The Experts below are selected from a list of 13422 Experts worldwide ranked by ideXlab platform
David D Moore - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of the hinge domain of the Nuclear Hormone Receptor lrh 1 stimulates transactivation
Journal of Biological Chemistry, 2006Co-Authors: Yunhee Choi, Steven S Chua, Young Joo Park, David D MooreAbstract:Abstract The Nuclear Receptor LRH-1 (NR5A2) functions to regulate expression of a number of genes associated with bile acid homeostasis and other liver functions, but mechanisms that modulate its activity remain unclear. We have found that mitogenic stimuli, including treatment with phorbol myristate (PMA), increase LRH-1 transactivation. This response maps to the hinge and ligand binding domains of LRH-1 and is blocked by the mitogen-activated protein kinase ERK1/2 inhibitor U0126. LRH-1 is a phosphoprotein and hinge domain serine residues at 238 and 243 are required for effective phosphorylation, both in vitro and in cells. Preventing phosphorylation of these residues by mutating both to alanine decreases PMA-dependent LRH-1 transactivation and mimicking phosphorylation by mutation to positively charged aspartate residues increases basal transactivation. Although serine phosphorylation of the hinge of SF-1 (NR5A1), the closest relative of LRH-1, confers a similar response, the specific targets differ in the two closely related orphan Receptors. These results define a novel pathway for the modulation of LRH-1 transactivation and identify specific LRH-1 residues as downstream targets of mitogenic stimuli. This pathway may contribute to recently described proliferative functions of LRH-1.
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the orphan Nuclear Receptor shp inhibits hepatocyte Nuclear factor 4 and retinoid x Receptor transactivation two mechanisms for repression
Molecular and Cellular Biology, 2000Co-Authors: Helen Dell, Dennis H Dowhan, Margarita Hadzopouloucladaras, David D MooreAbstract:The orphan Nuclear Hormone Receptor SHP interacts with a number of other Nuclear Hormone Receptors and inhibits their transcriptional activity. Several mechanisms have been suggested to account for this inhibition. Here we show that SHP inhibits transactivation by the orphan Receptor hepatocyte Nuclear factor 4 (HNF-4) and the retinoid X Receptor (RXR) by at least two mechanisms. SHP interacts with the same HNF-4 surface recognized by transcriptional coactivators and competes with them for binding in vivo. The minimal SHP sequences previously found to be required for interaction with other Receptors are sufficient for interaction with HNF-4, although deletion results indicate that additional C-terminal sequences are necessary for full binding and coactivator competition. These additional sequences include those associated with direct transcriptional repressor activity of SHP. SHP also competes with coactivators for binding to ligand-activated RXR, and based on the ligand-dependent interaction with other Nuclear Receptors, it is likely that coactivator competition is a general feature of SHP-mediated repression. The minimal Receptor interaction domain of SHP is sufficient for full interaction with RXR, as previously described. This domain is also sufficient for full coactivator competition. Functionally, however, full inhibition of RXR transactivation requires the presence of the C-terminal repressor domain, with only weak inhibition associated with this Receptor interaction domain. Overall, these results suggest that SHP represses Nuclear Hormone Receptor-mediated transactivation via two separate steps: first by competition with coactivators and then by direct effects of its transcriptional repressor function.
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Differential Transactivation by Two Isoforms of the Orphan Nuclear Hormone Receptor CAR
Journal of Biological Chemistry, 1997Co-Authors: Hueng-sik Choi, Mirra Chung, Devendranath Simha, Wongi Seol, Iphigenia Tzameli, David D MooreAbstract:Abstract We have identified a new murine orphan member of the Nuclear Hormone Receptor superfamily, termed mCAR, that is closely related to the previously described human orphan MB67, referred to here as hCAR. Like hCAR, mCAR expression is highest in liver. In addition to the most abundant mCAR1 isoform, the mCAR gene expresses a truncated mCAR2 variant that is missing the C-terminal portion of the ligand binding/dimerization domain. The mCAR gene has 8 introns, and this mCAR2 variant is generated by a splicing event that skips the 8th exon. mCAR1, like hCAR, binds as a heterodimer with the retinoid X Receptor to the retinoic acid response element from the promoter of the retinoic acid Receptor β2 isoform. Consistent with its lack of a critical heterodimerization interface, the mCAR2 variant does not bind this site. Both mCAR1 and hCAR are apparently constitutive transcriptional activators. This activity is dependent on the presence of the conserved C-terminal AF-2 transcriptional activation motif. As expected from its inability to bind DNA, the mCAR2 variant neither transactivates by itself nor inhibits transactivation by hCAR or mCAR1.
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two Receptor interacting domains in the Nuclear Hormone Receptor corepressor rip13 n cor
Molecular Endocrinology, 1996Co-Authors: Wongi Seol, Matthew J Mahon, David D MooreAbstract:The thyroid Hormone Receptor (TR) and the retinoic acid Receptor (RAR) act as transcriptional repressors when they are not occupied by their cognate ligands. This repressor function is mediated by proteins called corepressors. One of the Nuclear Hormone Receptor corepressors, N-CoR, was originally isolated as a retinoid X Receptor-interacting protein called RIP13. We have isolated a new potential variant of RIP13/N-CoR that is missing previously described transcriptional repressor domains but is similar in structure to the related corepressor termed SMRT or TRAC-2. Detailed analysis of the interaction with TR and RAR demonstrates that RIP13/N-CoR contains a new Receptor interaction domain, termed ID-II, in addition to the previously described domain, referred to here as ID-I. Both ID-I and ID-II are capable of interacting independently with either TR or RAR, as assessed by the yeast two-hybrid system, by a mammalian two-hybrid system, or by direct in vitro binding. Results with all three approaches confir...
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an orphan Nuclear Hormone Receptor that lacks a dna binding domain and heterodimerizes with other Receptors
Science, 1996Co-Authors: Wongi Seol, Hueng-sik Choi, David D MooreAbstract:SHP is an orphan member of the Nuclear Hormone Receptor superfamily that contains the dimerization and ligand-binding domain found in other family members but lacks the conserved DNA binding domain. In the yeast two-hybrid system, SHP interacted with several conventional and orphan members of the Receptor superfamily, including retinoid Receptors, the thyroid Hormone Receptor, and the orphan Receptor MB67. SHP also interacted directly with these Receptors in vitro. In mammalian cells, SHP specifically inhibited transactivation by the superfamily members with which it interacted. These results suggest that SHP functions as a negative regulator of Receptor-dependent signaling pathways.
Kaveh Ashrafi - One of the best experts on this subject based on the ideXlab platform.
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defects in the c elegans acyl coa synthase acs 3 and Nuclear Hormone Receptor nhr 25 cause sensitivity to distinct but overlapping stresses
PLOS ONE, 2014Co-Authors: Jordan D Ward, Brendan C Mullaney, Marc R Van Gilst, Benjamin J Schiller, Le D He, Sarah Petnic, Carole Couillault, Nathalie Pujol, Teresita U Bernal, Kaveh AshrafiAbstract:Metazoan transcription factors control distinct networks of genes in specific tissues, yet understanding how these networks are integrated into physiology, development, and homeostasis remains challenging. Inactivation of the Nuclear Hormone Receptor nhr-25 ameliorates developmental and metabolic phenotypes associated with loss of function of an acyl-CoA synthetase gene, acs-3. ACS-3 activity prevents aberrantly high NHR-25 activity. Here, we investigated this relationship further by examining gene expression patterns following acs-3 and nhr-25 inactivation. Unexpectedly, we found that the acs-3 mutation or nhr-25 RNAi resulted in similar transcriptomes with enrichment in innate immunity and stress response gene expression. Mutants of either gene exhibited distinct sensitivities to pathogens and environmental stresses. Only nhr-25 was required for wild-type levels of resistance to the bacterial pathogen P. aeruginosa and only acs-3 was required for wild-type levels of resistance to osmotic stress and the oxidative stress generator, juglone. Inactivation of either acs-3 or nhr-25 compromised lifespan and resistance to the fungal pathogen D. coniospora. Double mutants exhibited more severe defects in the lifespan and P. aeruginosa assays, but were similar to the single mutants in other assays. Finally, acs-3 mutants displayed defects in their epidermal surface barrier, potentially accounting for the observed sensitivities. Together, these data indicate that inactivation of either acs-3 or nhr-25 causes stress sensitivity and increased expression of innate immunity/stress genes, most likely by different mechanisms. Elevated expression of these immune/stress genes appears to abrogate the transcriptional signatures relevant to metabolism and development.
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regulation of c elegans fat uptake and storage by acyl coa synthase 3 is dependent on nr5a family Nuclear Hormone Receptor nhr 25
Cell Metabolism, 2010Co-Authors: Brendan C Mullaney, Raymond D Blind, George A Lemieux, Carissa L Perez, Ida Coordt Elle, Nils J Faergeman, Marc R Van Gilst, Holly A Ingraham, Kaveh AshrafiAbstract:Summary Acyl-CoA synthases are important for lipid synthesis and breakdown, generation of signaling molecules, and lipid modification of proteins, highlighting the challenge of understanding metabolic pathways within intact organisms. From a C. elegans mutagenesis screen, we found that loss of ACS-3, a long-chain acyl-CoA synthase, causes enhanced intestinal lipid uptake, de novo fat synthesis, and accumulation of enlarged, neutral lipid-rich intestinal depots. Here, we show that ACS-3 functions in seam cells, epidermal cells anatomically distinct from sites of fat uptake and storage, and that acs-3 mutant phenotypes require the Nuclear Hormone Receptor NHR-25, a key regulator of C. elegans molting. Our findings suggest that ACS-3-derived long-chain fatty acyl-CoAs, perhaps incorporated into complex ligands such as phosphoinositides, modulate NHR-25 function, which in turn regulates an endocrine program of lipid uptake and synthesis. These results reveal a link between acyl-CoA synthase function and an NR5A family Nuclear Receptor in C. elegans .
M A Lazar - One of the best experts on this subject based on the ideXlab platform.
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Cloning and characterization of a corepressor and potential component of the Nuclear Hormone Receptor repression complex.
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: I Zamir, R M Lavinsky, James Dawson, Michael G Rosenfeld, Christopher K. Glass, M A LazarAbstract:Nuclear Hormone Receptors are potent repressors of transcription in the unliganded state. We describe here the cloning of a Nuclear Receptor corepressor that we call SUN-CoR (Small Unique Nuclear Receptor CoRepressor), which shows no homology to previously described Nuclear Hormone Receptor corepressors, N-CoR, or SMRT. SUN-CoR is a highly basic, 16-kDa Nuclear protein that is expressed at high levels in adult tissues and is induced during adipocyte and myogenic differentiation. SUN-CoR potentiates transcriptional repression by thyroid Hormone Receptor and RevErb in vivo, represses transcription when fused to a heterologous DNA binding domain, and interacts with RevErb as well as with thyroid Hormone Receptor in vitro. SUN-CoR also interacts with N-CoR and SMRT in vitro and with endogenous N-CoR in cells. We conclude that SUN-CoR is a corepressor and may function as an additional component of the complex involved in transcriptional repression by unliganded and orphan Nuclear Hormone Receptors.
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a Nuclear Hormone Receptor corepressor mediates transcriptional silencing by Receptors with distinct repression domains
Molecular and Cellular Biology, 1996Co-Authors: I Zamir, G B Atkins, A Hörlein, H. P. Harding, Michael G Rosenfeld, Christopher K. Glass, M A LazarAbstract:Ligand-independent transcriptional repression is an important function of Nuclear Hormone Receptors. An interactionscreenwiththerepressiondomainoftheorphanReceptorRevErbidentifiedN-CoR,thecorepressor for thyroid Hormone Receptor (TR) and retinoic acid Receptor (RAR). N-CoR is likely to be a bona fide transcriptional corepressor for RevErb because (i) RevErb interacts with endogenous N-CoR, (ii) ectopic N-CoRpotentiatesRevErb-mediatedrepression,and(iii)transcriptionalrepressionbyRevErbcorrelateswith itsabilitytobindN-CoR.Remarkably,aregionhomologoustotheCoRboxwhichisnecessaryforTRandRAR to interact with N-CoR is not required for RevErb. Rather, two short regions of RevErb separated by ;200 amino acids are required for interaction with N-CoR. The primary amino acid sequence of the N-terminal regionofRevErbessentialforN-CoRinteractionisnothomologoustothatofTRorRAR,whereassimilarities exist among the C-terminal domains of the Receptors. N-CoR contains two adjacent but distinct interaction domains, one of which binds tightly to both RevErb and TR whereas the other binds more weakly and differentially interacts with the Nuclear Receptors. These results indicate that multiple Nuclear Receptors, utilizing different primary amino acid sequences, repress transcription by interacting with N-CoR. Regulation of gene expression is essential for cellular differentiation, development, and maintenance of homeostasis. These processes are regulated at the transcriptional level by sequence-specific transcriptional activators and repressors which communicate with the basal transcription apparatus (for reviews, see references 51 and 59). Many activation domains have been shown to interact directly with components of the basal transcription apparatus, while others interact indirectly
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A Nuclear Hormone Receptor corepressor mediates transcriptional silencing by Receptors with distinct repression domains.
Molecular and cellular biology, 1996Co-Authors: I Zamir, G B Atkins, A Hörlein, H. P. Harding, Michael G Rosenfeld, Christopher K. Glass, M A LazarAbstract:Ligand-independent transcriptional repression is an important function of Nuclear Hormone Receptors. An interaction screen with the repression domain of the orphan Receptor RevErb identified N-CoR, the corepressor for thyroid Hormone Receptor (TR) and retinoic acid Receptor (RAR). N-CoR is likely to be a bona fide transcriptional corepressor for RevErb because (i) RevErb interacts with endogenous N-CoR, (ii) ectopic N-CoR potentiates RevErb-mediated repression, and (iii) transcriptional repression by RevErb correlates with its ability to bind N-CoR. Remarkably, a region homologous to the CoR box which is necessary for TR and RAR to interact with N-CoR is not required for RevErb. Rather, two short regions of RevErb separated by approximately 200 amino acids are required for interaction with N-CoR. The primary amino acid sequence of the N-terminal region of RevErb essential for N-CoR interaction is not homologous to that of TR or RAR, whereas similarities exist among the C-terminal domains of the Receptors. N-CoR contains two adjacent but distinct interaction domains, one of which binds tightly to both RevErb and TR whereas the other binds more weakly and differentially interacts with the Nuclear Receptors. These results indicate that multiple Nuclear Receptors, utilizing different primary amino acid sequences, repress transcription by interacting with N-CoR.
George E O Muscat - One of the best experts on this subject based on the ideXlab platform.
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minireview Nuclear Hormone Receptor 4a signaling implications for metabolic disease
Molecular Endocrinology, 2010Co-Authors: Michael A Pearen, George E O MuscatAbstract:Numerous members of the Nuclear Hormone Receptor (NR) superfamily have been demonstrated to regulate metabolic function in a cell- and tissue-specific manner. This review brings together recent studies that have associated members of the NR superfamily, the orphan NR4A subgroup, with the regulation of metabolic function and disease. The orphan NR4A subgroup includes Nur77 (NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3). Expression of these Receptors is induced in multiple tissues by a diverse range of stimuli, including stimuli associated with metabolic function, such as: β-adrenoceptor agonists, cold, fatty acids, glucose, insulin, cholesterol, and thiazolidinediones. In vitro and in vivo gain- and loss-of-function studies in major metabolic tissues (including skeletal muscle, adipose, and liver cells and tissues) have associated the NR4A subgroup with specific aspects of lipid, carbohydrate, and energy homeostasis. Most excitingly, although these orphan Receptors do not have known endogenous ligands, several ...
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nur77 regulates lipolysis in skeletal muscle cells evidence for cross talk between the β adrenergic and an orphan Nuclear Hormone Receptor pathway
Journal of Biological Chemistry, 2005Co-Authors: Megan A Maxwell, Mark E Cleasby, Angus Harding, Annika Stark, Gregory J Cooney, George E O MuscatAbstract:Abstract Skeletal muscle is a major mass peripheral tissue that accounts for ∼40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces β-adrenergic Receptor (β-AR)-mediated adaptive thermogenesis. β-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30–60 min of β-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the Nuclear Hormone Receptor, Nur77. In contrast, the expression of other Nuclear Receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase γ3, UCP3, CD36, adiponectin Receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the Nuclear Hormone Receptor and β-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.
Brendan C Mullaney - One of the best experts on this subject based on the ideXlab platform.
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defects in the c elegans acyl coa synthase acs 3 and Nuclear Hormone Receptor nhr 25 cause sensitivity to distinct but overlapping stresses
PLOS ONE, 2014Co-Authors: Jordan D Ward, Brendan C Mullaney, Marc R Van Gilst, Benjamin J Schiller, Le D He, Sarah Petnic, Carole Couillault, Nathalie Pujol, Teresita U Bernal, Kaveh AshrafiAbstract:Metazoan transcription factors control distinct networks of genes in specific tissues, yet understanding how these networks are integrated into physiology, development, and homeostasis remains challenging. Inactivation of the Nuclear Hormone Receptor nhr-25 ameliorates developmental and metabolic phenotypes associated with loss of function of an acyl-CoA synthetase gene, acs-3. ACS-3 activity prevents aberrantly high NHR-25 activity. Here, we investigated this relationship further by examining gene expression patterns following acs-3 and nhr-25 inactivation. Unexpectedly, we found that the acs-3 mutation or nhr-25 RNAi resulted in similar transcriptomes with enrichment in innate immunity and stress response gene expression. Mutants of either gene exhibited distinct sensitivities to pathogens and environmental stresses. Only nhr-25 was required for wild-type levels of resistance to the bacterial pathogen P. aeruginosa and only acs-3 was required for wild-type levels of resistance to osmotic stress and the oxidative stress generator, juglone. Inactivation of either acs-3 or nhr-25 compromised lifespan and resistance to the fungal pathogen D. coniospora. Double mutants exhibited more severe defects in the lifespan and P. aeruginosa assays, but were similar to the single mutants in other assays. Finally, acs-3 mutants displayed defects in their epidermal surface barrier, potentially accounting for the observed sensitivities. Together, these data indicate that inactivation of either acs-3 or nhr-25 causes stress sensitivity and increased expression of innate immunity/stress genes, most likely by different mechanisms. Elevated expression of these immune/stress genes appears to abrogate the transcriptional signatures relevant to metabolism and development.
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regulation of c elegans fat uptake and storage by acyl coa synthase 3 is dependent on nr5a family Nuclear Hormone Receptor nhr 25
Cell Metabolism, 2010Co-Authors: Brendan C Mullaney, Raymond D Blind, George A Lemieux, Carissa L Perez, Ida Coordt Elle, Nils J Faergeman, Marc R Van Gilst, Holly A Ingraham, Kaveh AshrafiAbstract:Summary Acyl-CoA synthases are important for lipid synthesis and breakdown, generation of signaling molecules, and lipid modification of proteins, highlighting the challenge of understanding metabolic pathways within intact organisms. From a C. elegans mutagenesis screen, we found that loss of ACS-3, a long-chain acyl-CoA synthase, causes enhanced intestinal lipid uptake, de novo fat synthesis, and accumulation of enlarged, neutral lipid-rich intestinal depots. Here, we show that ACS-3 functions in seam cells, epidermal cells anatomically distinct from sites of fat uptake and storage, and that acs-3 mutant phenotypes require the Nuclear Hormone Receptor NHR-25, a key regulator of C. elegans molting. Our findings suggest that ACS-3-derived long-chain fatty acyl-CoAs, perhaps incorporated into complex ligands such as phosphoinositides, modulate NHR-25 function, which in turn regulates an endocrine program of lipid uptake and synthesis. These results reveal a link between acyl-CoA synthase function and an NR5A family Nuclear Receptor in C. elegans .
