciate ligament (ACL) injury is common among females due to many anatomic, hormonal, and neuromuscular risk factors. One modifiable risk factor that places females at increased risk of ACL injury is a poor hamstrings: quadriceps (H:Q) co-activation ratio, which should be 0.6 or greater in order to decrease the stress placed on the ACL. Exercises that produce more quadriceps dominant muscle activation can add to the tension placed upon the ACL, potentially increasing the risk of ACL injury. Hypothesis/Purpose The purpose of this systematic review was to compare quadriceps and hamstring muscle activation during common closed kinetic chain therapeutic exercises in healthy female knees to determine what exercises are able to produce adequate H:Q co-activation ratios. Study Design Systematic Review Methods Multiple online databases were systematically searched and screened for inclusion. Eight articles were identified for inclusion. Data on mean electromyography (EMG) activation of both quadriceps and hamstring muscles, % maximal voluntary isometric contraction (MVIC), and H:Q co-activation ratios were extracted from the studies. Quality assessment was performed on all included studies. Results Exercises analyzed in the studies included variations of the double leg squat, variations of the single leg squat, lateral step-up, Fitter, Stairmaster® (Core Health and Fitness, Vancouver, WA), and slide board. All exercises, except the squat machine with posterior support at the level of the scapula and feet placed 50 cm in front of the hips, produced higher quadriceps muscle activation compared to hamstring muscle activation. Conclusion Overall, two leg squats demonstrate poor H:Q co-activation ratios. Single leg exercises, when performed between 30 and 90 degrees of knee flexion, produce adequate H:Q ratios, thereby potentially reducing the risk of tensile stress on the ACL and ACL injury. Level of Evidence 2a- Systematic Review of Cohort Studies PMID

  10. Playing in the Gutters: Enhancing Children's Cognitive and Social Play.

    ERIC Educational Resources Information Center

    Dinwiddie, Sue A.

    1993-01-01

    Adding plastic gutters to the nursery school's sand area began as a science curriculum enhancement and evolved into a whole curriculum that stimulated cognitive exploration, cooperative dramatic play, language enhancement, and general fun. The children manipulated the gutters and materials such as sand, water, buckets, and tennis balls in a…

  11. Parent-Child Play across Cultures: Advancing Play Research

    ERIC Educational Resources Information Center

    Roopnarine, Jaipaul L.; Davidson, Kimberly L.

    2015-01-01

    In this article, the authors argue for a greater understanding of children's play across cultures through better integration of scientific thinking about the developed and developing societies, through consideration of socialization beliefs and goals, and, finally, through the use of more complex models in research investigations. They draw on…

  12. Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise.

    PubMed

    Baar, Keith

    2004-05-01

    Endurance exercise training induces an increase in the respiratory capacity of muscle, resulting in an increased capacity to generate ATP as well as improved efficiency of muscle contraction. Such adaptations are largely the result of a coordinated genetic response that increases mitochondrial proteins, fatty acid oxidation enzymes and the exercise- and insulin-stimulated glucose transporter GLUT4, and shifts the contractile and regulatory proteins to their more efficient isoforms. In recent years a number of the transcriptional regulators involved in this genetic response have been identified and these factors can be classified into two different groups. The first group comprises transcription factors such as nuclear respiratory factors (NRF) 1 and 2 and PPAR alpha that bind DNA in a sequence-specific manner. The second group, referred to as transcriptional co-activators, alter transcription without directly binding to DNA. The PPAR gamma co-activator (PGC) family of proteins have been identified as the central family of transcriptional co-activators for induction of mitochondrial biogenesis. PGC-1 alpha is activated by exercise, and is sufficient to produce the endurance phenotype through direct interactions with NRF-1 and PPAR alpha, and potentially NRF-2. Furthering the understanding of the activation of PGC proteins following exercise has implications beyond improving athletic performance, including the possibility of providing targets for the treatment of frailty in the elderly, obesity and diseases such as mitochondrial myopathies and diabetes.

  13. AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors.

    PubMed Central

    Henttu, P M; Kalkhoven, E; Parker, M G

    1997-01-01

    Hormone-dependent transcriptional activation by nuclear receptors depends on the presence of a conserved C-terminal amphipathic alpha-helix (helix 12) in the ligand-binding domain. Here we show that a lysine residue, which is conserved in most nuclear receptors in the predicted helix 3, is also required for estrogen-dependent transactivation. The replacement of lysine 366 with alanine appreciably reduced activation function 2 (AF-2) activity without affecting steroid- or DNA-binding activity in the mouse estrogen receptor. The mutation dramatically reduced the ability of the receptor to bind steroid receptor coactivator 1 (SRC-1) but had no effect on receptor-interacting protein 140 (RIP-140) binding, indicating that while their sites of interaction overlap, they are not entirely consistent and in keeping with the proposal that the recruitment of coactivators, such as SRC-1, is required for AF-2 activity. Although the function of RIP-140 remains to be established, RIP-140 appears to be capable of recruiting the basal transcription machinery, since overexpression of the protein markedly increased the transcriptional activity of the mutant receptor. Since the lysine residue is conserved, we propose that it is required, together with residues in helix 12, to form the surface by which members of the nuclear receptor family interact with coactivators. PMID:9121431

  14. Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions

    PubMed Central

    Pavek, Petr

    2016-01-01

    Pregnane X receptor is a ligand-activated nuclear receptor (NR) that mainly controls inducible expression of xenobiotics handling genes including biotransformation enzymes and drug transporters. Nowadays it is clear that PXR is also involved in regulation of intermediate metabolism through trans-activation and trans-repression of genes controlling glucose, lipid, cholesterol, bile acid, and bilirubin homeostasis. In these processes PXR cross-talks with other NRs. Accumulating evidence suggests that the cross-talk is often mediated by competing for common coactivators or by disruption of coactivation and activity of other transcription factors by the ligand-activated PXR. In this respect mainly PXR-CAR and PXR-HNF4α interference have been reported and several cytochrome P450 enzymes (such as CYP7A1 and CYP8B1), phase II enzymes (SULT1E1, Gsta2, Ugt1a1), drug and endobiotic transporters (OCT1, Mrp2, Mrp3, Oatp1a, and Oatp4) as well as intermediate metabolism enzymes (PEPCK1 and G6Pase) have been shown as down-regulated genes after PXR activation. In this review, I summarize our current knowledge of PXR-mediated repression and coactivation interference in PXR-controlled gene expression regulation. PMID:27932985

  15. Cannabinoid CB1 receptors activation and coactivation with D2 receptors modulate GABAergic neurotransmission in the globus pallidus and increase motor asymmetry.

    PubMed

    Muñoz-Arenas, Guadalupe; Paz-Bermúdez, Francisco; Báez-Cordero, Ana; Caballero-Florán, René; González-Hernández, Brenda; Florán, Benjamín; Limón, I Daniel

    2015-03-01

    The cannabinoid CB1 (CB1R) and dopaminergic D2 (D2R) receptors modify GABAergic transmission in the globus pallidus. Although dopaminergic denervation produces changes in the expression and supersensitization of these receptors, the consequences of these changes on GABAergic neurotransmission are unknown. The aim of this study was to show the effects of CB1R and D2R activation and coactivation on the uptake and release of [(3) H]GABA in the globus pallidus of hemiparkinsonian rats as well as their effects on motor behavior. The activation of CB1R blocked GABA uptake and decreased GABA release in the globus pallidus in the dopamine denervated side, whereas the co-activation of CB1R-D2R increased GABA release and had no effect on GABA uptake. A microinjection of the CB1R agonist ACEA into the globus pallidus ipsilaterally to a 6-OHDA lesion potentiated turning behavior that was induced by methamphetamine. However, a microinjection of the D2R agonist quinpirole did not modify this behavior, and a microinjection of a mixture of CB1R and D2R agonists significantly potentiated turning behavior. The behavioral effects produced after the activation of the CB1R and the co-activation of CB1R and D2R can be explained by increased GABAergic neurotransmission produced by a block of GABA uptake and an increase in the release of GABA in the globus pallidus, respectively.

  16. TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription.

    PubMed

    Jiang, Chao; Ito, Mitsuhiro; Piening, Valerie; Bruck, Kristy; Roeder, Robert G; Xiao, Hua

    2004-06-25

    Deregulation of c-myc expression is implicated in the pathogenesis of many neoplasias. Estrogen receptor alpha (ERalpha) can increase the rate of c-myc transcription through the recruitment of a variety of cofactors to the promoter, yet the precise roles of these cofactors in transcription and tumorigenesis are largely unknown. We show here that a putative tumor suppressor TIP30, also called CC3 or Htatip2, interacts with an ERalpha-interacting coactivator CIA. Using chromatin immunoprecipitation assays, we demonstrate that TIP30 and CIA are distinct cofactors that are dynamically associated with the promoter and downstream regions of the c-myc gene in response to estrogen. Both TIP30 and CIA are recruited to the c-myc gene promoter by liganded ERalpha in the second transcription cycle. TIP30 overexpression represses ERalpha-mediated c-myc transcription, whereas TIP30 deficiency enhances c-myc transcription in both the absence and presence of estrogen. Ectopic CIA cooperates with TIP30 to repress ERalpha-mediated c-myc transcription. Moreover, virgin TIP30 knockout mice exhibit increased c-myc expression in mammary glands. Together, these results reveal an important role for TIP30 in the regulation of ERalpha-mediated c-myc transcription and suggest a mechanism for tumorigenesis promoted by TIP30 deficiency.

  17. PC4 Coactivates MyoD by Relieving the Histone Deacetylase 4-Mediated Inhibition of Myocyte Enhancer Factor 2C

    PubMed Central

    Micheli, Laura; Leonardi, Luca; Conti, Filippo; Buanne, Pasquale; Canu, Nadia; Caruso, Maurizia; Tirone, Felice

    2005-01-01

    Histone deacetylase 4 (HDAC4) negatively regulates skeletal myogenesis by associating with the myocyte enhancer factor 2 (MEF2) transcription factors. Our data indicate that the gene PC4 (interferon-related developmental regulator 1 [IFRD1], Tis7), which we have previously shown to be required for myoblast differentiation, is both induced by MyoD and potentiates the transcriptional activity of MyoD, thus revealing a positive regulatory loop between these molecules. Enhancement by PC4 of MyoD-dependent activation of muscle gene promoters occurs selectively through MEF2 binding sites. Furthermore, PC4 localizes in the nucleus of differentiating myoblasts, associates with MEF2C, and is able to counteract the HDAC4-mediated inhibition of MEF2C. This latter action can be explained by the observed ability of PC4 to dose dependently displace HDAC4 from MEF2C. Consistently, we have observed that (i) the region of PC4 that binds MEF2C is sufficient to counteract the inhibition by HDAC4; (ii) PC4, although able to bind HDAC4, does not inhibit the enzymatic activity of HDAC4; and (iii) PC4 overcomes the inhibition mediated by the amino-terminal domain of HDAC4, which associates with MEF2C but not with PC4. Together, our findings strongly suggest that PC4 acts as a coactivator of MyoD and MEF2C by removing the inhibitory effect of HDAC4, thus exerting a pivotal function during myogenesis. PMID:15743821

  18. Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone.

    PubMed

    Jové, Mireia; Salla, Joel; Planavila, Anna; Cabrero, Agatha; Michalik, Liliane; Wahli, Walter; Laguna, Juan C; Vázquez-Carrera, Manuel

    2004-01-01

    Type 2 diabetes has been related to a decrease of mitochondrial DNA (mtDNA) content. In this study, we show increased expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) and its target genes involved in fatty acid metabolism in skeletal muscle of Zucker Diabetic Fatty (ZDF) (fa/fa) rats. In contrast, the mRNA levels of genes involved in glucose transport and utilization (GLUT4 and phosphofructokinase) were decreased, whereas the expression of pyruvate dehydrogenase kinase 4 (PDK-4), which suppresses glucose oxidation, was increased. The shift from glucose to fatty acids as the source of energy in skeletal muscle of ZDF rats was accompanied by a reduction of subunit 1 of complex I (NADH dehydrogenase subunit 1, ND1) and subunit II of complex IV (cytochrome c oxidase II, COII), two genes of the electronic transport chain encoded by mtDNA. The transcript levels of PPARgamma Coactivator 1 (PGC-1) showed a significant reduction. Treatment with troglitazone (30 mg/kg/day) for 15 days reduced insulin values and reversed the increase in PDK-4 mRNA levels, suggesting improved insulin sensitivity. In addition, troglitazone treatment restored ND1 and PGC-1 expression in skeletal muscle. These results suggest that troglitazone may avoid mitochondrial metabolic derangement during the development of diabetes mellitus 2 in skeletal muscle.

  19. Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation*

    PubMed Central

    Li, Qiuling; Li, Yuewei; Gu, Bingnan; Fang, Lei; Zhou, Pengbo; Bao, Shilai; Huang, Lan; Dai, Xing

    2015-01-01

    Pygopus 2 (Pygo2/PYGO2) is an evolutionarily conserved coactivator and chromatin effector in the Wnt/β-catenin signaling pathway that regulates cell growth and differentiation in various normal and malignant tissues. Although PYGO2 is highly overexpressed in a number of human cancers, the molecular mechanism underlying its deregulation is largely unknown. Here we report that Pygo2 protein is degraded through the ubiquitin/proteasome pathway and is posttranslationally stabilized through phosphorylation by activated phosphatidylinositol 3-kinase/Akt signaling. Specifically, Pygo2 is stabilized upon inhibition of the proteasome, and its intracellular level is regulated by Cullin 4 (Cul4) and DNA damage-binding protein 1 (DDB1), components of the Cul4-DDB1 E3 ubiquitin ligase complex. Furthermore, Pygo2 is phosphorylated at multiple residues, and Akt-mediated phosphorylation at serine 48 leads to its decreased ubiquitylation and increased stability. Finally, we provide evidence that Akt and its upstream growth factors act in parallel with Wnt to stabilize Pygo2. Taken together, our findings highlight chromatin regulator Pygo2 as a common node downstream of oncogenic Wnt and Akt signaling pathways and underscore posttranslational modification, particularly phosphorylation and ubiquitylation, as a significant mode of regulation of Pygo2 protein expression. PMID:26170450

  20. Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid-induced anxiogenic amygdala CRH expression.

    PubMed

    Zalachoras, I; Verhoeve, S L; Toonen, L J; van Weert, L T C M; van Vlodrop, A M; Mol, I M; Meelis, W; de Kloet, E R; Meijer, O C

    2016-12-01

    Maladaptive glucocorticoid effects contribute to stress-related psychopathology. The glucocorticoid receptor (GR) that mediates many of these effects uses multiple signaling pathways. We have tested the hypothesis that manipulation of downstream factors ('coregulators') can abrogate potentially maladaptive GR-mediated effects on fear-motivated behavior that are linked to corticotropin releasing hormone (CRH). For this purpose the expression ratio of two splice variants of steroid receptor coactivator-1 (SRC-1) was altered via antisense-mediated 'exon-skipping' in the central amygdala of the mouse brain. We observed that a change in splicing towards the repressive isoform SRC-1a strongly reduced glucocorticoid-induced responsiveness of Crh mRNA expression and increased methylation of the Crh promoter. The transcriptional GR target gene Fkbp5 remained responsive to glucocorticoids, indicating gene specificity of the effect. The shift of the SRC-1 splice variants altered glucocorticoid-dependent exploratory behavior and attenuated consolidation of contextual fear memory. In conclusion, our findings demonstrate that manipulation of GR signaling pathways related to the Crh gene can selectively diminish potentially maladaptive effects of glucocorticoids.

  1. PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans

    PubMed Central

    Koves, Timothy R.; Sparks, Lauren M.; Kovalik, J. P.; Mosedale, Merrie; Arumugam, Ramamani; DeBalsi, Karen L.; Everingham, Karen; Thorne, Leigh; Phielix, Esther; Meex, Ruth C.; Kien, C. Lawrence; Hesselink, Matthijs K. C.; Schrauwen, Patrick; Muoio, Deborah M.

    2013-01-01

    Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1α in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identified a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercise-trained subjects. These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance. PMID:23175776

  2. Transient α-helices in the disordered RPEL motifs of the serum response factor coactivator MKL1

    NASA Astrophysics Data System (ADS)

    Mizuguchi, Mineyuki; Fuju, Takahiro; Obita, Takayuki; Ishikawa, Mitsuru; Tsuda, Masaaki; Tabuchi, Akiko

    2014-06-01

    The megakaryoblastic leukemia 1 (MKL1) protein functions as a transcriptional coactivator of the serum response factor. MKL1 has three RPEL motifs (RPEL1, RPEL2, and RPEL3) in its N-terminal region. MKL1 binds to monomeric G-actin through RPEL motifs, and the dissociation of MKL1 from G-actin promotes the translocation of MKL1 to the nucleus. Although structural data are available for RPEL motifs of MKL1 in complex with G-actin, the structural characteristics of RPEL motifs in the free state have been poorly defined. Here we characterized the structures of free RPEL motifs using NMR and CD spectroscopy. NMR and CD measurements showed that free RPEL motifs are largely unstructured in solution. However, NMR analysis identified transient α-helices in the regions where helices α1 and α2 are induced upon binding to G-actin. Proline mutagenesis showed that the transient α-helices are locally formed without helix-helix interactions. The helix content is higher in the order of RPEL1, RPEL2, and RPEL3. The amount of preformed structure may correlate with the binding affinity between the intrinsically disordered protein and its target molecule.

  3. Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart

    PubMed Central

    Lai, Ling; Leone, Teresa C.; Zechner, Christoph; Schaeffer, Paul J.; Kelly, Sean M.; Flanagan, Daniel P.; Medeiros, Denis M.; Kovacs, Attila; Kelly, Daniel P.

    2008-01-01

    Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPARγ coactivator-1 (PGC-1) α and β have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1α and PGC-1β (PGC-1αβ−/− mice) were generated to investigate the convergence of their functions in vivo. The phenotype of PGC-1β−/− mice was minimal under nonstressed conditions, including normal heart function, similar to that of PGC-1α−/− mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1αβ−/− mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output. Cardiac-specific ablation of the PGC-1β gene on a PGC-1α-deficient background phenocopied the generalized PGC-1αβ−/− mice. The hearts of the PGC-1αβ−/− mice exhibited signatures of a maturational defect including reduced growth, a late fetal arrest in mitochondrial biogenesis, and persistence of a fetal pattern of gene expression. Brown adipose tissue (BAT) of PGC-1αβ−/− mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1α and PGC-1β share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT. PMID:18628400

  4. In vitro squelching of activated transcription by serum response factor: evidence for a common coactivator used by multiple transcriptional activators.

    PubMed Central

    Prywes, R; Zhu, H

    1992-01-01

    Low amounts of serum response factor (SRF) activate transcription in vitro from a fos promoter construct containing an SRF binding site. Using this human HeLa cell-derived in vitro transcription system, we have found that high amounts of SRF inhibited, or 'squelched', transcription from this construct. Transcription from several other promoters activated by different gene-specific factors, including CREB and the acidic activator VP16, was also inhibited by high amounts of SRF. Basal transcription, from TATA-only promoters, however, was not inhibited. These results suggest that SRF binds to a common factor(s) (termed coactivator) required for activated transcription by a diverse group of transcriptional activators. Inhibition of transcription by SRF could be blocked by a double stranded oligonucleotide containing an SRF binding site. Mutations in SRF which abolished its DNA binding activity also reduced its ability to inhibit transcription. In addition, a C-terminal truncation of SRF which reduced its ability to activate transcription also reduced SRF's ability to inhibit transcription. These results suggest that activation and inhibition of transcription may be mediated by SRF binding to the same factor and that SRF can only bind to this factor when SRF is bound to plasmid DNA. Images PMID:1531519

  5. "Cum play" among gay men.

    PubMed

    Prestage, Garrett; Hurley, Michael; Brown, Graham

    2013-10-01

    The exchange of semen, often referred to as "cum play," has featured in gay literature and may be a unique aspect of many gay men's sexual behavior. We investigated the prevalence of "cum play" and its context among 1153 HIV-negative and 147 HIV-positive Australian gay men in an online survey. Receptive cum play (partner ejaculating or rubbing his semen over participant's anus, or participant using partner's semen as lubricant) was reported by one in six HIV-negative and one quarter of HIV-positive men on the same occasion of protected anal intercourse with a casual partner (PAIC). HIV-negative men who engaged in receptive cum play during PAIC often believed that their partner was HIV seroconcordant and tended to trust that partner. They were also generally more optimistic about the likelihood of HIV transmission, and they often only used condoms at their partners' instigation. Cum play was not uncommon and highlights the narrowness (or danger) of focusing on condom use without considering the implications of broader sexual practices and their meaning for sexual health promotion. "Safe sex" for some gay and bisexual men does not necessarily mean consistent commitment to condom use or to avoiding semen exchange. Many feel confident in their knowledge of their partner's HIV serostatus and only use condoms with these partners at their partner's request. Their commitment to safe sex may not necessarily be compromised by their practice of cum play, but the extent to which this could represent a risk for HIV transmission depends on the reliability of their assessment of their partners' HIV serostatus.

  6. The beauty of match play.

    PubMed

    Clark, Russell D

    2006-06-01

    This study investigated whether higher seeded players have an advanage in the only match play event on the PGA Tour. Analysis showed that the higher seeded won 54% of the time (p=.06); the correlation was .17 (p<.01) between higher seeded players winning and the difference in World Rankings between players. Given professional golfers are at the highest end of the distribution of golf ability, these players are so nearly equal in ability, it is mainly a matter of chance who will win a match play event or who will have the best round on any given day.

  7. Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

    PubMed

    Tolu, S; Eddine, R; Marti, F; David, V; Graupner, M; Pons, S; Baudonnat, M; Husson, M; Besson, M; Reperant, C; Zemdegs, J; Pagès, C; Hay, Y A H; Lambolez, B; Caboche, J; Gutkin, B; Gardier, A M; Changeux, J-P; Faure, P; Maskos, U

    2013-03-01

    Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

  8. Rasd1 modulates the coactivator function of NonO in the cyclic AMP pathway.

    PubMed

    Ong, Shufen Angeline; Tan, Jen Jen; Tew, Wai Loon; Chen, Ken-Shiung

    2011-01-01

    All living organisms exhibit autonomous daily physiological and behavioural rhythms to help them synchronize with the environment. Entrainment of circadian rhythm is achieved via activation of cyclic AMP (cAMP) and mitogen-activated protein kinase signaling pathways. NonO (p54nrb) is a multifunctional protein involved in transcriptional activation of the cAMP pathway and is involved in circadian rhythm control. Rasd1 is a monomeric G protein implicated to play a pivotal role in potentiating both photic and nonphotic responses of the circadian rhythm. In this study, we have identified and validated NonO as an interacting partner of Rasd1 via affinity pulldown, co-immunoprecipitation and indirect immunofluorescence studies. The GTP-hydrolysis activity of Rasd1 is required for the functional interaction. Functional interaction of Rasd1-NonO in the cAMP pathway was investigated via reporter gene assays, chromatin immunoprecipitation and gene knockdown. We showed that Rasd1 and NonO interact at the CRE-site of specific target genes. These findings reveal a novel mechanism by which the coregulator activity of NonO can be modulated.

  9. Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways

    PubMed Central

    Kikuchi, Ippei; Takahashi-Kanemitsu, Atsushi; Sakiyama, Natsuki; Tang, Chao; Tang, Pei-Jung; Noda, Saori; Nakao, Kazuki; Kassai, Hidetoshi; Sato, Toshiro; Aiba, Atsu; Hatakeyama, Masanori

    2016-01-01

    Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner. PMID:27650679

  10. Teaching Technical Skills through Play.

    ERIC Educational Resources Information Center

    Gullion, Laurie

    The value of light-hearted play in teaching technical recreational sport skills is immense. Children as well as adults can learn more quickly and completely with a games-oriented approach. Often without realizing the hidden goal of excellent skiing or paddling, participants respond to intriguing tasks in a game, immerse themselves in good…

  11. Playing It Safe: Part II.

    ERIC Educational Resources Information Center

    Penman, Kenneth A.; Niccolai, Frances R.

    1985-01-01

    Explains how to prevent outdoor sports injuries; discusses related litigation and specific cases involving playing field turf, tennis, skiing, and pools; and sets out facility design and maintenance considerations and recommendations. A sidebar provides information about injury insurance available to NCAA schools. Part I of this article appeared…

  12. Teaching Shakespeare Through Play Production.

    ERIC Educational Resources Information Center

    Stodder, Joseph H.

    1995-01-01

    A performance-oriented approach to teaching William Shakespeare's literature has been found to be effective and enthusiastically received by college students. Ten years of teaching Shakespeare through full play production has shown that the rewards, eloquently expressed in the testimony of students, more than compensate for extra work required of…

  13. Play Orientation in Physics Education.

    ERIC Educational Resources Information Center

    Von Aufshnaiter, Stefan; Schwedes, Hannelore

    1989-01-01

    Described is a curriculum project developed in Germany. The importance of playing and gaming for the acquisition of cognitive and social capacities, the relationships among acting, reasoning, and learning in physics instruction, and the spheres of subjective experience are discussed. The framework and evaluation of the curriculum are outlined. (YP)

  14. Play: The Reversal Theory Perspective.

    ERIC Educational Resources Information Center

    Kerr, J. H.

    The intention of this theoretical paper is to present a reversal theory interpretation of play phenomena. Reversal theory, a developing theory in psychology, concerns the complex relationship between experience and motivation. One of the central charactieristics of the theory is that it attempts to understand why so much of human behavior is…

  15. Moral Education through Play Therapy

    ERIC Educational Resources Information Center

    Mahalle, Salwa; Zakaria, Gamal Abdul Nasir; Nawi, Aliff

    2014-01-01

    This paper will discuss on how sand therapy (as one type of play therapies) can be applied as an additional technique or approach in counseling. The research questions for this study are to see what are the development, challenges faced by the therapist during the sessions given and how sand therapy can aid to the progress of the client. It is a…

  16. Building Curriculum during Block Play

    ERIC Educational Resources Information Center

    Andrews, Nicole

    2015-01-01

    Blocks are not just for play! In this article, Nicole Andrews describes observing the interactions of three young boys enthusiastically engaged in the kindergarten block center of their classroom, using blocks in a building project that displayed their ability to use critical thinking skills, physics exploration, and the development of language…

  17. Creative Play in Language Learning.

    ERIC Educational Resources Information Center

    DeSelms, Carolann

    Creativity is the formulation and expression of an idea which is novel and useful to the creator. It is inherent in the foreign language classroom. Interpretation of experience, or creative play, is a normal part of first language use; with guidance it can be part of the second language learning experience. The effective teacher will consciously…

  18. Electronic Instruments -- Played or Used?

    ERIC Educational Resources Information Center

    Ulveland, Randall Dana

    1998-01-01

    Compares the experience of playing an acoustic instrument to an electronic instrument by analyzing the constant structures and relationships between the experiences. Concludes that students' understanding of the physical experience of making music increases when experiences with acoustic instruments precede their exposure to electronic…

  19. Science Adventures in Children's Play.

    ERIC Educational Resources Information Center

    Rieger, Edythe

    The stated purpose of this pamphlet is to suggest simple, natural, interesting experiences in children's play that have science implications. It tells how the teacher may capitalize on the innate curiosity of children by incorporating science discovery in daily classroom experiences. This how-to-do-it manual directs map-making and activities for…

  20. Obama Plays Cheerleader for STEM

    ERIC Educational Resources Information Center

    Robelen, Erik W.

    2010-01-01

    Amid a struggling economy, a raft of foreign-policy headaches, and the tail end of a heated campaign season, President Barack Obama carved out time in his schedule last month to watch students in the State Dining Room demonstrate a solar-powered model car, a water-purification system, and a soccer-playing robot. The science fair was the fifth…

  1. Sculpting Cells with Play Doh.

    ERIC Educational Resources Information Center

    Way, Virginia A.

    1982-01-01

    Suggests using Play Doh to mold models of the nucleus, mitochondria, and inner cellular structures. Students can conceptualize the cell's structures as three-dimensional even though they appear two-dimensional under a microscope. Includes instructions for preparing homemade dough. (Author/JN)

  2. Interpretive Reproduction in Children's Play

    ERIC Educational Resources Information Center

    Corsaro, William A.

    2012-01-01

    The author looks at children's play from the perspective of interpretive reproduction, emphasizing the way children create their own unique peer cultures, which he defines as a set of routines, artifacts, values, and concerns that children engage in with their playmates. The article focuses on two types of routines in the peer culture of preschool…

  3. Playing Videogames: The Electronic Friend.

    ERIC Educational Resources Information Center

    Selnow, Gary W.

    1984-01-01

    Concluded that the children in this study (ages 10-14) played video games in arcades for some of the same reasons they watched television: (1) escape; (2) a sense of personal involvement in the action; and (3) a source of or substitute for companionship. (PD)

  4. Play Chinese Games. 1987, Revised.

    ERIC Educational Resources Information Center

    White, Caryn

    This document, designed to introduce all ages to a selection of popular Chinese games, describes these games and provides instructions and materials for making the items needed to play most of them. Section 1 suggests class activities that can be related to some of the games. Section 2 presents instructions for the physical or outdoor games of:…

  5. Child-Centered Play Therapy

    ERIC Educational Resources Information Center

    VanFleet, Rise; Sywulak, Andrea E.; Sniscak, Cynthia Caparosa

    2010-01-01

    Highly practical, instructive, and authoritative, this book vividly describes how to conduct child-centered play therapy. The authors are master clinicians who explain core therapeutic principles and techniques, using rich case material to illustrate treatment of a wide range of difficulties. The focus is on nondirective interventions that allow…

  6. Fort Play Children Recreate Recess

    ERIC Educational Resources Information Center

    Powell, Mark

    2007-01-01

    Recess beckons well before it actually arrives. Its allure can be heard in children's lunchtime conversations as they discuss imaginary roles, plans, alliances and teams, with an obvious appetite for play and its unbounded possibility. For some children, recess provides the most important reasons to come to school. In team sports, games of chase…

  7. Leptin is a coactivator of TGF-beta in unilateral ureteral obstructive kidney disease.

    PubMed

    Kümpers, Philipp; Gueler, Faikah; Rong, Song; Mengel, Michael; Tossidou, Irini; Peters, Imke; Haller, Hermann; Schiffer, Mario

    2007-10-01

    Progressive tubulointerstitial fibrosis is the common end point leading to end-stage renal disease in experimental and clinical settings. Since the peptide hormone leptin is involved not only in the regulation of obesity but also in the regulation of inflammation and fibrosis, we tested the hypothesis whether leptin deficiency has an impact on tubulointerstitial fibrosis in mice. Leptin-deficient (ob/ob) and leptin receptor-deficient mice (db/db) were exposed to 14 days of unilateral ureteral obstruction (UUO). The degree of fibrosis and inflammation was compared with that in sham-operated mice by performing immunohistochemistry, quantitative PCR, and Western blotting. We found that tubulointerstitial fibrosis was significantly reduced in the obstructed kidneys of ob/ob compared with db/db mice or control mice. Detailed analysis of infiltrating inflammatory cells by immunohistochemistry revealed a significant reduction of CD4(+) cells at 14 days after UUO in both ob/ob and db/db mice. In contrast, we could not detect significant differences in CD8(+) cells and macrophage content. Transforming growth factor (TGF)-beta mRNA levels, TGF-beta-induced Smad-2/3 activation, and the upregulation of downstream target genes were significantly reduced in ob/ob mice. In addition, we demonstrated that leptin could enhance TGF-beta signaling in normal rat kidney fibroblasts in vitro. We conclude that leptin can serve as a cofactor of TGF-beta activation and thus plays an important role in renal tubulointerstitial fibrosis. Therefore, selective blockade of the leptin axis might provide a therapeutic possibility to prevent or delay fibrotic kidney disease.

  8. Winnetka deformation zone: Surface expression of coactive slip on a blind fault during the Northridge earthquake sequence, California. Evidence that coactive faulting occurred in the Canoga Park, Winnetka, and Northridge areas during the 17 January 1994, Northridge, California earthquake

    SciTech Connect

    Cruikshank, K.M.; Johnson, A.M.; Fleming, R.W.; Jones, R.L.

    1996-12-31

    observations that a large earthquake sequence can include rupture along both a main fault and nearby faults with quite different senses of slip. Faults near the main fault that approach the ground surface or cut the surface in an area have the potential of moving coactively in a major earthquake. Movement on such faults is associated with significant damage during an earthquake. The fault that produced the main Northridge shock and the faults that moved coactively in the Northridge area probably are parts of a large structure. Such interrelationships may be key to understanding earthquakes and damage caused by tectonism.

  9. Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha.

    PubMed

    Ding, Xunshan; Lichti, Kristin; Kim, Insook; Gonzalez, Frank J; Staudinger, Jeff L

    2006-09-08

    Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor (CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1alpha interaction with hepatocyte nuclear factor 4alpha (HNF4alpha, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4-RE) located in its proximal promoter. Expression of PGC-1alpha in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4alpha is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1alpha, HNF4alpha, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.

  10. Challenging Return to Play Decisions

    PubMed Central

    Asplund, Chad A.; O’Connor, Francis G.

    2015-01-01

    Context: Sports medicine providers frequently return athletes to play after sports-related injuries and conditions. Many of these conditions have guidelines or medical evidence to guide the decision-making process. Occasionally, however, sports medicine providers are challenged with complex medical conditions for which there is little evidence-based guidance and physicians are instructed to individualize treatment; included in this group of conditions are exertional heat stroke (EHS), exertional rhabdomyolysis (ER), and exertional collapse associated with sickle cell trait (ECAST). Evidence Acquisition: The MEDLINE (2000-2015) database was searched using the following search terms: exertional heat stroke, exertional rhabdomyolysis, and exertional collapse associated with sickle cell trait. References from consensus statements, review articles, and book chapters were also utilized. Study Design: Clinical review. Level of Evidence: Level 4. Results: These entities are unique in that they may cause organ system damage capable of leading to short- or long-term detriments to physical activity and may not lend to complete recovery, potentially putting the athlete at risk with premature return to play. Conclusion: With a better understanding of the pathophysiology of EHS, ER, and ECAST and the factors associated with recovery, better decisions regarding return to play may be made. PMID:26896216

  11. Estrogen target gene regulation and coactivator expression in rat uterus after developmental exposure to the ultraviolet filter 4-methylbenzylidene camphor.

    PubMed

    Durrer, Stefan; Maerkel, Kirsten; Schlumpf, Margret; Lichtensteiger, Walter

    2005-05-01

    Because the estrogen receptor (ER) ligand type influences transactivation, it is important to obtain information on molecular actions of nonclassical ER agonists. UV filters from cosmetics represent new classes of endocrine active chemicals, including the preferential ER beta ligands 4-methylbenzylidene camphor (4-MBC) and 3-benzylidene camphor. We studied estrogen target gene expression in uterus of Long Evans rats after developmental exposure to 4-MBC (0.7, 7, 24, and 47 mg/kg x d) administered in feed to the parent generation before mating, during pregnancy and lactation, and to the offspring until adulthood. 4-MBC altered steady-state levels of mRNAs encoding for ER alpha, ER beta, progesterone receptor (PR), IGF-I, androgen receptor, determined by real-time RT-PCR in uterus of 12-wk-old offspring. Western-blot analyses of the same tissue homogenates indicated changes in ER alpha and PR but not ER beta proteins. To assess sensitivity to estradiol (E2), offspring were ovariectomized on d 70, injected with E2 (10 or 50 microg/kg sc) on d 84, and killed 6 h later. Acute up-regulation of PR and IGF-I and down-regulation of ER alpha and androgen receptor by E2 were dose-dependently reduced in 4-MBC-exposed rats. The reduced response to E2 was accompanied by reduced coactivator SRC-1 mRNA and protein levels. Our data indicate that developmental exposure to 4-MBC affects the regulation of estrogen target genes and the expression of nuclear receptor coregulators in uterus at mRNA and protein levels.

  12. On the Origin of Muscle Synergies: Invariant Balance in the Co-activation of Agonist and Antagonist Muscle Pairs

    PubMed Central

    Hirai, Hiroaki; Miyazaki, Fumio; Naritomi, Hiroaki; Koba, Keitaro; Oku, Takanori; Uno, Kanna; Uemura, Mitsunori; Nishi, Tomoki; Kageyama, Masayuki; Krebs, Hermano Igo

    2015-01-01

    Investigation of neural representation of movement planning has attracted the attention of neuroscientists, as it may reveal the sensorimotor transformation essential to motor control. The analysis of muscle synergies based on the activity of agonist–antagonist (AA) muscle pairs may provide insight into such transformations, especially for a reference frame in the muscle space. In this study, we examined the AA concept using the following explanatory variables: the AA ratio, which is related to the equilibrium-joint angle, and the AA sum, which is associated with joint stiffness. We formulated muscle synergies as a function of AA sums, positing that muscle synergies are composite units of mechanical impedance. The AA concept can be regarded as another form of the equilibrium-point (EP) hypothesis, and it can be extended to the concept of EP-based synergies. We introduce, here, a novel tool for analyzing the neurological and motor functions underlying human movements and review some initial insights from our results about the relationships between muscle synergies, endpoint stiffness, and virtual trajectories (time series of EP). Our results suggest that (1) muscle synergies reflect an invariant balance in the co-activation of AA muscle pairs; (2) each synergy represents the basis for the radial, tangential, and null movements of the virtual trajectory in the polar coordinates centered on the specific joint at the base of the body; and (3) the alteration of muscle synergies (for example, due to spasticity or rigidity following neurological injury) results in significant distortion of endpoint stiffness and concomitant virtual trajectories. These results indicate that muscle synergies (i.e., the balance of muscle mechanical impedance) are essential for motor control. PMID:26636079

  13. P53 Modulates The Activity Of The GLI1 Oncogene Through Interactions With The Shared Coactivator TAF9

    PubMed Central

    Yoon, Joon Won; Lamm, Marilyn; Iannaccone, Stephen; Higashiyama, Nicole; Leong, King Fu; Iannaccone, Philip; Walterhouse, David

    2015-01-01

    The GLI1 oncogene and p53 tumor suppressor gene function in an inhibitory loop that controls stem cell and tumor cell numbers. Since GLI1 and p53 both interact with the coactivator TATA Binding Protein Associated Factor 9 (TAF9), we hypothesized that competition between these transcription factors for TAF9 in cancer cells may contribute to the inhibitory loop and directly affect GLI1 function and cellular phenotype. We showed that TAF9 interacts with the oncogenic GLI family members GLI1 and GLI2 but not GLI3 in cell-free pull-down assays and with GLI1 in rhabdomyosarcoma and osteosarcoma cell lines. Removal of the TAF9-binding acidic alpha helical transactivation domain of GLI1 produced a significant reduction in the ability of GLI1 to transform cells. We then introduced a point mutation into GLI1 (L1052I) that eliminates TAF9 binding and a point mutation into GLI3 (I1510L) that establishes binding. Wild-type and mutant GLI proteins that bind TAF9 showed enhanced transactivating and cell transforming activity compared with those that did not. Therefore, GLI-TAF9 binding appears important for oncogenic activity. We then determined whether wild-type p53 down-regulates GLI function by sequestering TAF9. We showed that p53 binds TAF9 with greater affinity than does GLI1 and that co-expression of p53 with GLI1 or GLI2 down-regulated GLI-induced transactivation, which could be abrogated using mutant forms of GLI1 or p53. This suggests that p53 sequesters TAF9 from GLI1, which may contribute to inhibition of GLI1 activity by p53 and potentially impact therapeutic success of agents targeting GLI-TAF9 interactions in cancer. PMID:26282181

  14. Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members

    PubMed Central

    Moresco, James J.; Vaughan, Joan M.; Matsumura, Shigenobu; Yates, John R.; Montminy, Marc

    2017-01-01

    The second messenger cAMP stimulates cellular gene expression via the PKA-mediated phosphorylation of the transcription factor CREB and through dephosphorylation of the cAMP-responsive transcriptional coactivators (CRTCs). Under basal conditions, CRTCs are phosphorylated by members of the AMPK family of Ser/Thr kinases and sequestered in the cytoplasm via a phosphorylation-dependent association with 14-3-3 proteins. Increases in cAMP promote the dephosphorylation and nuclear translocation of CRTCs, where they bind to CREB and stimulate relevant target genes. Although they share considerable sequence homology, members of the CRTC family exert non-overlapping effects on cellular gene expression through as yet unidentified mechanisms. Here we show that the three CRTCs exhibit distinct patterns of 14-3-3 binding at three conserved sites corresponding to S70, S171, and S275 (in CRTC2). S171 functions as the gatekeeper site for 14-3-3 binding; it acts cooperatively with S275 in stabilizing this interaction following its phosphorylation by the cAMP-responsive SIK and the cAMP-nonresponsive MARK kinases. Although S171 contains a consensus recognition site for phosphorylation by AMPK family members, S70 and S275 carry variant motifs (MNTGGS275LPDL), lacking basic residues that are otherwise critical for SIK/MARK recognition as well as 14-3-3 binding. Correspondingly, the activity of these motifs differs between CRTC family members. As the variant (SLPDL) motif is present and apparently phosphorylated in other mammalian proteins, our studies suggest that the regulation of cellular targets by AMPK family members is more extensive than previously appreciated. PMID:28235073

  15. Impact of Oxidative Stress and Peroxisome Proliferator–Activated Receptor γ Coactivator-1α in Hepatic Insulin Resistance

    PubMed Central

    Kumashiro, Naoki; Tamura, Yoshifumi; Uchida, Toyoyoshi; Ogihara, Takeshi; Fujitani, Yoshio; Hirose, Takahisa; Mochizuki, Hideki; Kawamori, Ryuzo; Watada, Hirotaka

    2008-01-01

    OBJECTIVE—Recent studies identified accumulation of reactive oxygen species (ROS) as a common pathway causing insulin resistance. However, whether and how the reduction of ROS levels improves insulin resistance remains to be elucidated. The present study was designed to define this mechanism. RESEARCH DESIGN AND METHODS—We investigated the effect of overexpression of superoxide dismutase (SOD)1 in liver of obese diabetic model (db/db) mice by adenoviral injection. RESULTS—db/db mice had high ROS levels in liver. Overexpression of SOD1 in liver of db/db mice reduced hepatic ROS and blood glucose level. These changes were accompanied by improvement in insulin resistance and reduction of hepatic gene expression of phosphoenol-pyruvate carboxykinase and peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), which is the main regulator of gluconeogenic genes. The inhibition of hepatic insulin resistance was accompanied by attenuation of phosphorylation of cAMP-responsive element-binding protein (CREB), which is a main regulator of PGC-1α expression, and attenuation of Jun NH2-terminal kinase (JNK) phosphorylation. Simultaneously, overexpression of SOD1 in db/db mice enhanced the inactivation of forkhead box class O1, another regulator of PGC-1α expression, without the changes of insulin-induced Akt phosphorylation in liver. In hepatocyte cell lines, ROS induced phosphorylation of JNK and CREB, and the latter, together with PGC-1α expression, was inhibited by a JNK inhibitor. CONCLUSIONS—Our results indicate that the reduction of ROS is a potential therapeutic target of liver insulin resistance, at least partly by the reduced expression of PGC-1α. PMID:18487450

  16. Prognostic value of the Hippo pathway transcriptional coactivators YAP/TAZ and β1-integrin in conventional osteosarcoma

    PubMed Central

    Bouvier, Corinne; Macagno, Nicolas; Nguyen, Quy; Loundou, Anderson; Jiguet-Jiglaire, Carine; Gentet, Jean-Claude; Jouve, Jean-Luc; Rochwerger, Alexandre; Mattei, Jean-Camille; Bouvard, Daniel; Salas, Sébastien

    2016-01-01

    Introduction Currently, very few studies are available concerning the mammalian Hippo pathway in bone sarcomas. YAP/TAZ transcription co-activators are key downstream effectors of this pathway and may also have oncogenic properties. Additionally, recent in-vitro experiments showed that expression of β1-integrin promoted metastasis in osteosarcomas. This study investigated the expression of YAP/TAZ and β1-integrin in human osteosarcomas. Materials and methods We performed automated immunohistochemistry on tissue-microarrays (TMA) in which 69 conventional osteosarcomas biopsies performed prior to chemotherapy were embedded. Cellular localization and semi-quantitative analysis of each immunostain was performed using Immunoreactive Score (IRS) and correlated to clinico-pathological data. Results Cytoplasmic expression of β1-integrin was noted in 54/59 osteosarcomas (92%), with 33/59 cases (56%) displaying membranous staining. YAP/TAZ was expressed in 27/45 osteosarcomas (60%), with 14 cases (31%) showing cytoplasmic expression while 13 other cases (28%) displayed nuclear expression. No link was found between YAP/TAZ or β1-integrin expression and response to chemotherapy. In univariate analysis, YAP/TAZ immunoreactive score was pejoratively correlated with overall survival (p = 0.01). Expression of β1-integrin on cell membrane was also pejorative for OS (p = 0.045). In multivariate analysis, YAP/TAZ nuclear expression was an independent prognostic factor for PFS (p = 0.035). Conclusion this study indicates that β1-integrin and YAP/TAZ proteins are linked to prognosis and therefore could be therapeutic targets in conventional osteosarcomas. PMID:27608849

  17. A novel variant of the putative demethylase gene, s-JMJD1C, is a coactivator of the AR.

    PubMed

    Wolf, Siegmund S; Patchev, Vladimir K; Obendorf, Maik

    2007-04-01

    Evidence is accumulating in support of the view that tissue-specific effects of steroid hormones depend on the recruitment of nuclear receptor comodulator proteins. The latter interact directly with the hormone receptors and modify their transcriptional effects on specific target genes. The mechanisms of comodulator influence on nuclear receptor-controlled gene transcription is only partially understood. Here, we describe the discovery of a new AR coactivator which belongs to the JmjC containing enzyme family as a novel variant of JMJD1C (jumonji domain-containing 1C). By using a fragment of the human AR (aa 325-919) as bait in a yeast two-hybrid screen, a region of the human JMJD1C gene was identified as interacting with AR. A novel splice variant s-JMJD1C was amplified by RACE, and the binding to AR was analysed by GST-pull-down and mammalian one-hybrid experiments. As a nuclear-localized protein, the s-JMJD1C gene is expressed in a variety of human tissues. In the brain, this protein is present in several, but not confined to, AR-expressing neuronal populations and its abundance varies with the hormonal status in a region-specific fashion. Interestingly, the expression of s-JMJD1C is reduced in breast cancer tumors and significantly higher in normal breast tissues indicating a putative role in tumor suppression. As s-JMJD1C has putative demethylase activity, removal of methylation seems to be important for nuclear receptor-based gene regulation.

  18. Orexin excites rat inferior vestibular nuclear neurons via co-activation of OX1 and OX 2 receptors.

    PubMed

    Yu, Lei; Zhang, Xiao-Yang; Chen, Zhang-Peng; Zhuang, Qian-Xing; Zhu, Jing-Ning; Wang, Jian-Jun

    2015-06-01

    Orexin deficiency results in cataplexy, a motor deficit characterized by sudden loss of muscle tone, strongly indicating an active role of central orexinergic system in motor control. However, effects of orexin on neurons in central motor structures are still largely unknown. Our previous studies have revealed that orexin excites neurons in the cerebellar nuclei and lateral vestibular nucleus, two important subcortical motor centers for control of muscle tone. Here, we report that both orexin-A and orexin-B depolarizes and increases the firing rate of neurons in the inferior vestibular nucleus (IVN), the largest nucleus in the vestibular nuclear complex and holding an important position in integration of information signals in the control of body posture. TTX does not block orexin-induced excitation on IVN neurons, suggesting a direct postsynaptic action of the neuropeptide. Furthermore, bath application of orexin induces an inward current on IVN neurons in a concentration-dependent manner. SB334867 and TCS-OX2-29, specific OX1 and OX2 receptor antagonists, blocked the excitatory effect of orexin, and [Ala(11), D-Leu(15)]-orexin B, a selective OX2 receptor agonist, mimics the orexin-induced inward current on IVN neurons. qPCR and immunofluorescence results show that both OX1 and OX2 receptor mRNAs and proteins are expressed and localized in the rat IVN. These results demonstrate that orexin excites the IVN neurons by co-activation of both OX1 and OX2 receptors, suggesting that via the direct modulation on the IVN, the central orexinergic system may actively participate in the central vestibular-mediated postural and motor control.

  19. On the Origin of Muscle Synergies: Invariant Balance in the Co-activation of Agonist and Antagonist Muscle Pairs.

    PubMed

    Hirai, Hiroaki; Miyazaki, Fumio; Naritomi, Hiroaki; Koba, Keitaro; Oku, Takanori; Uno, Kanna; Uemura, Mitsunori; Nishi, Tomoki; Kageyama, Masayuki; Krebs, Hermano Igo

    2015-01-01

    Investigation of neural representation of movement planning has attracted the attention of neuroscientists, as it may reveal the sensorimotor transformation essential to motor control. The analysis of muscle synergies based on the activity of agonist-antagonist (AA) muscle pairs may provide insight into such transformations, especially for a reference frame in the muscle space. In this study, we examined the AA concept using the following explanatory variables: the AA ratio, which is related to the equilibrium-joint angle, and the AA sum, which is associated with joint stiffness. We formulated muscle synergies as a function of AA sums, positing that muscle synergies are composite units of mechanical impedance. The AA concept can be regarded as another form of the equilibrium-point (EP) hypothesis, and it can be extended to the concept of EP-based synergies. We introduce, here, a novel tool for analyzing the neurological and motor functions underlying human movements and review some initial insights from our results about the relationships between muscle synergies, endpoint stiffness, and virtual trajectories (time series of EP). Our results suggest that (1) muscle synergies reflect an invariant balance in the co-activation of AA muscle pairs; (2) each synergy represents the basis for the radial, tangential, and null movements of the virtual trajectory in the polar coordinates centered on the specific joint at the base of the body; and (3) the alteration of muscle synergies (for example, due to spasticity or rigidity following neurological injury) results in significant distortion of endpoint stiffness and concomitant virtual trajectories. These results indicate that muscle synergies (i.e., the balance of muscle mechanical impedance) are essential for motor control.

  20. Cardiopulmonary changes during clarinet playing.

    PubMed

    Hahnengress, Maria L; Böning, Dieter

    2010-12-01

    Since playing wind instrument impedes normal respiratory functions, its effect on expiratory and blood gases as well as on cardiac function was investigated. In 15 skilled clarinettists expiratory PO(2) and PCO(2) were measured in gas drawn from a modified clarinet barrel when playing a composition (Robert Schumann's "Phantasiestücke" Op. 73 for clarinet and piano) with increasing difficulty from movement 1 to movement 3. Blood gases were measured in arterialized ear lobe blood at the end of each movement and the electrocardiogram was recorded continuously. From the expiratory gas pressures one may conclude that the most advanced players adapt their ventilation to the requirements of the composition and sustain expiration during difficult parts of the composition until hypoxic alveolar PO(2) values are reached (minimum 77 mmHg). Less trained clarinettists tend to hyperventilation or shallow breathing. Oxygen saturation in arterialized blood showed a slight step-wise decrease from movement to movement [control 96.6 ± 0.5 (SD)%, end of concert 95.6 ± 1.0%]. SO(2) was significantly higher because of possibly more effective ventilation in instrumentalists with practise time exceeding 2 h daily. Mean heart rate increased to values like during moderate to heavy physical exercise depending on artistic fitness and the difficulty of the movement (maximal individual value 173 beats/min). Additionally, a large variation might be caused through intrathoracic pressure changes, changing exertion, respiratory influences and emotion. The electrocardiogram showed no pathological events. In general, clarinet playing at a professional level imposes strain on ventilation and circulation but usually not on a pathophysiological level.

  1. Supervising the uncanny: the play within the play.

    PubMed

    Leader, Carol

    2015-11-01

    The writer offers a combined experience in analysis and the performing arts to explore uncanny aspects of the unconscious subtext of the patient's inner drama; subtext which can remain hidden from view in supervision. Freud and Jung's understanding of uncanny experience is considered together with a painting from medieval alchemy and Matte Blanco's conceptions concerning the symmetrical nature of unconscious process. Theatre and the work of the theatre director and actor in approaching the multidimensional aspects of a play are then introduced. Finally clinical case material from group supervision demonstrates how the 'theatre of therapy' and the work of the supervisory couple and group promote the emergence of a more authentic conscious asymmetrical response to the patient's 'script' that can break the 'spell' of the transference/countertransference relationship. This in turn brings meaning to the underlying and implicit 'stage directions' that the patient has been unconsciously communicating.

  2. Carob pod insoluble fiber exerts anti-atherosclerotic effects in rabbits through sirtuin-1 and peroxisome proliferator-activated receptor-γ coactivator-1α.

    PubMed

    Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Lahera, Vicente; de las Heras, Natalia

    2014-09-01

    The aim of this study was to evaluate the potential effects of an insoluble dietary fiber from carob pod (IFC) (1 g ⋅ kg(-1) ⋅ d(-1) in the diet) on alterations associated with atherosclerosis in rabbits with dyslipidemia. Male New Zealand rabbits (n = 30) were fed the following diets for 8 wk: 1) a control diet (SF412; Panlab) as a control group representing normal conditions; 2) a control supplemented with 0.5% cholesterol + 14% coconut oil (DL) (SF302; Panlab) for 8 wk as a dyslipidemic group; and 3) a control containing 0.5% cholesterol + 14% coconut oil plus IFC (1 g ⋅ kg(-1) ⋅ d(-1)) (DL+IFC) for 8 wk. IFC was administered in a pellet mixed with the DL diet. The DL-fed group developed mixed dyslipidemia and atherosclerotic lesions, which were associated with endothelial dysfunction, inflammation, and fibrosis. Furthermore, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein expression in the aorta were reduced to 77% and 63% of the control group, respectively (P < 0.05), in these rabbits. Administration of IFC to DL-fed rabbits reduced the size of the aortic lesion significantly (DL, 15.2% and DL+IFC, 2.6%) and normalized acetylcholine-induced relaxation (maximal response: control, 89.3%; DL, 61.6%; DL+IFC, 87.1%; P < 0.05) and endothelial nitric oxide synthase expression (DL, 52% and DL+IFC, 104% of the control group). IFC administration to DL-fed rabbits also reduced cluster of differentiation 36 (DL, 148% and DL+IFC, 104% of the control group; P < 0.05), plasminogen activator inhibitor-1 (DL, 141% and DL+IFC, 107% of the control group), tumor necrosis factor-α (DL, 166% and DL+IFC, 120% of the control group), vascular cell adhesion molecule-1 (DL, 153% and DL+IFC, 110% of the control group), transforming growth factor-β (DL, 173% and DL+IFC, 99% of the control group), and collagen I (DL, 157% and DL+IFC, 112% of the control group) in the aorta. These effects were accompanied by an enhancement of

  3. Opposing effects of corepressor and coactivators in determining the dose-response curve of agonists, and residual agonist activity of antagonists, for glucocorticoid receptor-regulated gene expression.

    PubMed

    Szapary, D; Huang, Y; Simons, S S

    1999-12-01

    A distinguishing, but unexplained, characteristic of steroid hormone action is the dose-response curve for the regulation of gene expression. We have previously reported that the dose-response curve for glucocorticoid induction of a transfected reporter gene in CV-1 and HeLa cells is repositioned in the presence of increasing concentrations of glucocorticoid receptors (GRs). This behavior is now shown to be independent of the reporter, promoter, or enhancer, consistent with our proposal that a transacting factor(s) was being titrated by added receptors. Candidate factors have been identified by the observation that changes in glucocorticoid induction parameters in CV-1 cells could be reproduced by varying the cellular levels of coactivators [transcriptional intermediary factor 2 (TIF2), steroid receptor coactivator 1 (SRC-1), and amplified in breast cancer 1 (AIB1)], comodulator [CREB-binding protein (CBP)], or corepressor [silencing mediator for retinoid and thyroid-hormone receptors (SMRT)] without concomitant increases in GR. Significantly, the effects of TIF2 and SMRT were mutually antagonistic. Similarly, additional SMRT could reverse the action of increased levels of GRs in HeLa cells, thus indicating that the effects of cofactors on transcription may be general for GR in a variety of cells. These data further indicate that GRs are yet an additional target of the corepressor SMRT. At the same time, these cofactors were found to be capable of regulating the level of residual agonist activity displayed by antiglucocorticoids. Finally, these observations suggest that a novel role for cofactors is to participate in processes that determine the dose-response curve, and partial agonist activity, of GR-steroid complexes. This new activity of cofactors is disconnected from their ability to increase or decrease GR transactivation. An equilibrium model is proposed in which the ratio of coactivator-corepressor bound to either receptor-agonist or -antagonist complexes

  4. Effects of location and timing of co-activated neurons in the auditory midbrain on cortical activity: implications for a new central auditory prosthesis

    NASA Astrophysics Data System (ADS)

    Straka, Małgorzata M.; McMahon, Melissa; Markovitz, Craig D.; Lim, Hubert H.

    2014-08-01

    Objective. An increasing number of deaf individuals are being implanted with central auditory prostheses, but their performance has generally been poorer than for cochlear implant users. The goal of this study is to investigate stimulation strategies for improving hearing performance with a new auditory midbrain implant (AMI). Previous studies have shown that repeated electrical stimulation of a single site in each isofrequency lamina of the central nucleus of the inferior colliculus (ICC) causes strong suppressive effects in elicited responses within the primary auditory cortex (A1). Here we investigate if improved cortical activity can be achieved by co-activating neurons with different timing and locations across an ICC lamina and if this cortical activity varies across A1. Approach. We electrically stimulated two sites at different locations across an isofrequency ICC lamina using varying delays in ketamine-anesthetized guinea pigs. We recorded and analyzed spike activity and local field potentials across different layers and locations of A1. Results. Co-activating two sites within an isofrequency lamina with short inter-pulse intervals (<5 ms) could elicit cortical activity that is enhanced beyond a linear summation of activity elicited by the individual sites. A significantly greater extent of normalized cortical activity was observed for stimulation of the rostral-lateral region of an ICC lamina compared to the caudal-medial region. We did not identify any location trends across A1, but the most cortical enhancement was observed in supragranular layers, suggesting further integration of the stimuli through the cortical layers. Significance. The topographic organization identified by this study provides further evidence for the presence of functional zones across an ICC lamina with locations consistent with those identified by previous studies. Clinically, these results suggest that co-activating different neural populations in the rostral-lateral ICC rather

  5. Play behaviours and play object preferences of young children with autistic disorder in a clinical play environment.

    PubMed

    Dominguez, Anna; Ziviani, Jenny; Rodger, Sylvia

    2006-01-01

    Play is the primary occupation of childhood and provides a potentially powerful means of assessing and treating children with autistic disorder. This study utilized a cross-sectional comparison design to investigate the nature of play engagement in children with AD (n = 24), relative to typically developing children (n = 34) matched for chronological age. Play behaviours were recorded in a clinical play environment. Videotapes comprising 15 minutes of the children's spontaneous play behaviour were analysed using time-interval analysis. The particular play behaviours observed and play objects used were coded. Differences in play behaviours (p < 0.0001) and play object preferences (p < 0.0001) were identified between the groups. Findings regarding play behaviour contribute to contention in the literature surrounding functional and symbolic play. Explanations for play object preferences are postulated. Recommendations are made regarding clinical application of findings in terms of enhancing assessment and intervention by augmenting motivation.

  6. Myocardin marks the earliest cardiac gene expression and plays an important role in heart development.

    PubMed

    Chen, Jian-Fu; Wang, Shusheng; Wu, Qiulian; Cao, Dongsun; Nguyen, Thiha; Chen, Yiping; Wang, Da-Zhi

    2008-10-01

    Myocardin belongs to the SAP domain family of transcription factors and is expressed specifically in cardiac and smooth muscle during embryogenesis and in adulthood. Myocardin functions as a transcriptional coactivator of SRF and is sufficient and necessary for smooth muscle gene expression. However, the in vivo function of myocardin during cardiogenesis is not completely understood. Here we clone myocardin from chick embryonic hearts and show that myocardin protein sequences are highly conserved cross species. Detailed studies of chick myocardin expression reveal that myocardin is expressed in cardiac and smooth muscle lineage during early embryogenesis, similar to that found in mouse. Interestingly, the expression of myocardin in the heart was found enriched in the outflow tract and the sinoatrial segments shortly after the formation of linear heart tube. Such expression pattern is also maintained in later developing embryos, suggesting that myocardin may play a unique role in the formation of those cardiac modules. Similar to its mouse counterpart, chick myocardin is able to activate cardiac and smooth muscle promoter reporter genes and induce smooth muscle gene expression in nonmuscle cells. Ectopic overexpression of myocardin enlarged the embryonic chick heart. Conversely, repression of the endogenous chick myocardin using antisense oligonucleotides or a dominant negative mutant form of myocardin inhibited cardiogenesis. Together, our data place myocardin as one of the earliest cardiac marker genes for cardiogenesis and support the idea that myocardin plays an essential role in cardiac gene expression and cardiogenesis.

  7. Intensity of tennis match play

    PubMed Central

    Fernandez, J; Mendez‐Villanueva, A; Pluim, B M

    2006-01-01

    This review focuses on the characteristics of tennis players during match play and provides a greater insight into the energy demands of tennis. A tennis match often lasts longer than an hour and in some cases more than five hours. During a match there is a combination of periods of maximal or near maximal work and longer periods of moderate and low intensity activity. Match intensity varies considerably depending on the players' level, style, and sex. It is also influenced by factors such as court surface and ball type. This has important implications for the training of tennis players, which should resemble match intensity and include interval training with appropriate work to rest ratios. PMID:16632566

  8. Chin force in violin playing.

    PubMed

    Obata, Satoshi; Kinoshita, Hiroshi

    2012-06-01

    Force generated between the left mandible of violinists and the chinrest of the violin was examined using a force-sensing chinrest developed in this study. A strain-gauge force sensor was built, and it was fixed between the violin's top plate and a chin cup. Fifteen professional/amateur violinists held the violin statically, played musical scales with different sound properties and sounding techniques, as well as an excerpt from a Max Bruch concerto. Peak and mean forces were evaluated for each task. In a separate experiment, lateral movement of the lower teeth due to different levels of voluntary chin force exertion was measured. Static holding forces observed were 15 and 22 N with and without the help of the left hand, respectively. Peak force increased from 16 N at soft dynamics to 20 N at strong dynamics during scales. The force further increased to 29 N with the use of vibrato technique and 35 N during shifts. Tempo and hand position did not affect the force. Playing a Bruch concerto induced a mean peak force of 52 N, ranging from 31 to 82 N among the violinists. The developed force-sensing chinrest could accurately record the generated chin force. Typical chin force to stabilize the violin during ordinary musical performance was less than 30 N, but it could momentarily exceed 50 N when technically demanding musical pieces were performed. The lateral shift of the mandible was fairly small (<0.4 mm) even with high chin-force exertion, possibly due to clenching of the molars.

  9. Hand kinematics of piano playing

    PubMed Central

    Flanders, Martha; Soechting, John F.

    2011-01-01

    Dexterous use of the hand represents a sophisticated sensorimotor function. In behaviors such as playing the piano, it can involve strong temporal and spatial constraints. The purpose of this study was to determine fundamental patterns of covariation of motion across joints and digits of the human hand. Joint motion was recorded while 5 expert pianists played 30 excerpts from musical pieces, which featured ∼50 different tone sequences and fingering. Principal component analysis and cluster analysis using an expectation-maximization algorithm revealed that joint velocities could be categorized into several patterns, which help to simplify the description of the movements of the multiple degrees of freedom of the hand. For the thumb keystroke, two distinct patterns of joint movement covariation emerged and they depended on the spatiotemporal patterns of the task. For example, the thumb-under maneuver was clearly separated into two clusters based on the direction of hand translation along the keyboard. While the pattern of the thumb joint velocities differed between these clusters, the motions at the metacarpo-phalangeal and proximal-phalangeal joints of the four fingers were more consistent. For a keystroke executed with one of the fingers, there were three distinct patterns of joint rotations, across which motion at the striking finger was fairly consistent, but motion of the other fingers was more variable. Furthermore, the amount of movement spillover of the striking finger to the adjacent fingers was small irrespective of the finger used for the keystroke. These findings describe an unparalleled amount of independent motion of the fingers. PMID:21880938

  10. Play for All. [CD-ROM].

    ERIC Educational Resources Information Center

    Moore, Robin C.; Goltsman, Susan M.

    A CD-ROM provides a tour of some of the world's greatest play environments, presenting 94 photographic images that illustrate the key concepts and recommendations from Play For All guidelines. It is organized into 10 categories covering a range of play area settings, including play equipment, sand settings, water settings, play props, and animal…

  11. Play Therapy: The Art of the Relationship.

    ERIC Educational Resources Information Center

    Landreth, Garry L.

    Play therapy, described as a dynamic approach to counseling with children which allows the therapist to fully experience the child's world, is discussed in this book. These topics are presented: (1) the meaning of play, including functions of play and symbolic play; (2) history and development of play therapy, including psychoanalytic, release,…

  12. Drought prediction using co-active neuro-fuzzy inference system, validation, and uncertainty analysis (case study: Birjand, Iran)

    NASA Astrophysics Data System (ADS)

    Memarian, Hadi; Pourreza Bilondi, Mohsen; Rezaei, Majid

    2016-08-01

    This work aims to assess the capability of co-active neuro-fuzzy inference system (CANFIS) for drought forecasting of Birjand, Iran through the combination of global climatic signals with rainfall and lagged values of Standardized Precipitation Index (SPI) index. Using stepwise regression and correlation analyses, the signals NINO 1 + 2, NINO 3, Multivariate Enso Index, Tropical Southern Atlantic index, Atlantic Multi-decadal Oscillation index, and NINO 3.4 were recognized as the effective signals on the drought event in Birjand. Based on the results from stepwise regression analysis and regarding the processor limitations, eight models were extracted for further processing by CANFIS. The metrics P-factor and D-factor were utilized for uncertainty analysis, based on the sequential uncertainty fitting algorithm. Sensitivity analysis showed that for all models, NINO indices and rainfall variable had the largest impact on network performance. In model 4 (as the model with the lowest error during training and testing processes), NINO 1 + 2(t-5) with an average sensitivity of 0.7 showed the highest impact on network performance. Next, the variables rainfall, NINO 1 + 2(t), and NINO 3(t-6) with the average sensitivity of 0.59, 0.28, and 0.28, respectively, could have the highest effect on network performance. The findings based on network performance metrics indicated that the global indices with a time lag represented a better correlation with El Niño Southern Oscillation (ENSO). Uncertainty analysis of the model 4 demonstrated that 68 % of the observed data were bracketed by the 95PPU and D-Factor value (0.79) was also within a reasonable range. Therefore, the fourth model with a combination of the input variables NINO 1 + 2 (with 5 months of lag and without any lag), monthly rainfall, and NINO 3 (with 6 months of lag) and correlation coefficient of 0.903 (between observed and simulated SPI) was selected as the most accurate model for drought forecasting using CANFIS

  13. Semenogelin I promotes prostate cancer cell growth via functioning as an androgen receptor coactivator and protecting against zinc cytotoxicity.

    PubMed

    Ishiguro, Hitoshi; Izumi, Koji; Kashiwagi, Eiji; Zheng, Yichun; Li, Yi; Kawahara, Takashi; Miyamoto, Hiroshi

    2015-01-01

    A seminal plasma protein, semenogelin I (SgI), contributes to sperm clotting, upon binding to Zn(2+), and can be proteolyzed by prostate-specific antigen (PSA), resulting in release of the trapped spermatozoa after ejaculation. In contrast, the role of SgI in the development and progression of any types of malignancies remains largely unknown. We previously demonstrated that SgI was overexpressed in prostate cancer tissues and its expression was enhanced by zinc treatment in LNCaP cells. In the current study, using cell lines stably expressing SgI, we investigated its biological functions, in conjunction with zinc, androgen, and androgen receptor (AR), in prostate cancer. Zinc, without SgI, inhibited cell growth of both AR-positive and AR-negative lines. Co-expression of SgI prevented zinc inhibiting dihydrotestosterone-mediated proliferation of AR-positive cells, whereas SgI and/or dihydrotestosterone showed marginal effects in AR-negative cells. Similar effects of SgI overexpression in LNCaP on dihydrotestosterone-induced cell invasion, such as its significant enhancement with zinc, were seen. Overexpression of SgI in LNCaP and CWR22Rv1 cells also augmented dihydrotestosterone-mediated PSA expression (mRNA, protein) in the presence of zinc. However, culture in the conditioned medium containing secreted forms of SgI failed to significantly increase cell viability with or without zinc. In luciferase reporter gene assays, SgI showed even slight inhibitory effects (8% and 15% decreases in PC3 and CWR22Rv1, respectively) at 0 μM zinc and significant stimulatory effects (2.1- and 3.2-fold) at 100 μM zinc on dihydrotestosterone-enhanced AR transactivation. Co-immunoprecipitation then demonstrated dihydrotestosterone-induced physical interactions between AR and SgI. These results suggest that intracellular SgI, together with zinc, functions as an AR coactivator and thereby promotes androgen-mediated prostate cancer progression.

  14. Superhero Play: What's a Teacher to Do?

    ERIC Educational Resources Information Center

    Bauer, Karen L.; Dettore, Ernest

    1997-01-01

    Examines the appeal of superheroes to children and adults' beliefs about superhero play, and suggests some potential benefits of such play. Offers examples of ways to successfully incorporate superhero play into an early childhood classroom. (Author/KB)

  15. Taking Play Seriously: The Experimental Playground

    ERIC Educational Resources Information Center

    American School and University, 1976

    1976-01-01

    Paul Friedberg designs playgrounds that provide opportunities for physical play, which develops motor skills; social play, the interaction between children; and cognitive play, the problem-solving process. (Author/MLF)

  16. Oct-1 POU and octamer DNA co-operate to recognise the Bob-1 transcription co-activator via induced folding.

    PubMed

    Chang, J F; Phillips, K; Lundbäck, T; Gstaiger, M; Ladbury, J E; Luisi, B

    1999-05-21

    The expression of immunoglobulin genes is controlled in part by the DNA-binding protein Oct-1 and the B cell-specific transcription co-activator, Bob1 (also known as OCA-B or OBF-1) that together form a complex on the Igkappa promoter. We have characterised the assembly of the ternary complex using biophysical methods. Bob1 binds specifically as a monomer to the complex of the Oct-1 DNA-binding domain (Oct-1 POU) and the Igkappa promoter, but binds weakly to either Oct-1 POU or the Igkappa promoter alone, indicating that both are required to make an avid complex. Ternary complex formation requires a defined DNA sequence, as the stability of the complex can be strongly affected by a single base-pair change or by removing 5-methyl groups from selected thymine bases.In isolation, Bob1 appears to have little secondary structure, but may become partially structured upon recruitment into the ternary complex as demonstrated by circular dichroism spectra and calorimetry. These and other findings suggest that ternary complex formation requires a defined geometry of the POU/DNA complex, and that the co-activator makes stereo-specific contacts to both the POU protein and the major groove of the DNA that induces its fold.

  17. Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury.

    PubMed

    Yuan, Yanggang; Huang, Songming; Wang, Wenyan; Wang, Yingying; Zhang, Ping; Zhu, Chunhua; Ding, Guixia; Liu, Bicheng; Yang, Tianxin; Zhang, Aihua

    2012-10-01

    Glomerular podocytes are highly specialized epithelial cells whose injury in glomerular diseases causes proteinuria. Since mitochondrial dysfunction is an early event in podocyte injury, we tested whether a major regulator of oxidative metabolism and mitochondrial function, the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), affects podocyte damage. Aldosterone-induced injury decreased PGC-1α expression, and induced mitochondrial and podocyte damage in dose- and time-dependent manners. The suppression of endogenous PGC-1α by RNAi caused podocyte mitochondrial damage and apoptosis while its increase by infection with an adenoviral vector prevented aldosterone-induced mitochondrial malfunction and inhibited injury. Overexpression of the silent mating type information regulation 2 homolog 1, a gene upstream of PGC-1α, prevented aldosterone-induced mitochondrial damage and podocyte injury by upregulating PGC-1α at both the transcriptional and post-translational levels. Resveratrol, a SIRT1 activator, attenuated aldosterone-induced mitochondrial malfunction and podocyte injury in vitro and in aldosterone-infused mice in vivo. Hence, endogenous PGC-1α may be important for maintenance of mitochondrial function in podocytes under normal conditions. Activators of SIRT1, such as resveratol, may be therapeutically useful in glomerular diseases to promote and maintain PGC-1α expression and, consequently, podocyte integrity.

  18. A liver X receptor (LXR)-{beta} alternative splicing variant (LXRBSV) acts as an RNA co-activator of LXR-{beta}

    SciTech Connect

    Hashimoto, Koshi; Ishida, Emi; Matsumoto, Shunichi; Shibusawa, Nobuyuki; Okada, Shuichi; Monden, Tsuyoshi; Satoh, Tetsurou; Yamada, Masanobu; Mori, Masatomo

    2009-12-25

    We report the isolation and functional characterization of a novel transcriptional co-activator, termed LXRBSV. LXRBSV is an alternative splicing variant of liver X receptor (LXR)-{beta} LXRBSV has an intronic sequence between exons 2 and 3 in the mouse LXR-{beta} gene. The LXRBSV gene is expressed in various tissues including the liver and brain. We sub-cloned LXRBSV into pSG5, a mammalian expression vector, and LXRBSV in pSG5 augmented human Sterol Response Element Binding Protein (SREBP)-1c promoter activity in HepG2 cells in a ligand (TO901317) dependent manner. The transactivation mediated by LXRBSV is selective for LXR-{beta}. The LXRBSV protein was deduced to be 64 amino acids in length; however, a GAL4-LXRBSV fusion protein was not able to induce transactivation. Serial deletion constructs of LXRBSV demonstrated that the intronic sequence inserted in LXRBSV is required for its transactivation activity. An ATG mutant of LXRBSV was able to induce transactivation as wild type. Furthermore, LXRBSV functions in the presence of cycloheximide. Taken together, we have concluded that LXRBSV acts as an RNA transcript not as a protein. In the current study, we have demonstrated for the first time that an alternative splicing variant of a nuclear receptor acts as an RNA co-activator.

  19. Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function

    SciTech Connect

    Nitz, Inke . E-mail: initz@molnut.uni-kiel.de; Ewert, Agnes; Klapper, Maja; Doering, Frank

    2007-02-09

    Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha} and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.

  20. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity.

    PubMed

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun; Nishina, Hiroshi

    2014-01-17

    YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP's functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP's co-activation of TEAD-mediated CTGF transcription.

  1. Finger Forces in Clarinet Playing

    PubMed Central

    Hofmann, Alex; Goebl, Werner

    2016-01-01

    Clarinettists close and open multiple tone holes to alter the pitch of the tones. Their fingering technique must be fast, precise, and coordinated with the tongue articulation. In this empirical study, finger force profiles and tongue techniques of clarinet students (N = 17) and professional clarinettists (N = 6) were investigated under controlled performance conditions. First, in an expressive-performance task, eight selected excerpts from the first Weber Concerto were performed. These excerpts were chosen to fit in a 2 × 2 × 2 design (register: low–high; tempo: slow–fast, dynamics: soft–loud). There was an additional condition controlled by the experimenter, which determined the expression levels (low–high) of the performers. Second, a technical-exercise task, an isochronous 23-tone melody was designed that required different effectors to produce the sequence (finger-only, tongue-only, combined tongue-finger actions). The melody was performed in three tempo conditions (slow, medium, fast) in a synchronization-continuation paradigm. Participants played on a sensor-equipped Viennese clarinet, which tracked finger forces and reed oscillations simultaneously. From the data, average finger force (Fmean) and peak force (Fmax) were calculated. The overall finger forces were low (Fmean = 1.17 N, Fmax = 3.05 N) compared to those on other musical instruments (e.g., guitar). Participants applied the largest finger forces during the high expression level performance conditions (Fmean = 1.21 N). For the technical exercise task, timing and articulation information were extracted from the reed signal. Here, the timing precision of the fingers deteriorated the timing precision of the tongue for combined tongue-finger actions, especially for faster tempi. Although individual finger force profiles were overlapping, the group of professional players applied less finger force overall (Fmean = 0.54 N). Such sensor instruments provide useful insights into player

  2. Play Deprivation: A Factor in Juvenile Violence.

    ERIC Educational Resources Information Center

    Frost, Joe; Jacobs, Paul J.

    1995-01-01

    Notes that the increasing number of violent crimes committed by children is a result of play deprivation. Discusses different forms of play and distinguishes between controlled and free play. Examines factors such as inadequate outdoor spaces, organized sports, and hi-tech entertainment which interfere with spontaneous play. Discusses the concept…

  3. Pretend Play in the Early Childhood Classroom

    ERIC Educational Resources Information Center

    McEntire, Nancy

    2009-01-01

    This article presents and summarizes recent resources related to pretend play in the early childhood classroom. These include "Contemporary Perspectives on Play in Early Childhood Education" by Olivia N. Sarachoe and Bernard Spodek; "Dramatic Play: Bring It Back" by Tammy Benson; and "The Importance of Being Playful" by Elena Bodrova and Deborah…

  4. Play and the Young Child: Musical Implications.

    ERIC Educational Resources Information Center

    Brophy, Tim

    After noting the near-universal presence of rhythmic response in play in all cultures, this paper looks first at the historical development of theories of play, and then examines current theories of play and their implications in the teaching of music to young children. The first section reviews 19th and early 20th century theories of play,…

  5. Reconceptualizing Play: Aesthetic Self-Definitions

    ERIC Educational Resources Information Center

    Guss, Faith

    2005-01-01

    This article aims to trouble the identity of children's dramatic play(ing). It contains two interweaving threads of discourse. In one thread lies a discussion of how children can trouble and extend their own identities through the aesthetic form-languages and conventions they employ and deploy in their dramatic playing/pretend playing. Whereas…

  6. Children, Play, and Development. Fourth Edition

    ERIC Educational Resources Information Center

    Hughes, Fergus P.

    2010-01-01

    Children, Play, and Development, Fourth Edition, discusses the relationship of play to the physical, social, intellectual, and emotional growth of the child. Author Fergus P. Hughes focuses on the historical, sociocultural, and ethological context of play; the role of development in play; and the wide range of theories that provide a framework for…

  7. Play Therapy: Practice, Issues, and Trends

    ERIC Educational Resources Information Center

    Homeyer, Linda E.; Morrison, Mary O.

    2008-01-01

    Play therapy is an effective means of responding to the mental health needs of young children and is widely accepted as a valuable and developmentally appropriate intervention. The authors discuss the importance of play in development, the therapeutic benefits of play, the rich history of play therapy, and recent research and current issues and…

  8. Strategies for Family Facilitation of Play Dates

    ERIC Educational Resources Information Center

    Chambers, Cynthia R.; Horn, Eva M.

    2010-01-01

    Play dates can serve several functions for young children, including children with social difficulties, such as developmental delays, behavioral disorders, autism spectrum disorders, and shyness. Play dates provide children with additional opportunities to be around peers and to practice skills associated with peer play interactions. Play dates…

  9. Introduction to Plays, English: 5112.44.

    ERIC Educational Resources Information Center

    Ozan, Ruth S.

    Several plays are studied to introduce students to theatrical terms and to the elements of a play in this quinmester course for Dade County High Schools. Several approaches to the study of the play are suggested such as individual and a large group production of a play, the use of a unified theme such as Youth vs. Tradition, or the line of…

  10. Play and Social Interaction in Middle Childhood

    ERIC Educational Resources Information Center

    Bergen, Doris; Fromberg, Doris Pronin

    2009-01-01

    This article discusses traditional and contemporary definitions of middle childhood play, the value of such play for children's development and learning, the implications of home, school, and societal practices that have resulted in changing the play scenario of middle childhood, and suggestions for assuring that play's value will be maintained…

  11. How the Brain Makes Play Fun

    ERIC Educational Resources Information Center

    Vanderschuren, Louk J. M. J.

    2010-01-01

    In this article, the author describes the empirical studies that have investigated whether play (mostly social play) is rewarding. He then discusses the brain circuits and neurotransmitters that underlie the pleasurable aspects of play. He concludes that the pleasure of play has the ability to reinforce learning activities and that the brain's…

  12. Play and Community in the Classroom.

    ERIC Educational Resources Information Center

    King, Nechie R.

    1997-01-01

    Children recognize two kinds of classroom play: instrumental play organized by teachers for academic purposes; and illicit play stressing surreptitious, unsanctioned activities like whispering and clowning around. Each is associated with a particular form of classroom community. This article considers how the nature of classroom play influences…

  13. Children's Spontaneous Play in Writer's Workshop

    ERIC Educational Resources Information Center

    Lysaker, Judith T.; Wheat, Jennifer; Benson, Emily

    2010-01-01

    Research on the relationship between literacy and play has a rich history. Yet few studies have examined children's use of spontaneous play during literacy events as children are learning to read and write. This case study examines the use of play and the quality of playfulness in a kindergarten/first grade multiage classroom during Writer's…

  14. Active Gaming: The Future of Play?

    ERIC Educational Resources Information Center

    Witherspoon, Lisa; Manning, John P.

    2012-01-01

    The authors examine technology-driven games--especially active gaming--as an evolving form of children's play. They offer an overview of play and its developmental benefits, describe the literature on the emergence of technology-driven play, and reflect on the diminishment of physical play in contemporary culture. They suggest that active gaming,…

  15. Conceptualizing the Play Policies in Preschool Curriculums

    ERIC Educational Resources Information Center

    Sener, Tulin

    2013-01-01

    This research attempted to describe the play policies in preschool institutions in Ankara, Turkey. The aim of this study is to determine the approaches of the preschools to the children's play. "Play Policy Questionnaire" administered to all directors and teachers of 20 public preschools and 20 private preschools. Play policy of each…

  16. Teatro! Hispanic Plays for Young People.

    ERIC Educational Resources Information Center

    Vigil, Angel

    This collection of 14 folk drama scripts is drawn from the Hispanic culture and traditions of the American Southwest and designed for use in educational settings. The plays are short, simple, and easy to produce. A single play can fill a class period, while several plays grouped together would make a school assembly. Six plays, intended for grades…

  17. Psychiatrists' Perceptions of Role-Playing Games.

    PubMed

    Lis, Eric; Chiniara, Carl; Biskin, Robert; Montoro, Richard

    2015-09-01

    The literature has seen a surge in research on the mental health impacts of technologies such as Facebook, video games, and massively-multiplayer online role-playing games such as World of Warcraft, but little is known regarding the mental health impact of non-video role-playing games, such as Dungeons & Dragons. The present study examines how psychiatrists' perceive role-playing games and whether they play them. Psychiatrists at a tertiary care centre in Canada completed a questionnaire assessing history of playing role-playing games and whether they associate them with psychopathology. Forty-eight psychiatrists responded. Twenty-three percent have played a role-playing game over their lifetimes. Twenty-two percent believed there was an association between psychopathology and role-playing games. A majority of psychiatrists who responded do not associate role-playing games with psychopathology. Implications for clinical practice and future research are discussed.

  18. Play in adulthood. A developmental consideration.

    PubMed

    Colarusso, C A

    1993-01-01

    This paper is about normal development, addressing the basic characteristics and evolution of play throughout life, with particular emphasis on the nature of play in adulthood. Although the psychoanalytic literature on play in childhood is extensive, undoubtedly because of its relevance to child analysis, very little has been written on the subject of adult play or on the relationship between adult play and its childhood antecedents.

  19. Coactivator-Associated Arginine Methyltransferase-1 Function in Alveolar Epithelial Senescence and Elastase-Induced Emphysema Susceptibility.

    PubMed

    Sarker, Rim S J; John-Schuster, Gerrit; Bohla, Alexander; Mutze, Kathrin; Burgstaller, Gerald; Bedford, Mark T; Königshoff, Melanie; Eickelberg, Oliver; Yildirim, Ali Ö

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible loss of lung function and is one of the most prevalent and severe diseases worldwide. A major feature of COPD is emphysema, which is the progressive loss of alveolar tissue. Coactivator-associated arginine methyltransferase-1 (CARM1) regulates histone methylation and the transcription of genes involved in senescence, proliferation, and differentiation. Complete loss of CARM1 leads to disrupted differentiation and maturation of alveolar epithelial type II (ATII) cells. We thus hypothesized that CARM1 regulates the development and progression of emphysema. To address this, we investigated the contribution of CARM1 to alveolar rarefication using the mouse model of elastase-induced emphysema in vivo and small interfering (si)RNA-mediated knockdown in ATII-like LA4 cells in vitro. We demonstrate that emphysema progression in vivo is associated with a time-dependent down-regulation of CARM1. Importantly, elastase-treated CARM1 haploinsufficient mice show significantly increased airspace enlargement (52.5 ± 9.6 μm versus 38.8 ± 5.5 μm; P < 0.01) and lung compliance (2.8 ± 0.32 μl/cm H2O versus 2.4 ± 0.4 μl/cm H2O; P < 0.04) compared with controls. The knockdown of CARM1 in LA4 cells led to decreased sirtuin 1 expression (0.034 ± 0.003 versus 0.022 ± 0.001; P < 0.05) but increased expression of p16 (0.27 ± 0.013 versus 0.31 ± 0.010; P < 0.5) and p21 (0.81 ± 0.088 versus 1.28 ± 0.063; P < 0.01) and higher β-galactosidase-positive senescent cells (50.57 ± 7.36% versus 2.21 ± 0.34%; P < 0.001) compared with scrambled siRNA. We further demonstrated that CARM1 haploinsufficiency impairs transdifferentiation and wound healing (32.18 ± 0.9512% versus 8.769 ± 1.967%; P < 0.001) of alveolar epithelial cells. Overall, these results reveal a novel function of CARM1 in regulating emphysema development

  20. Transforming Play: An Analysis of First-, Third-, and Fifth-Graders' Play.

    ERIC Educational Resources Information Center

    Bagley, Donna M.; Chaille, Christine

    1996-01-01

    Compared children's play with transformational objects (vehicles that change to robots) to play with representational objects (cars and figures). Found that those playing with transformers engaged in more parallel play and manipulative activity, while those with representational objects displayed more social play and more symbolic play. Found no…

  1. Exploring Play/Playfulness and Learning in the Adult and Higher Education Classroom

    ERIC Educational Resources Information Center

    Tanis, David J.

    2012-01-01

    Play and playfulness and their role in learning are researched extensively in early childhood education. However, as the child matures into an adult, play and playfulness are given less attention in the teaching and learning process. In adult education, there is very little research about play/playfulness and its significance for learning. Despite…

  2. Forms of vitality play in infancy.

    PubMed

    Español, Silvia; Martínez, Mauricio; Bordoni, Mariana; Camarasa, Rosario; Carretero, Soledad

    2014-12-01

    In this paper we report a qualitative study based on the constant comparative method to initiate the systematic study of forms of vitality play. This is an unnoticed non-figurative play frame linked to early social play and temporal arts in which child and adult elaborate the dynamics of their own movements and sounds in a repetition-variation form. In the introduction we present the theoretical underpinnings and the sporadic observations we have done in previous studies. Then, by the iterative observations of the recorded material of a longitudinal case study on play during the third year of life, we generated the general category of forms of vitality play and four subcategories of display modes of forms of vitality play (improvised forms of vitality play, ritualized forms of vitality play, forms of vitality play combined with pretend play, and forms of vitality play combined with role playing) which are illustrated with descriptive narratives. We discuss the properties of the developed categories, the limits of the present study, and the need to continue systematizing the research on this playful activity.

  3. Play and Development From an Ethological Perspective

    ERIC Educational Resources Information Center

    Vandenberg, Brian

    1978-01-01

    A review of play in nonhuman animals indicates that play increases with phylogenetic status, is important for mature social development in more advanced species, reflects intentional activity, and is essential for the development of tool-using strategies. (Author)

  4. Orientation to Middle School: A Guidance Play.

    ERIC Educational Resources Information Center

    Childress, Natalie Wilson

    1982-01-01

    Presents a play that gives elementary school students a lighthearted but informative overview of middle school life. The play presents information about curriculum, lockers, physical education, materials, and classwork. Notes student reactions to the presentation. (RC)

  5. Imaginary Play Companions: Characteristics and Functions.

    ERIC Educational Resources Information Center

    Kalyan-Masih, V.

    1986-01-01

    Investigates some of the following characteristics associated with young children playing with imaginary play companions (IPCs): intelligence, parental and socioeconomic and educational background, family size, and birth order. Compares these children to those without IPCs. (HOD)

  6. Growing as One Plays with a Balloon

    ERIC Educational Resources Information Center

    Torbert, Marianne

    2006-01-01

    In this article, the author recounts her experience with Tracy, who was playing with a balloon outside her office when she was five years old, and gives an up-to-date story of Tracy since 1985, 1990, and 2006. In reflecting on Tracy's play, the author realizes that Tracy is helping her see clearly what play is really all about, that in playing to…

  7. Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300.

    PubMed

    Dyson, H Jane; Wright, Peter E

    2016-03-25

    The transcriptional coactivators CREB-binding protein (CBP) and p300 undergo a particularly rich set of interactions with disordered and partly ordered partners, as a part of their ubiquitous role in facilitating transcription of genes. CBP and p300 contain a number of small structured domains that provide scaffolds for the interaction of disordered transactivation domains from a wide variety of partners, including p53, hypoxia-inducible factor 1α (HIF-1α), NF-κB, and STAT proteins, and are the targets for the interactions of disordered viral proteins that compete with cellular factors to disrupt signaling and subvert the cell cycle. The functional diversity of the CBP/p300 interactome provides an excellent example of the power of intrinsic disorder to facilitate the complexity of living systems.

  8. Estrogen-Related Receptor alpha (ERR (alpha))-Coactivator Interactions as Targets for Discovery of New Anti-Breast Cancer Therapeutics

    DTIC Science & Technology

    2007-03-01

    Lu c. A ct . ( re l. to T AT A- lu c) A. pTATA-Luc pERE(5x)-Luc pERRE (5x)-Luc - - - Figure 3. GRIP1 is a specific coactivator of “activated” ERRα...AGGTCACAGTGACCT-3’) upstream of the firefly luciferase reporter gene. pERRE (5x)-Luc contains five copies of the consensus estrogen-related receptor response...7 7- 42 3 ER R α 1 ER R α 1 7 7- 42 3 pTATA-Luc pERE(5x)-Luc pERRE (5x)-Luc Expression plasmid: Reporter: ER R α 1 ER R α 1 7 7- 42 3- - - B. 12

  9. Steroid receptor coactivator-interacting protein (SIP) inhibits caspase-independent apoptosis by preventing apoptosis-inducing factor (AIF) from being released from mitochondria.

    PubMed

    Wang, Dandan; Liang, Jing; Zhang, Yu; Gui, Bin; Wang, Feng; Yi, Xia; Sun, Luyang; Yao, Zhi; Shang, Yongfeng

    2012-04-13

    Apoptosis-inducing factor (AIF) is a caspase-independent death effector. Normally residing in the mitochondrial intermembrane space, AIF is released and translocated to the nucleus in response to proapoptotic stimuli. Nuclear AIF binds to DNA and induces chromatin condensation and DNA fragmentation, characteristics of apoptosis. Until now, it remained to be clarified how the mitochondrial-nuclear translocation of AIF is regulated. Here we report that steroid receptor coactivator-interacting protein (SIP) interacts directly with AIF in mitochondria and specifically inhibits caspase-independent and AIF-dependent apoptosis. Challenging cells with apoptotic stimuli leads to rapid degradation of SIP, and subsequently AIF is liberated from mitochondria and translocated to the nucleus to induce apoptosis. Together, our data demonstrate that SIP is a novel regulator in caspase-independent and AIF-mediated apoptosis.

  10. Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300*

    PubMed Central

    2016-01-01

    The transcriptional coactivators CREB-binding protein (CBP) and p300 undergo a particularly rich set of interactions with disordered and partly ordered partners, as a part of their ubiquitous role in facilitating transcription of genes. CBP and p300 contain a number of small structured domains that provide scaffolds for the interaction of disordered transactivation domains from a wide variety of partners, including p53, hypoxia-inducible factor 1α (HIF-1α), NF-κB, and STAT proteins, and are the targets for the interactions of disordered viral proteins that compete with cellular factors to disrupt signaling and subvert the cell cycle. The functional diversity of the CBP/p300 interactome provides an excellent example of the power of intrinsic disorder to facilitate the complexity of living systems. PMID:26851278

  11. Young Children's Playfully Complex Communication: Distributed Imagination

    ERIC Educational Resources Information Center

    Alcock, Sophie

    2010-01-01

    This paper draws on research exploring young children's playful and humorous communication. It explores how playful activity mediates and connects children in complex activity systems where imagination, cognition, and consciousness become distributed across individuals. Children's playfulness is mediated and distributed via artefacts (tools, signs…

  12. Children in Play, Story, and School.

    ERIC Educational Resources Information Center

    Goncu, Artin, Ed.; Klein, Elisa L.

    In honor of the contributions of Greta G. Fein to the fields of developmental psychology and early childhood education, a community of scholars prepared this volume to explore how social play arises, social play's developmental and educational significance, and the ways in which social play can be promoted in early childhood settings. In addition,…

  13. Curious Play: Children's Exploration of Nature

    ERIC Educational Resources Information Center

    Gurholt, Kirsti Pedersen; Sanderud, Jostein Rønning

    2016-01-01

    This article explores the concept of "curious play" as a theoretical framework to understand and communicate children's experiences of free play in nature. The concept emerged interactively from three sources of inspiration: an ethnographically inspired study of children playing in nature; as a critique of the concept of "risky…

  14. Empirically Based Play Interventions for Children

    ERIC Educational Resources Information Center

    Reddy, Linda A., Ed.; Files-Hall, Tara M., Ed.; Schaefer, Charles E., Ed.

    2005-01-01

    "Empirically Based Play Interventions for Children" is a compilation of innovative, well-designed play interventions, presented for the first time in one text. Play therapy is the oldest and most popular form of child therapy in clinical practice and is widely considered by practitioners to be uniquely responsive to children's developmental needs.…

  15. Hyperbole and Humor in Children's Language Play.

    ERIC Educational Resources Information Center

    Varga, Donna

    2000-01-01

    Examined processes by which 4- and 5-year-olds initiate, organize, and maintain language play interactions. Found that as children voice incongruities of greater proportion, the emotional climate of play is heightened and ingenious verbal representations are provoked. Identified developmental features of hyperbolic language play. Contextualized…

  16. Play under Siege: A Historical Overview

    ERIC Educational Resources Information Center

    Zigler, Edward F.; Bishop-Josef, Sandra J.

    2009-01-01

    In this updated version of their chapter from "Children's Play: The Roots of Reading" (published by ZERO TO THREE in 2004), the authors describe the recent attack on play, in both early childhood and elementary education. They provide a historical overview of the contentious relationship between play and cognitive development. The authors stress…

  17. The Play Professional in the United Kingdom

    ERIC Educational Resources Information Center

    Millbank, Anna-Marie

    2005-01-01

    Playwork is a respected field of study composed of experts who have studied the theories and practices of play for the purposes of training other individuals in best practices to better facilitate children's play. The profession is founded on the belief that play is an essential childhood element and the right of every child. In this article, the…

  18. Superheroes: An Opportunity for Prosocial Play

    ERIC Educational Resources Information Center

    De-Souza, Desalyn; Radell, Jacqueline

    2011-01-01

    Superhero play has long been thought of as violent, aggressive, and disruptive. Some argue that aggressive play should not be allowed because it exposes children to inappropriate concepts and attitudes and sends the message that the use of aggression can achieve a desired goal. However, educators know that pretend play is an avenue for healthy…

  19. Turkish Adaptation of Test of Pretended Play

    ERIC Educational Resources Information Center

    Aydin, Aydan

    2012-01-01

    The objective of present research is to conduct validity and reliability analysis of the verbal section of Test of Pretended Play that will measure pretended play behaviors of pre-school age children (3-6 years of age). Test of Pretended Play was first developed by Vicky Lewis and Jill Boucher in 1997. This test aimed to measure pretended play…

  20. Learning through Play. Pediatric Round Table: 3.

    ERIC Educational Resources Information Center

    Chance, Paul

    Summarized in this volume are concepts, presented and developed at a roundtable discussion by scientists and child health professionals, focusing on aspects of children's play behavior. Participants sought to answer three questions: (1) What is play behavior and what is known about it? (2) How does play contribute to infant and child development?…

  1. Pretend Play of Children with Cerebral Palsy

    ERIC Educational Resources Information Center

    Pfeifer, Luzia Iara; Pacciulio, Amanda Mota; dos Santos, Camila Abrao; dos Santos, Jair Licio; Stagnitti, Karen Ellen

    2011-01-01

    Background and Purpose: Evaluate self-initiated pretend play of children with cerebral palsy. Method: Twenty preschool children participated in the study. Pretend play ability was measured by using the child-initiated pretend play assessment culturally adapted to Brazil. Results: There were significant negative correlations between the children's…

  2. Playing Fair: An Essential Element in Contracting

    ERIC Educational Resources Information Center

    Peeler, Tom

    2012-01-01

    Playing fair has a value with which people are all familiar. From the sandboxes of childhood and the competitive sports of youth to the business transactions of adulthood, people have been told how important it is to play fair. Playing fair in contracting is not only essential, it's the legal and ethical thing to do. In this article, the author…

  3. Short-Term Play Therapy for Children.

    ERIC Educational Resources Information Center

    Kaduson, Heidi Gerard, Ed.; Schaefer, Charles E., Ed.

    Play therapy offers a powerful means of helping children resolve a wide range of psychological difficulties, and many play approaches are ideally suited to short-term work. This book brings together leading play therapists to share their expertise on facilitating children's healing in a shorter time frame. The book provides knowledge and skills…

  4. Game Playing: Negotiating Rules and Identities

    ERIC Educational Resources Information Center

    Winther-Lindqvist, Ditte

    2009-01-01

    Beginning with Lev Vygotsky's long-established assertion that the play of children always involves both imaginary play and rules of behavior, this article argues for a theoretical framework that connects such play with the construction of social identities in kindergarten peer groups. It begins with a discussion of Ivy Schousboe's model of the…

  5. Dimensions of Play: Reflections and Directions.

    ERIC Educational Resources Information Center

    Jambor, Tom

    For many children, societal changes have restricted the opportunities for and the right to play. Adults deal with these violations of children's right to play by trying to correct problems, preventing future problems, or by denying that problems can or could exist. In order to meet the challenge of preserving children's play rights, we need to be…

  6. Play as Education in the School Curriculum.

    ERIC Educational Resources Information Center

    Ediger, Marlow

    Friedrich Froebel, an early advocate of the use of play in kindergarten teaching, argued that the ultimate goal of education was developing the creative person. According to Froebel, teachers could promote creativity through play by using gifts, occupations, and mother play songs. By contrast, Johann Herbart called for a subject centered…

  7. Physical Development: Taking Time for Physical Play

    ERIC Educational Resources Information Center

    Strickland, Eric

    2004-01-01

    This article discusses children's physical development through physical play. Here, the author gives ways to incorporate opportunities for physical play. For infants, time for play may have to revolve around nap schedules. This may mean allowing for different wake-sleep cycles for different infants. Teachers can divide the infants into groups so…

  8. Gender Differences in Students' Mathematics Game Playing

    ERIC Educational Resources Information Center

    Lowrie, Tom; Jorgensen, Robyn

    2011-01-01

    The investigation monitored the digital game-playing behaviours of 428 primary-aged students (aged 10-12 years). Chi-square analysis revealed that boys tend to spend more time playing digital games than girls while boys and girls play quite different game genres. Subsequent analysis revealed statistically significant gender differences in terms of…

  9. Cell cycle-dependent expression of Dub3, Nanog and the p160 family of nuclear receptor coactivators (NCoAs) in mouse embryonic stem cells.

    PubMed

    van der Laan, Siem; Golfetto, Eleonora; Vanacker, Jean-Marc; Maiorano, Domenico

    2014-01-01

    Pluripotency of embryonic stem cells (ESC) is tightly regulated by a network of transcription factors among which the estrogen-related receptor β (Esrrb). Esrrb contributes to the relaxation of the G1 to S-phase (G1/S) checkpoint in mouse ESCs by transcriptional control of the deubiquitylase Dub3 gene, contributing to Cdc25A persistence after DNA damage. We show that in mESCs, Dub3 gene expression is cell cycle regulated and is maximal prior G1/S transition. In addition, following UV-induced DNA damage in G1, Dub3 expression markedly increases in S-phase also suggesting a role in checkpoint recovery. Unexpectedly, we also observed cell cycle-regulation of Nanog expression, and not Oct4, reaching high levels prior to G1/S transition, finely mirroring Cyclin E1 fluctuations. Curiously, while Esrrb showed only limited cell-cycle oscillations, transcript levels of the p160 family of nuclear receptor coactivators (NCoAs) displayed strong cell cycle-dependent fluctuations. Since NCoAs function in concert with Esrrb in transcriptional activation, we focussed on NCoA1 whose levels specifically increase prior onset of Dub3 transcription. Using a reporter assay, we show that NCoA1 potentiates Esrrb-mediated transcription of Dub3 and we present evidence of protein interaction between the SRC1 splice variant NCoA1 and Esrrb. Finally, we show a differential developmental regulation of all members of the p160 family during neural conversion of mESCs. These findings suggest that in mouse ESCs, changes in the relative concentration of a coactivator at a given cell cycle phase, may contribute to modulation of the transcriptional activity of the core transcription factors of the pluripotent network and be implicated in cell fate decisions upon onset of differentiation.

  10. Cell Cycle-Dependent Expression of Dub3, Nanog and the p160 Family of Nuclear Receptor Coactivators (NCoAs) in Mouse Embryonic Stem Cells

    PubMed Central

    van der Laan, Siem; Golfetto, Eleonora; Vanacker, Jean-Marc; Maiorano, Domenico

    2014-01-01

    Pluripotency of embryonic stem cells (ESC) is tightly regulated by a network of transcription factors among which the estrogen-related receptor β (Esrrb). Esrrb contributes to the relaxation of the G1 to S-phase (G1/S) checkpoint in mouse ESCs by transcriptional control of the deubiquitylase Dub3 gene, contributing to Cdc25A persistence after DNA damage. We show that in mESCs, Dub3 gene expression is cell cycle regulated and is maximal prior G1/S transition. In addition, following UV-induced DNA damage in G1, Dub3 expression markedly increases in S-phase also suggesting a role in checkpoint recovery. Unexpectedly, we also observed cell cycle-regulation of Nanog expression, and not Oct4, reaching high levels prior to G1/S transition, finely mirroring Cyclin E1 fluctuations. Curiously, while Esrrb showed only limited cell-cycle oscillations, transcript levels of the p160 family of nuclear receptor coactivators (NCoAs) displayed strong cell cycle-dependent fluctuations. Since NCoAs function in concert with Esrrb in transcriptional activation, we focussed on NCoA1 whose levels specifically increase prior onset of Dub3 transcription. Using a reporter assay, we show that NCoA1 potentiates Esrrb-mediated transcription of Dub3 and we present evidence of protein interaction between the SRC1 splice variant NCoA1 and Esrrb. Finally, we show a differential developmental regulation of all members of the p160 family during neural conversion of mESCs. These findings suggest that in mouse ESCs, changes in the relative concentration of a coactivator at a given cell cycle phase, may contribute to modulation of the transcriptional activity of the core transcription factors of the pluripotent network and be implicated in cell fate decisions upon onset of differentiation. PMID:24695638

  11. X-Ray Crystal Structure of the Ancestral 3-Ketosteroid Receptor-Progesterone-Mifepristone Complex Shows Mifepristone Bound at the Coactivator Binding Interface

    SciTech Connect

    Colucci, Jennifer K.; Ortlund, Eric A.

    2013-12-12

    Steroid receptors are a subfamily of nuclear receptors found throughout all metazoans. They are highly important in the regulation of development, inflammation, and reproduction and their misregulation has been implicated in hormone insensitivity syndromes and cancer. Steroid binding to SRs drives a conformational change in the ligand binding domain that promotes nuclear localization and subsequent interaction with coregulator proteins to affect gene regulation. SRs are important pharmaceutical targets, yet most SR-targeting drugs have off-target pharmacology leading to unwanted side effects. A better understanding of the structural mechanisms dictating ligand specificity and the evolution of the forces that created the SR-hormone pairs will enable the design of better pharmaceutical ligands. In order to investigate this relationship, we attempted to crystallize the ancestral 3-ketosteroid receptor (ancSR2) with mifepristone, a SR antagonist. Here, we present the x-ray crystal structure of the ancestral 3-keto steroid receptor (ancSR2)-progesterone complex at a resolution of 2.05 Å. This improves upon our previously reported structure of the ancSR2-progesterone complex, permitting unambiguous assignment of the ligand conformation within the binding pocket. Surprisingly, we find mifepristone, fortuitously docked at the protein surface, poised to interfere with coregulator binding. Recent attention has been given to generating pharmaceuticals that block the coregulator binding site in order to obstruct coregulator binding and achieve tissue-specific SR regulation independent of hormone binding. Mifepristone’s interaction with the coactivator cleft of this SR suggests that it may be a useful molecular scaffold for further coactivator binding inhibitor development.

  12. Pathway of PPAR-gamma coactivators in thermogenesis: a pivotal traditional Chinese medicine-associated target for individualized treatment of rheumatoid arthritis

    PubMed Central

    Bai, Ming; Zhang, Bo; Liu, Chunfang; Sun, Yanqun; Li, Shao; Lin, Na

    2016-01-01

    Traditional Chinese medicine (TCM) syndromes have been regarded as the crucial clinical manifestations for individualized diagnosis and treatment of complex diseases, including rheumatoid arthritis (RA) and cancer. Especially, RA patients are classified into cold and hot syndromes with different clinical manifestations, interventions and molecular mechanisms. Better effectiveness of a classic cold syndrome-specific herbal formula Wu-tou decoction (WTD) has been achieved. To explore molecular mechanisms of syndrome-specific formulae is of great clinical significance to improve the effectiveness and pertinence of treatment for the complex diseases with personalized conditions. However, the scientific basis of WTD treatment on RA with the cold syndrome remains unclear. Here, we predicted the putative targets for composite compounds contained in WTD using drugCIPHER-CS and constructed a WTD herbs-putative targets-RA related genes network. Next, a list of major WTD targets was identified based on their topological features, including the degree, node betweenness, closeness and k-coreness in the above pharmacological network. Importantly, pathway enrichment analysis revealed that these major WTD targets were significantly associated with the pathway of peroxisome proliferator-activated receptor (PPAR)-gamma (PPAR-γ) coactivators in thermogenesis. These computational findings were subsequently verified by experiments on a rat model of collagen-induced arthritis (CIA) with cold or hot syndromes, and on human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) cell line. In conclusion, the pathway of PPAR-γ coactivators in thermogenesis might be one of the potential pharmacological targets of WTD to alleviate RA with the TCM cold syndrome. These findings may open new avenues for designing individualized treatment regimens for RA patients. PMID:26895106

  13. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

    SciTech Connect

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun Nishina, Hiroshi

    2014-01-17

    Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription.

  14. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by small heterodimer partner.

    PubMed

    Shin, Dong-Ju; Osborne, Timothy F

    2008-05-30

    Cholesterol 7alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of hepatic bile acid biosynthesis from cholesterol. During fasting and in type I diabetes, elevated levels of peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) induce expression of the Cyp7A1 gene and overexpression of PGC-1alpha in hepatoma cells stimulates bile acid synthesis. Using Ad-PGC-1alpha-RNA interference to induce acute disruption of PGC-1alpha in mice, here we show that PGC-1alpha is necessary for fasting-mediated induction of CYP7A1. Co-immunoprecipitation and promoter activation studies reveal that the induction of CYP7A1 is mediated by direct interaction between PGC-1alpha and the AF2 domain of liver receptor homolog-1 (LRH-1). In contrast, the very similar PGC-1beta could not substitute for PGC-1alpha. We also show that transactivation of PGC-1alpha and LRH-1 is repressed by the small heterodimer partner (SHP). Treatment of mice with GW4064, a synthetic agonist for farnesoid X receptor, induced SHP expression and decreased both the recruitment of PGC-1alpha to the Cyp7A1 promoter and the fasting-induced expression of CYP7A1 mRNA. These data suggest that PGC-1alpha is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1alpha to inhibit CYP7A1 expression. Overall, these studies provide further evidence for the important role of PGC-1alpha in bile acid homeostasis and suggest that pharmacological targeting of farnesoid X receptor in vivo can be used to reverse the increase in CYP7A1 associated with adverse metabolic conditions.

  15. Regulation of carnitine palmitoyltransferase I (CPT-Iα) gene expression by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) isoforms

    PubMed Central

    Sadana, Prabodh; Zhang, Yi; Song, Shulan; Cook, George A.; Elam, Marshall B.; Park, Edwards A.

    2007-01-01

    Summary The peroxisome proliferator-activated receptor gamma coactivators (PGC-1) have important roles in mitochondrial biogenesis and metabolic control in a variety of tissues. There are multiple isoforms of PGC-1 including PGC-1α and PGC-1β. Both the PGC-1α and β isoforms promote mitochondrial biogenesis and fatty acid oxidation, but only PGC-1α stimulates gluconeogenesis in the liver. Carnitine palmitoyltransferase I (CPT-I) is a key enzyme regulating mitochondrial fatty acid oxidation. In these studies, we determined that PGC-1β stimulated expression of the “liver” isoform of CPT-I (CPT-Iα) but that PGC-1β did not induce pyruvate dehydrogenase kinase 4 (PDK4) which is a regulator of pyruvate metabolism. The CPT-Iα gene is induced by thyroid hormone. We found that T3 increased the expression of PGC-1β and that PGC-1β enhanced the T3 induction of CPT-Iα. The thyroid hormone receptor interacts with PGC-1β in a ligand dependent manner. Unlike PGC-1α, the interaction of PGC-1β and the T3 receptor does not occur exclusively through the leucine-X-X-leucine-leucine motif in PGC-1β. We have found that PGC-1β is associated with the CPT-Iα gene in vivo. Overall, our results demonstrate that PGC-1β is a coactivator in the T3 induction of CPT-Iα and that PGC-1β has similarities and differences with the PGC-1α isoform. PMID:17239528

  16. Transcription coactivator PRIP, the peroxisome proliferator-activated receptor (PPAR)-interacting protein, is redundant for the function of nuclear receptors PParalpha and CAR, the constitutive androstane receptor, in mouse liver.

    PubMed

    Sarkar, Joy; Qi, Chao; Guo, Dongsheng; Ahmed, Mohamed R; Jia, Yuzhi; Usuda, Nobuteru; Viswakarma, Navin; Rao, M Sambasiva; Reddy, Janardan K

    2007-01-01

    Disruption of the genes encoding for the transcription coactivators, peroxisome proliferator-activated receptor (PPAR)-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) and PPAR-binding protein (PBP/TRAP220/DRIP205/MED1), results in embryonic lethality by affecting placental and multiorgan development. Targeted deletion of coactivator PBP gene in liver parenchymal cells (PBP(LIV-/-)) results in the near abrogation of the induction of PPARalpha and CAR (constitutive androstane receptor)-regulated genes in liver. Here, we show that targeted deletion of coactivator PRIP gene in liver (PRIP(LIV-/-)) does not affect the induction of PPARalpha-regulated pleiotropic responses, including hepatomegaly, hepatic peroxisome proliferation, and induction of mRNAs of genes involved in fatty acid oxidation system, indicating that PRIP is not essential for PPARalpha-mediated transcriptional activity. We also provide additional data to show that liver-specific deletion of PRIP gene does not interfere with the induction of genes regulated by nuclear receptor CAR. Furthermore, disruption of PRIP gene in liver did not alter zoxazolamine-induced paralysis, and acetaminophen-induced hepatotoxicity. Studies with adenovirally driven EGFP-CAR expression in liver demonstrated that, unlike PBP, the absence of PRIP does not prevent phenobarbital-mediated nuclear translocation/retention of the receptor CAR in liver in vivo and cultured hepatocytes in vitro. These results show that PRIP deficiency in liver does not interfere with the function of nuclear receptors PPARalpha and CAR. The dependence of PPARalpha- and CAR-regulated gene transcription on coactivator PBP but not on PRIP attests to the existence of coactivator selectivity in nuclear receptor function.

  17. Playful relationships: a contextual analysis of mother-toddler interaction and symbolic play.

    PubMed

    Fiese, B H

    1990-10-01

    The relation between social interaction and complexity of toddler's symbolic play was investigated. 57 toddlers between 15 and 24 months of age were observed under 4 conditions: (1) child play alone, (2) child play with mother, (3) child modeling mother, and (4) child play with mother following the modeling condition. Each subject was rated on complexity of play, maternal attention directing, reciprocity, and maternal intrusiveness. Significant condition effects were found in which more complex forms of play were observed when the children were playing with their mothers than when playing by themselves. Maternal intrusions and questioning were negatively related to symbolic play. Turn-taking was negatively related to simple exploratory play. Results of a sequential analysis demonstrated that turn-taking was more likely to precede symbolic play, and maternal intrusiveness was more likely to precede simple exploratory play. The role of active partnership in symbolic play development is discussed.

  18. Play and Mate Preference: Testing the Signal Theory of Adult Playfulness

    ERIC Educational Resources Information Center

    Chick, Garry; Yarnal, Careen; Purrington, Andrew

    2012-01-01

    The overwhelming majority of play research concerns juveniles. However, a full understanding of the phenomenon requires knowledge of play and playfulness across the life spans of those animals, including humans, who play in adulthood. The authors investigate a theory of play based on Darwin's concept of sexual selection that may account for the…

  19. Play concepts-northwest Palawan, Philippines

    NASA Astrophysics Data System (ADS)

    Williams, Harold H.

    The offshore area of northwest Palawan, Philippines, contains a number of provenexploration plays. These include • pinnacle reefs developed on Nido carbonate platforms (e.g. Nido, Matinloc, Cadlao);• a seaward horst block reef fairway with large pinnacle reefs (e.g. Malampaya—Camago trend);• early Miocene Galoc Clastic Unit turbidites (e.g. Octon, Galoc); and• four-way dip closures (e.g. West Linapacan, Octon). The recent discovery by Fletcher Challenge Petroleum at Calauit Field has shown a potentialexploration play in deep-water Nido Limestone turbidites. The traditional and, to date, only economically productive play in northwest Palawan has been the Nido Limestone reefs. This paper presents a review of the old play types and presents new untested play types. These new play types include • pre-Nido syn-rift plays;• pre-Nido marine turbidite play: and• mid-Miocene reefs. It also presents new insights into factors controlling reef development on the carbonate platforms where four reef types are now recognized. The Galoc Clastic Unit turbidite play is discussed and new play fairways presented.

  20. Adult Playfulness, Humor Styles, and Subjective Happiness.

    PubMed

    Yue, Xiao D; Leung, Chun-Lok; Hiranandani, Neelam A

    2016-12-01

    Playfulness has been referred to as a disposition that involves reframing a situation to amuse others and to make the situation more stimulating and enjoyable. It may serve to shift one's perspective when dealing with environmental threats. Despite all the benefits of playfulness towards psychological well-being, it remains a largely understudied subject in psychology, particularly in Chinese societies. Hence, this study examined the association between adult playfulness, humor styles, and subjective happiness among a sample of 166 university students in Hong Kong and 159 students in Guangzhou, who completed a self-administered questionnaire, including the Short Measure for Adult Playfulness, the Chinese Humor Styles Questionnaire, and the Subjective Happiness Scale. Results showed that adult playfulness was positively correlated with affiliative humor, self-enhancing humor, and subjective happiness in both Hong Kong and Guangzhou samples. By its implication, highly playful Chinese students preferred using affiliative and self-enhancing humor to amuse themselves and others.

  1. Predictive factors of excessive online poker playing.

    PubMed

    Hopley, Anthony A B; Nicki, Richard M

    2010-08-01

    Despite the widespread rise of online poker playing, there is a paucity of research examining potential predictors for excessive poker playing. The aim of this study was to build on recent research examining motives for Texas Hold'em play in students by determining whether predictors of other kinds of excessive gambling apply to Texas Hold'em. Impulsivity, negative mood states, dissociation, and boredom proneness have been linked to general problem gambling and may play a role in online poker. Participants of this study were self-selected online poker players (N = 179) who completed an online survey. Results revealed that participants played an average of 20 hours of online poker a week and approximately 9% of the sample was classified as a problem gambler according to the Canadian Problem Gambling Index. Problem gambling, in this sample, was uniquely predicted by time played, dissociation, boredom proneness, impulsivity, and negative affective states, namely depression, anxiety, and stress.

  2. Chinese and German Teachers' Conceptions of Play and Learning and Children's Play Behaviour

    ERIC Educational Resources Information Center

    Wu, Shu-Chen; Rao, Nirmala

    2011-01-01

    Commonalities and distinctions in Hong Kong-Chinese and German kindergarten teachers' conceptions of play and learning were examined. Six video clips of play episodes reflecting common play behavior and themes were selected from observations made during free play in two kindergartens in Hong Kong and two in Germany. Ten Chinese and seven German…

  3. Making the Case for Play Policy: Research-Based Reasons to Support Play-Based Environments

    ERIC Educational Resources Information Center

    Stegelin, Dolores A.

    2005-01-01

    This article can help teachers and directors become eloquent and effective advocates of play-based early learning environments. It defines play and play policy and discusses distinct research areas that support play policy and practice for physical, cognitive, social, and emotional development within diverse early childhood settings. Also…

  4. Virtual Playgrounds? Assessing the Playfulness of Massively Multiplayer Online Role-Playing Games

    ERIC Educational Resources Information Center

    Graham, Kerrie Lewis

    2010-01-01

    Millions of children and adults devote much of their leisure time to playing massively multiplayer online role-playing games (MMORPGs). Most observers commonly categorize computer games as a play activity, but this article asks whether MMORPGs contain activities that might not be play. The author examines the phenomenon of online gaming and…

  5. Playing with Mathematics: Play in Early Childhood as a Context for Mathematical Learning

    ERIC Educational Resources Information Center

    Mathematics Education Research Group of Australasia, 2010

    2010-01-01

    Play is an essential part of young children's lives. This symposium highlights the integral role of play in young children's mathematics learning and examines the teacher's role in facilitating and extending this. Papers examine key tenets of play, contributing to theoretical understandings and presenting data on teacher's perceptions of play and…

  6. Play at the Art Table: A Study of Children's Play Behaviors while Drawing.

    ERIC Educational Resources Information Center

    Escobedo, Theresa H.

    This descriptive study examined children's drawings and related language episodes to differentiate drawings exhibiting play from those exhibiting exploratory behavior. Drawings categorized as play were further analyzed to identify constructive and imaginary play. The play theory used as the basis of the study proposes that exploration and…

  7. Learning to Play: Play Deprivation among Young Children in Foster Care

    ERIC Educational Resources Information Center

    Comfort, Randy Lee

    2005-01-01

    Children who enter foster care typically have had little or not experience with play. This article describes the impact of play deprivation on early development. It provides guidelines for recognizing play deprivation and describes ways to help babies and young children develop a repertoire of play behaviors that is based on secure relationships…

  8. Play and Adversity: How the Playful Mammalian Brain Withstands Threats and Anxieties

    ERIC Educational Resources Information Center

    Siviy, Stephen M.

    2010-01-01

    Most mammals play, but they do so in a dangerous world. The dynamic relationship between the stresses created by their world and the activity of play helps to explain the evolution of play in mammals, as the author demonstrates in evidence garnered from experiments that introduce elements of fear to rats at play. The author describes the resulting…

  9. Nucleosome competition reveals processive acetylation by the SAGA HAT module

    PubMed Central

    Ringel, Alison E.; Cieniewicz, Anne M.; Taverna, Sean D.; Wolberger, Cynthia

    2015-01-01

    The Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator complex hyperacetylates histone tails in vivo in a manner that depends upon histone 3 lysine 4 trimethylation (H3K4me3), a histone mark enriched at promoters of actively transcribed genes. SAGA contains a separable subcomplex known as the histone acetyltransferase (HAT) module that contains the HAT, Gcn5, bound to Sgf29, Ada2, and Ada3. Sgf29 contains a tandem Tudor domain that recognizes H3K4me3-containing peptides and is required for histone hyperacetylation in vivo. However, the mechanism by which H3K4me3 recognition leads to lysine hyperacetylation is unknown, as in vitro studies show no effect of the H3K4me3 modification on histone peptide acetylation by Gcn5. To determine how H3K4me3 binding by Sgf29 leads to histone hyperacetylation by Gcn5, we used differential fluorescent labeling of histones to monitor acetylation of individual subpopulations of methylated and unmodified nucleosomes in a mixture. We find that the SAGA HAT module preferentially acetylates H3K4me3 nucleosomes in a mixture containing excess unmodified nucleosomes and that this effect requires the Tudor domain of Sgf29. The H3K4me3 mark promotes processive, multisite acetylation of histone H3 by Gcn5 that can account for the different acetylation patterns established by SAGA at promoters versus coding regions. Our results establish a model for Sgf29 function at gene promoters and define a mechanism governing crosstalk between histone modifications. PMID:26401015

  10. Executive Functions Development and Playing Games

    ERIC Educational Resources Information Center

    Petty, Ana Lucia; de Souza, Maria Thereza C. Coelho

    2012-01-01

    The aim of this paper is to discuss executive functions and playing games, considering Piaget's work (1967) and the neuropsychological framework (Barkley, 1997, 2000; Cypel, 2007). Two questions guide the discussion: What are the intersections between playing games and the development of executive functions? Can we stimulate children with learning…

  11. Playing with Technology: Is It All Bad?

    ERIC Educational Resources Information Center

    Slutsky, Ruslan; Slutsky, Mindy; DeShelter, Lori M.

    2014-01-01

    Technology now plays a very large role in the way children of all ages play. Children want access to technology, so parents and teachers must determine the best ways to present it to them. Computers are a popular form of technology for children as young as age three. With that in mind, computer games should be problem-solving oriented and…

  12. Ordinal Position in Role Play Practice.

    ERIC Educational Resources Information Center

    Robinson, Sharon E.; Cabianca, William A.

    Although the effectiveness of role play and its vicarious learning experiences for counselor training is well documented, little research has focused on the impact of the order of playing the roles on skill development. To investigate the effect of ordinal position, 36 beginning counseling students, 24 female and 12 male, with a median age of 30,…

  13. Gender-Typed Play and Amniotic Testosterone

    ERIC Educational Resources Information Center

    Knickmeyer, Rebecca Christine; Wheelwright, Sally; Taylor, Kevin; Raggatt, Peter; Hackett, Gerald; Baron-Cohen, Simon

    2005-01-01

    Sex differences in play are apparent in a number of mammalian species, including humans. Prenatal testosterone may contribute to these differences. The authors report the first attempt to correlate gender-typed play in a normative sample of humans with measurements of amniotic testosterone (aT). Testosterone was measured in the amniotic fluid of…

  14. Teaching Peace: Alternatives to Violent Play.

    ERIC Educational Resources Information Center

    Jurek, Dianne Miller; Velazquez, Michaela

    1995-01-01

    To help combat the effects of violence on children and improve the quality and nature of play, early childhood teachers can: define violence by helping children become aware of the issue, help children resolve their own conflicts, create a peace place in the classroom, intervene when violent play occurs, evaluate media and toys, and educate…

  15. Using Role Play to Debate Animal Testing

    ERIC Educational Resources Information Center

    Agell, Laia; Soria, Vanessa; Carrió, Mar

    2015-01-01

    The use of animals in biomedical research is a socio-scientific issue in which decision-making is complicated. In this article, we describe an experience involving a role play activity performed during school visits to the Barcelona Biomedical Research Park (PRBB) to debate animal testing. Role playing games require students to defend different…

  16. Play Therapy for Children with Disabilities.

    ERIC Educational Resources Information Center

    Carmichael, Karla D.

    Play therapy can be used to help children with disabilities to develop a sense of strength and competency. Play therapy literature concerning children with disabilities is divided into two distinct approaches: (1) the "I am" attribute which deals with emotional adjustment and helps the child to develop positive self-esteem, personal competency,…

  17. Metamorphosis: Play, Spirituality and the Animal

    ERIC Educational Resources Information Center

    Bone, Jane

    2010-01-01

    Animal- and bird-becoming is an aspect of play as metamorphosis connected to spirituality in early childhood settings. The reconceptualisation of play presented here is supported by research that explored the spiritual experiences of young children in different early childhood contexts. Qualitative case study research carried out in Aotearoa New…

  18. An Early Historical Play: The "Seinte Resurreccion"

    ERIC Educational Resources Information Center

    Perry, Anne Amari

    1978-01-01

    Analyzes the realistic characterization and plot construction of an anonymously written medieval French play. The play, which relates the story of Christ's resurrection, achieves historical realism by replacing music and chant with dialogue, using a logical plot, and limiting historical anachronism. (AV)

  19. Pretend Play: Antecedent of Adult Creativity

    ERIC Educational Resources Information Center

    Russ, Sandra W.

    2016-01-01

    This article reviews the theoretical and empirical literature in the area of pretend play as a predictor of adult creativity. There is strong evidence that processes expressed in pretend play are associated with measures of creativity, especially with divergent thinking. There is some evidence from longitudinal studies that this association is…

  20. Mathematical Learning in a Context of Play

    ERIC Educational Resources Information Center

    Edo, Meque; Planas, Nuria; Badillo, Edelmira

    2009-01-01

    In this article we analyse a didactical situation centred on the creation and use of a symbolic play environment in a class of pupils aged five and six years-old. The main source of data for this paper comes from an experimentation planned in relation to the following research question: does symbolic play in simulated contexts help pupils to…

  1. Playing by Ear: Foundation or Frill?

    ERIC Educational Resources Information Center

    Woody, Robert H.

    2012-01-01

    Many people divide musicians into two types: those who can read music and those who play by ear. Formal music education tends to place great emphasis on producing musically literate performers but devotes much less attention to teaching students to make music without notation. Some would suggest that playing by ear is a specialized skill that is…

  2. Dimensions of Childhood Play and Toys

    ERIC Educational Resources Information Center

    Sandberg, Anette; Vuorinen, Tuula

    2008-01-01

    The purpose of this article is to describe and analyse play through a contemporary historical perspective, based upon pre-school teachers', students majoring in education, and teacher education students' descriptions of memories from their childhood regarding play and toys. The overall method is retrospective. The data consists of 111 interviews…

  3. The Let's Play! Project. Final Report.

    ERIC Educational Resources Information Center

    Mistrett, Susan

    This final report reviews activities and achievements of the "Let's Play!" project, an effort to apply assistive technology (AT) to promote the play skills of infants and toddlers with disabilities within their natural environments. The federally supported project was designed to assist county early intervention programs and developed,…

  4. The Excellence of Play. Second Edition

    ERIC Educational Resources Information Center

    Moyles, Janet, Ed.

    2005-01-01

    This second edition of "The Excellence of Play" encapsulates all of the many changes that have taken place in early childhood in the last decade. It examines the vital importance of play as a tool for learning and teaching for children and practitioners, supporting all those who work in early childhood education and care in developing and…

  5. Preschool Children's Outdoor Play Area Preferences

    ERIC Educational Resources Information Center

    Holmes, Robyn M.; Procaccino, Jill K.

    2009-01-01

    This study explores preschool children's outdoor play preferences. The sample was 40 (20 male, 20 female) primarily European-American three and four year olds. Data were collected via naturalistic observation and analyzed using repeated measures ANOVAs and MANOVAs. The independent variable was sex of child; dependent variable was play space…

  6. Games, Game-Playing and Technology.

    ERIC Educational Resources Information Center

    Avedon, Elliott M.

    1982-01-01

    Game-playing has become a more generalized phenomenon than ever, entering into public recreation, school programs, and commercial promotional efforts. Games require competitive interaction between two or more individuals, making game-playing useful in clinical therapy and opening games to technological innovation. The latest such innovation is the…

  7. Preschool Teacher's Conceptions of Computers and Play

    ERIC Educational Resources Information Center

    Sandberg, Anette

    2002-01-01

    There are many dimensions of play and play's significance for children's development and learning is often emphasized, but how do preschool teachers see children's use of computers in preschool? A qualitative study was done with 13 Swedish preschool teachers that had experience working with computers in preschool. The overall aim of this study was…

  8. Helping Young Children See Math in Play

    ERIC Educational Resources Information Center

    Parks, Amy Noelle; Blom, Diana Chang

    2013-01-01

    The purpose of this article is to provide strategies for recognizing meaningful mathematics in common play contexts in early childhood classrooms and to offer suggestions for how teachers might intervene in these moments to help children attend to the mathematical ideas embedded in their play. In particular, the author's focus on the concepts of…

  9. The Thing's the Play: Doing "Hamlet."

    ERIC Educational Resources Information Center

    Sowder, Wilbur H., Jr.

    1993-01-01

    Argues for the use of film in the teaching of William Shakespeare's "Hamlet" because the play was meant to be seen and heard and not just read. Outlines a method of teaching the play by which students select a scene and perform it. Gives an example of a successful student performance. (HB)

  10. Spontaneous Play: An Avenue for Intellectual Development.

    ERIC Educational Resources Information Center

    Almy, Millie

    1966-01-01

    It is generally conceded that there is much for a child to learn while attending nursery school, but the teacher is often unsure as to what type of curriculum or program will best assure such learning. Specifically, although play has been part of all nursery school programs, it is questioned whether spontaneous play (that is, relatively…

  11. Role-Playing Methods in the Classroom.

    ERIC Educational Resources Information Center

    Chesler, Mark; Fox, Robert

    This book, one of three Teacher Resource Booklets on Classroom Social Relations and Learning developed at the Center for Research on Utilization of Scientific Knowledge at the University of Michigan, discusses the theoretical background of role playing and gives a step-by-step discussion of how to use role playing in the classroom. There are…

  12. Children's Gendered Drawings of Play Behaviours

    ERIC Educational Resources Information Center

    Akseer, Tabasum; Lao, Mary Grace; Bosacki, Sandra

    2012-01-01

    According to child psychologists, vital links exist between children's drawings and their emotional, social, and cognitive development. Previous research has explored the important relations between drawings and play in educational settings. Given the vast research that explores the ambiguous topic of children's play, according to Richer (1990),…

  13. Habit tic deformity secondary to guitar playing.

    PubMed

    Wu, Jashin J

    2009-03-15

    A 29-year-old man exhibited linear ridges of the right thumbnail that had been present for ten years. After he stopped playing the guitar for three months, the proximal portion of the abnormality cleared. Nail changes similar to the habit tic deformity may be produced by guitar playing.

  14. Outdoor Play and Learning: Policy and Practice

    ERIC Educational Resources Information Center

    Burriss, Kathleen; Burriss, Larry

    2011-01-01

    This study describes national school district policy and practice regarding elementary school children's outdoor learning and play. District representatives from 173 randomly selected school districts completed questionnaires describing policy and practice related to recess, outdoor play, outdoor curricular studies, playground materials, ADA…

  15. Play Therapy: Basics and Beyond. Second Edition

    ERIC Educational Resources Information Center

    Kottman, Terry

    2011-01-01

    Written for use in play therapy and child counseling courses, this extraordinarily practical text provides a detailed examination of basic and advanced play therapy concepts and skills and guidance on when and how to use them. Kottman's multitheoretical approach and wealth of explicit techniques are also helpful for clinicians who want to gain…

  16. The Common Core's First Casualty: Playful Learning

    ERIC Educational Resources Information Center

    Bowdon, Jill

    2015-01-01

    Although the Common Core standards do not prescribe pedagogy or forbid playful learning, kindergarten teachers will find it challenging to maintain a playful classroom under this reform. Kindergarten teachers have to cover a more rigorous and accelerated curriculum now, and they are doing so in a context that rewards procedural teaching.

  17. Selecting major Appalachian basin gas plays

    SciTech Connect

    Patchen, D.G.; Nuttall, B.C.; Baranoski, M.T.; Harper, J.A.; Schwietering, J.F.; Van Tyne, A.; Aminian, K.; Smosna, R.A.

    1992-01-01

    Under a cooperative agreement with the Morgantown Energy Technology Center (METC) the Appalachian Oil and Natural Gas Research Consortium (AONGRC) is preparing a geologic atlas of the major gas plays in the Appalachian basin, and compiling a database for all fields in each geologic play. the first obligation under this agreement was to prepare a topical report that identifies the major gas plays, briefly describes each play, and explains how the plays were selected. Four main objectives have been defined for this initial task: assign each gas reservoir to a geologic play, based on age, trap type, degree of structural control, and depositional environment; organize all plays into geologically-similar groups based on the main criteria that defines each play; prepare a topical report for METC; and transfer this technology to industry through posters and talks at regional geological and engineering meetings including the Appalachian Petroleum Geology Symposium, Northeastern Section meeting of the Geological Society of America, the METC Gas Contractors Review meeting, the Kentucky Oil and Gas Association, and the Appalachian Energy Group.

  18. Selecting major Appalachian basin gas plays

    SciTech Connect

    Patchen, D.G.; Nuttall, B.C.; Baranoski, M.T.; Harper, J.A.; Schwietering, J.F.; Van Tyne, A.; Aminian, K.; Smosna, R.A.

    1992-06-01

    Under a cooperative agreement with the Morgantown Energy Technology Center (METC) the Appalachian Oil and Natural Gas Research Consortium (AONGRC) is preparing a geologic atlas of the major gas plays in the Appalachian basin, and compiling a database for all fields in each geologic play. the first obligation under this agreement was to prepare a topical report that identifies the major gas plays, briefly describes each play, and explains how the plays were selected. Four main objectives have been defined for this initial task: assign each gas reservoir to a geologic play, based on age, trap type, degree of structural control, and depositional environment; organize all plays into geologically-similar groups based on the main criteria that defines each play; prepare a topical report for METC; and transfer this technology to industry through posters and talks at regional geological and engineering meetings including the Appalachian Petroleum Geology Symposium, Northeastern Section meeting of the Geological Society of America, the METC Gas Contractors Review meeting, the Kentucky Oil and Gas Association, and the Appalachian Energy Group.

  19. Restaurant Role-Play in Psychology

    ERIC Educational Resources Information Center

    Borya, Anthony

    2013-01-01

    Research methods is perceived as a technical and difficult topic by some students. Using role-play to teach it can make it more accessible, meaningful and engaging. Role-playing the familiar roles of customer and waiting staff at a restaurant and discussing the variables that may affect the size of tips can help students to learn some of the key…

  20. It's Time to Stop Defending Play

    ERIC Educational Resources Information Center

    Burton, Rosemary

    2011-01-01

    Children learn through play. Talk to early childhood educators and they will say this is the core of what they know about how children learn best. Talk to many parents and they say that allowing children to simply play all day is not teaching kids anything. This is the signature argument that has defined the early childhood field. The author…