The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mitchell A Lazar - One of the best experts on this subject based on the ideXlab platform.
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the interaction between Nuclear Receptor Corepressor and histone deacetylase 3 regulates both positive and negative thyroid hormone action in vivo
Molecular Endocrinology, 2010Co-Authors: Seohee You, Xiao Hui Liao, Roy E Weiss, Mitchell A LazarAbstract:Thyroid hormone (TH) plays a critical role in development, growth, and metabolism by binding to Nuclear TH Receptors to modulate gene expression. In the absence of TH, TH Receptors repress genes that are TH-activated by recruiting the Nuclear Receptor Corepressor (NCoR), which exists in a tight complex with histone deacetylase 3 (HDAC3). Here we explored the actions of TH in the deacetylase activating domain mutant (DADm) mouse, whose NCoR-HDAC3 interaction is genetically disrupted. Several TH-activated genes were derepressed in the liver of euthyroid and hypothyroid DADm mice, consistent with the Corepressor paradigm and a critical role of the NCoR-HDAC3 interaction in basal repression. The role of Corepressors in genes that are down-regulated by TH is less well understood. Remarkably, circulating TSH levels were increased in euthyroid DADm mice, and the pituitary expression of TSHalpha, a classic TH-down-regulated gene, was modestly but significantly elevated regardless of TH status. Thus, the NCoR interaction with HDAC3 modulates expression of both positively- and negatively-regulated genes by TH in vivo.
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the interaction between Nuclear Receptor Corepressor and histone deacetylase 3 regulates both positive and negative thyroid hormone action in vivo
Molecular Endocrinology, 2010Co-Authors: Xiao Hui Liao, Roy E Weiss, Mitchell A LazarAbstract:Thyroid hormone (TH) plays a critical role in development, growth, and metabolism by binding to Nuclear TH Receptors to modulate gene expression. In the absence of TH, TH Receptors repress genes that are TH-activated by recruiting the Nuclear Receptor Corepressor (NCoR), which exists in a tight complex with histone deacetylase 3 (HDAC3). Here we explored the actions of TH in the deacetylase activating domain mutant (DADm) mouse, whose NCoR-HDAC3 interaction is genetically disrupted. Several TH-activated genes were derepressed in the liver of euthyroid and hypothyroid DADm mice, consistent with the Corepressor paradigm and a critical role of the NCoR-HDAC3 interaction in basal repression. The role of Corepressors in genes that are down-regulated by TH is less well understood. Remarkably, circulating TSH levels were increased in euthyroid DADm mice, and the pituitary expression of TSHα, a classic TH-down-regulated gene, was modestly but significantly elevated regardless of TH status. Thus, the NCoR interact...
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Nuclear Receptor Corepressor and histone deacetylase 3 govern circadian metabolic physiology
Nature, 2008Co-Authors: Theresa Alenghat, Shannon E Mullican, Katherine Meyers, Kirstin Leitner, Adetoun Adenijiadele, Jacqueline Avila, Maja Bucan, Klaus H Kaestner, Rexford S. Ahima, Mitchell A LazarAbstract:Nuclear Receptor Corepressor 1 (Ncor1) is an activator for the enzyme histone deacetylase 3 (Hdac3) that is required for embryogenesis, but its physiological functions are unknown. Now experiments in knock-out mice lacking Ncor1 show that disruption of the Ncor1–Hdac3 interaction causes aberrant regulation of clock genes and results in abnormal circadian behaviour — with a sleep–wake cycle closer to 23 hours than the normal 24. These mice are also leaner than normal and more insulin sensitive as a result of increased energy expenditure. Loss of a functional Ncor1–Hdac3 complex in vivo changes the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Targeting of the Ncor1–Hdac3 enzyme could be a highly specific intervention in diseases of nutritional stress such as obesity and diabetes. This paper shows that specific genetic disruption of the Ncor–HdaC3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin sensitive due to increased energy expenditure. Loss of a functional Ncor–HdaC3 complex in vivo changes the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1,2,3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4,5,6,7. The Nuclear Receptor Corepressor 1 (Ncor1) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (Hdac3)8. Lack of Ncor1 is incompatible with life, and hence it is unknown whether Ncor1, and particularly its regulation of Hdac3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the Ncor1–Hdac3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin-sensitive owing to increased energy expenditure. Unexpectedly, loss of a functional Ncor1–Hdac3 complex in vivo does not lead to sustained increases in known catabolic genes, but instead significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology.
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the orphan Nuclear Receptor rev erbα recruits the n cor histone deacetylase 3 Corepressor to regulate the circadian bmal1 gene
Molecular Endocrinology, 2005Co-Authors: Mitchell A LazarAbstract:Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan Nuclear Receptor Rev-erbα has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbα mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbα dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbα directly binds to the mouse Bmal1 promoter and recruits the endogenous Nuclear Receptor Corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level mark...
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the Nuclear Receptor Corepressor deacetylase activating domain is essential for repression by thyroid hormone Receptor
Molecular Endocrinology, 2005Co-Authors: Takahiro Ishizuka, Mitchell A LazarAbstract:Nuclear Receptor Corepressor (N-CoR) mediates repression by thyroid hormone Receptor (TR) as well as other Nuclear hormone Receptors and transcription factors. N-CoR contains several repression domains that repress transcription when fused to a heterologous DNA binding domain, but their relative importance in the full-length N-CoR molecule is unknown. Here we addressed this important issue by depleting N-CoR in human cells and replacing it with mutant and wild-type murine N-CoR. Although the N-terminal RD binds transducin β-like protein 1 (TBL1), TBLR1, and mSin3, deletion of this region did not affect the ability of N-CoR to mediate repression by TR. By contrast, deletion of the deacetylase activating domain (DAD) that binds and activates histone deacetylase 3 dramatically hampered N-CoR’s function as a TR Corepressor. Introduction of a single amino acid mutation in the DAD similarly disabled the Corepressor function of N-CoR. Thus, the DAD domain of N-CoR is singularly essential for repression by TR.
Anthony N. Hollenberg - One of the best experts on this subject based on the ideXlab platform.
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Nuclear Receptor Corepressor ncor1 regulates in vivo actions of a mutated thyroid hormone Receptor α
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Laura Fozzatti, Anthony N. Hollenberg, Jeong Won Park, Mark C Willingham, Sheueyann ChengAbstract:Genetic evidence from patients with mutations of the thyroid hormone Receptor α gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRα1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TRα1 mutants to properly release the Nuclear Corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1PV mice, expressing a dominant negative TRα1 mutant (TRα1PV), with mice expressing a mutant Ncor1 allele (Ncor1ΔID mice) that cannot recruit the TR or PV mutant. TRα1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1ΔID ameliorated abnormalities in the thyroid-pituitary axis of Thra1PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1PV/+ mice expressing NCOR1ΔID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated Receptor γ and CCAAT/enhancer-binding protein α gene, due to the inability of TRα1PV to recruit NCOR1ΔID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TRα1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRα1–NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRα1 mutant-mediated hypothyroidism in patients.
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resistance to thyroid hormone is modulated in vivo by the Nuclear Receptor Corepressor ncor1
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Laura Fozzatti, Inna Astapova, Anthony N. Hollenberg, Jeong Won Park, Mark C Willingham, Dong Wook Kim, Oksana Gavrilova, Sheueyann ChengAbstract:Mutations in the ligand-binding domain of the thyroid hormone Receptor β (TRβ) lead to resistance to thyroid hormone (RTH). These TRβ mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone Receptors (TRs), leading to dysregulation of the pituitary–thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRβ mutants cause RTH has been postulated to be an inability of the mutants to properly release the Nuclear Corepressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed ThrbPV mice (a model of RTH) expressing a human TRβ mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1ΔID mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1ΔID, the abnormally elevated thyroid-stimulating hormone and TH levels found in ThrbPV mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCOR1ΔID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRβ mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR–NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH.
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The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis
Molecular Endocrinology, 2011Co-Authors: Inna Astapova, Kristen R. Vella, Kaila A. Holtz, Michael A. Rosenberg, Preeti Ramadoss, Benjamin A. Rodwin, Xiao Hui Liao, Roy E Weiss, Anthony Rosenzweig, Anthony N. HollenbergAbstract:The role of Nuclear Receptor Corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoRΔID) that cannot be recruited to the thyroid hormone Receptor (TR). These mice present with low serum T4 and T3 concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T4 and T3 and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH.
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structural basis for Nuclear Receptor Corepressor recruitment by antagonist liganded androgen Receptor
Molecular Cancer Therapeutics, 2008Co-Authors: Myles C Hodgson, Anthony N. Hollenberg, Howard C Shen, Steven P. BalkAbstract:Androgen Receptor (AR) recruitment of transcriptional Corepressors NCoR and SMRT can be enhanced by antagonists such as mifepristone. This study shows that enhanced NCoR binding to the mifepristone-liganded AR is mediated by the NCoR COOH-terminal N1 CoRNR box and that this selectivity is due to charged residues unique to the COOH-terminal CoRNR boxes of NCoR and SMRT. Significantly, these residues are on a helical face adjacent to oppositely charged residues in helix 4 of the AR ligand-binding domain. Mutagenesis of these AR residues in helix 4, as well as mutation of lysine 720 in helix 3 (predicted to interact with the CoRNR box), markedly impaired AR recruitment of NCoR, indicating that N1 CoRNR box binding is being stabilized by these ionic interactions in the AR ligand-binding domain coactivator/Corepressor binding site. Finally, results using a helix 12-deleted AR indicate that mifepristone induces allosteric changes in addition to helix 12 displacement that are critical for NCoR binding. These findings show that AR antagonists can enhance Corepressor recruitment by stabilizing a distinct antagonist conformation of the AR coactivator/Corepressor binding site and support the development of additional antagonists that may be able to further enhance AR recruitment of Corepressors.
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determination of Nuclear Receptor Corepressor interactions with the thyroid hormone Receptor
Molecular Endocrinology, 2003Co-Authors: Anita Makowski, Ronald N. Cohen, Sabrina Brzostek, Anthony N. HollenbergAbstract:The thyroid hormone Receptor (TR) recruits the Nuclear Corepressors, Nuclear Receptor Corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone Receptors (SMRT), to target DNA elements in the absence of ligand. While the TR preferentially recruits NCoR, the mechanism remains unclear. The Corepressors interact with the TR via interacting domains (IDs) present in their C terminus which contain a conserved motif termed a CoRNR box. Despite their similarity, the Corepressor IDs allow for Nuclear Receptor specificity. Here we demonstrate that NCoR stabilizes the TR homodimer when bound to DNA by preventing its dissociation from thyroid hormone response elements. This suggests that NCoR acts to hold the repression complex in place on target elements. The TR homodimer recruits NCoR through two of its three IDs, one of which is not present in SMRT. This unique ID, N3, contains a CoRNR box but lacks the extended helical motif present in each of the other IDs. Instead, N3 contains an isoleucine just proximal to this motif. This isoleucine is also conserved in N2 but not in the corresponding S2 domain in SMRT. On thyroid hormone response elements and in mammalian cells this residue is critical in both N3 and N2 for high-affinity TR binding. In addition, this residue also controls specificity for the interactions of TR with NCoR. Together these data suggest that the specific recruitment of NCoR by the TR through a unique motif allows for stabilization of the repression complex on target elements.
Don J Chen - One of the best experts on this subject based on the ideXlab platform.
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regulation of androgen Receptor activity by the Nuclear Receptor Corepressor smrt
Journal of Biological Chemistry, 2003Co-Authors: Guoqing Liao, Liuhyow Chen, Aihua Zhang, Aparna Godavarthy, Fang Xia, Jagadish C Ghosh, Don J ChenAbstract:Androgen Receptor (AR) is a hormone-regulated transcription factor that mediates a wide array of biological processes including sexual differentiation, spermatogenesis, and prostate cancer progression. The transcriptional activity of AR and other members of the Nuclear Receptor superfamily are modulated by coregulatory proteins. In this study, we have investigated the regulation of AR transcriptional activity by the silencing mediator for retinoid and thyroid hormone Receptors (SMRT). We found that AR possesses an intrinsic transcriptional repression activity, and AR interacts directly with SMRT. One interacting surface on AR is mapped to the ligand-binding domain, and the presence of a DNA binding/hinge region enhances this interaction. The binding surface on SMRT is mapped to the C-terminal ID2 region, and mutation in the ID2 Corepressor motif inhibits the interaction. Overexpression of SMRT inhibits dihydrotestosterone-dependent transactivation by AR and further suppresses the antiandrogen flutamide-mediated inhibition of AR activity. We provide evidence to suggest that the mechanisms of SMRT-mediated inhibition of AR activity involves inhibition of AR N/C interaction and competition with the p160 coactivator. Our data establish a significant role of SMRT in modulating AR transcriptional activity.
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smrte inhibits mef2c transcriptional activation by targeting hdac4 and 5 to Nuclear domains
Journal of Biological Chemistry, 2001Co-Authors: Eun Ju Park, Don J ChenAbstract:The silencing mediator for retinoic acid and thyroid hormone Receptors (SMRT) mediates transcriptional repression by recruiting histone deacetylases (HDACs) to the DNA-bound Nuclear Receptor complex. The full-length SMRT (SMRTe) contains an N-terminal sequence that is highly conserved to the Nuclear Receptor Corepressor N-CoR. To date, little is known about the activity and function of the full-length SMRTe protein, despite extensive studies on separated Receptor interaction and transcriptional repression domains. Here we show that SMRTe inhibits MEF2C transcriptional activation by targeting selective HDACs to unique subNuclear domains. Indirect immunofluorescence studies with anti-SMRTe antibody reveal discrete cytoplasmic and Nuclear speckles, which contain RARalpha in an RA-sensitive manner. Formation of the SMRTe Nuclear speckles results in recruitment of several class I and class II HDACs to these subNuclear domains in a process depending on HDAC enzymatic activity. Intriguingly, although HDAC4 is located primarily in the cytoplasm, coexpression of SMRTe dramatically translocates HDAC4 from the cytoplasm into the nucleus, where HDAC4 prevents MEF2C from activating muscle differentiation. SMRTe also translocates HDAC5 from diffusive nucleoplasm into discrete Nuclear domains. Accordingly, SMRTe synergizes with HDAC4 and 5 to inhibit MEF2C transactivation of target promoter, suggesting that Nuclear domain targeting of HDAC4/5 may be important in preventing muscle cell differentiation. These results highlight an unexpected new function of the Nuclear Receptor Corepressor SMRTe for its role in regulating cellular trafficking of Nuclear Receptor and selective HDACs that may play an important role in regulation of cell growth and differentiation.
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smrte a silencing mediator for retinoid and thyroid hormone Receptors extended isoform that is more related to the Nuclear Receptor Corepressor
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Eun Ju Park, Daniel J Schroen, Maozhou Yang, Hui Li, Li Li, Don J ChenAbstract:SMRT (silencing mediator for retinoid and thyroid hormone Receptors) and N-CoR (Nuclear Receptor copressor) mediate transcriptional repression of important regulators that are involved in many signaling pathways. SMRT and N-CoR are related proteins that form complexes with mSin3A/B and histone deacetylases to induce local chromatin condensation and transcriptional repression. However, SMRT is substantially smaller than N-CoR, lacking an N-terminal domain of approximately 1,000 aa that are present in N-CoR. Here, we report the identification of SMRT-extended (SMRTe), which contains an N-terminal sequence that shows striking similarity with N-CoR. As in N-CoR, this SMRTe-N-terminal domain also represses basal transcription. We find that SMRTe expression is regulated during cell cycle progression and SMRTe transcripts are present in many embryonic tissues. These data redefine a structurally and functionally more related Nuclear Receptor Corepressor family and suggest an additional role for SMRTe in the regulation of cycle-specific gene expression in diverse signaling pathways.
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the Nuclear Receptor Corepressor smrt inhibits interstitial collagenase mmp 1 transcription through an hre independent mechanism
Biochemical and Biophysical Research Communications, 1997Co-Authors: Daniel J Schroen, Don J Chen, Matthew P Vincenti, Constance E BrinckerhoffAbstract:Abstract Nuclear Receptors inhibit synthesis of collagenase-1 (matrix metalloproeinase-1; MMP-1), an enzyme that degrades interstitial collagens and contributes to joint pathology in rheumatoid arthritis. SMRT (Silencing Mediator for Retinoid and Thyroid hormone Receptors) mediates the repressive effect of Nuclear Receptors at hormone responsive elements (HREs), prompting us to investigate whether this co-repressor could also regulate transcription of MMP-1, which lacks any known HREs. We find that primary synovial fibroblasts express SMRT. When over-expressed by transient transfection, SMRT inhibits MMP-1 promoter activity induced by interleukin-1 (IL-1), phorbol phorbol myristate acetate (PMA) or v-Src. SMRT apparently inhibits MMP-1 gene expression by interfering with one or more transcriptional elements clustered in a region between −321 and +63. We conclude that SMRT negatively regulates MMP-1 synthesis through a novel, HRE-independent mechanism that involves proximal regions of the MMP-1 promoter.
Sheueyann Cheng - One of the best experts on this subject based on the ideXlab platform.
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oncogenic actions of the Nuclear Receptor Corepressor ncor1 in a mouse model of thyroid cancer
PLOS ONE, 2013Co-Authors: Laura Fozzatti, Jeong Won Park, Li Zhao, Mark C Willingham, Sheueyann ChengAbstract:Studies have suggested that the Nuclear Receptor Corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (ThrbPV/PV mice) that spontaneously develops thyroid cancer. ThrbPV/PV mice harbor a dominantly negative thyroid hormone Receptor β (TRβ) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing ThrbPV mice with mice that globally express an NCOR1 mutant protein (NCOR1ΔID) in which the Receptor interaction domains have been modified so that it cannot interact with the TRβ, or PV, in mice. Remarkably, expression of NCOR1ΔID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of ThrbPV/PVNcor1ΔID/ΔID mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21waf1/cip1; Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in thyroids of ThrbPV/PV mice. In thyroids of ThrbPV/PVNcor1ΔID/ΔID mice, the p53/PV complex could not recruit NCOR1ΔID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of thyroid cancer.
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Nuclear Receptor Corepressor ncor1 regulates in vivo actions of a mutated thyroid hormone Receptor α
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Laura Fozzatti, Anthony N. Hollenberg, Jeong Won Park, Mark C Willingham, Sheueyann ChengAbstract:Genetic evidence from patients with mutations of the thyroid hormone Receptor α gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRα1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TRα1 mutants to properly release the Nuclear Corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1PV mice, expressing a dominant negative TRα1 mutant (TRα1PV), with mice expressing a mutant Ncor1 allele (Ncor1ΔID mice) that cannot recruit the TR or PV mutant. TRα1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1ΔID ameliorated abnormalities in the thyroid-pituitary axis of Thra1PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1PV/+ mice expressing NCOR1ΔID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated Receptor γ and CCAAT/enhancer-binding protein α gene, due to the inability of TRα1PV to recruit NCOR1ΔID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TRα1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRα1–NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRα1 mutant-mediated hypothyroidism in patients.
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resistance to thyroid hormone is modulated in vivo by the Nuclear Receptor Corepressor ncor1
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Laura Fozzatti, Inna Astapova, Anthony N. Hollenberg, Jeong Won Park, Mark C Willingham, Dong Wook Kim, Oksana Gavrilova, Sheueyann ChengAbstract:Mutations in the ligand-binding domain of the thyroid hormone Receptor β (TRβ) lead to resistance to thyroid hormone (RTH). These TRβ mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone Receptors (TRs), leading to dysregulation of the pituitary–thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRβ mutants cause RTH has been postulated to be an inability of the mutants to properly release the Nuclear Corepressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed ThrbPV mice (a model of RTH) expressing a human TRβ mutant (PV) with mice expressing a mutant Ncor1 allele (Ncor1ΔID mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCOR1ΔID, the abnormally elevated thyroid-stimulating hormone and TH levels found in ThrbPV mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCOR1ΔID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRβ mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR–NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH.
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smrt repression of Nuclear Receptors controls the adipogenic set point and metabolic homeostasis
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Russell R Nofsinger, Sheueyann Cheng, Grant D Barish, Suk Hyun Hong, Johan W Jonker, Hao Ying, Mathias Leblanc, Liming Pei, Yeon Joo Kang, Michael C NelsonAbstract:The Nuclear Receptor Corepressor, silencing mediator of retinoid and thyroid hormone Receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the Receptor interaction domain (RID) of SMRT (SMRTmRID) that solely disrupts its interaction with Nuclear hormone Receptors (NHRs). SMRTmRID mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRTmRID mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRTmRID-derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.
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Nuclear Receptor Corepressor is a novel regulator of phosphatidylinositol 3 kinase signaling
Molecular and Cellular Biology, 2007Co-Authors: Fumihiko Furuya, Li Zhao, Celine J Guigon, John A Hanover, Sheueyann ChengAbstract:Thyroid hormone Nuclear Receptors (TRs) are ligand-dependent transcription factors that mediate the biological activities of thyroid hormone (T3) in growth, development, differentiation, and maintenance of metabolic homeostasis. There are two TR genes, TRα and TRβ, located on chromosomes 17 and 3, respectively, that encode four major T3-binding TR isoforms (α1, β1, β2, and β3). The TRs are ligand-dependent transcription factors, consisting of modular functional structures with the N-terminal A/B, central DNA-binding, and C-terminal ligand-binding domains. In the presence of T3, TRs associate with coactivators to regulate target gene transcription. In the absence of T3, TRs assume a different conformation that recruits Corepressors to mediate gene silencing. This ligand-dependent switch in recruitment of coactivators or Corepressors caused by TRs alters chromatin structures to signal changes in transcription programs. In the past decades, strides have been made in understanding the role of Corepressors in the biology of TRs. These advances have been mainly focused on the actions of Corepressors in nucleus-initiated transcription of TR. However, recent studies show that the Nuclear Receptor Corepressor (NCoR) is localized not only in the nucleus but also in the cytoplasm (6, 16). The redistribution of Nuclear NCoR to the cytoplasm provides a mechanism for controlling differentiation of neural stem cells into astrocytes (6). Moreover, Sardi et al. showed that cytoplasmic NCoR forms complexes with a cleaved product of ErbB4 (a member of the epidermal growth factor Receptor family) and the signaling protein TAB2 and translocates into the nucleus to regulate astrogenesis in the developing brain (16). Still, it is not clear whether, in addition to its presence in neural cells, NCoR is also localized in the cytoplasm of other cell types to mediate cellular functions that are independent of transcription regulation. Our recent discovery that TRβ or its mutant TRβPV (PV) forms complexes with p85α, the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), and activates PI3K signaling (5) provides an opportunity to address the functional role of cytoplasmic NCoR in the context of TR biology. PV was identified in a patient with resistance to thyroid hormone (21). PV has a C insertion at codon 448 that produces a frame shift in the carboxyl-terminal 14 amino acids of TRβ1 (13), resulting in the complete loss of T3 binding activity and transcriptional capacity (11). A knock-in mutant mouse harboring the PV mutation that recapitulates human resistance to thyroid hormone (TRβPV mouse) was created (8). Moreover, as a homozygous TRβPV/PV mouse, it spontaneously develops a follicular thyroid carcinoma similar to human thyroid cancer through pathological progression of capsular invasion, vascular invasion, anaplasia, and metastasis (18, 24). Using this mouse model, we found that PV physically associates with p85α to constitutively activate the PI3K activity and, via downstream effectors, to increase cell proliferation and motility to promote thyroid carcinogenesis in TRβPV/PV mice (5). That PV is also associated with NCoR in thyroid tumors of TRβPV/PV mice (1) raises the possibility that NCoR could play a role in thyroid carcinogenesis by modulating the interaction of PV with PI3K. In the present study, we tested this hypothesis and found that NCoR competed with TRβ or PV for binding to p85α in the nucleus as well as in the cytoplasm. An alteration of cellular NCoR protein levels by overexpression led to reduced PI3K/protein kinase B (AKT) signaling. Conversely, knocking down cellular NCoR by small interfering RNA (siRNA) approaches increased PI3K activity, phosphorylation of AKT, and cell motility. In thyroid tumors, cellular NCoR protein abundance was significantly lower than it was in wild-type thyroids, thereby facilitating the interaction of PV with p85α to activate PI3K signaling. Thus, the present study identified a novel function of NCoR that regulated PI3K signaling via protein-protein interaction to alter the activity of TRβ or PV independent of nucleus-initiated transcription.
Stephen W Ragsdale - One of the best experts on this subject based on the ideXlab platform.
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high affinity heme binding to a heme regulatory motif on the Nuclear Receptor rev erbβ leads to its degradation and indirectly regulates its interaction with Nuclear Receptor Corepressor
Journal of Biological Chemistry, 2016Co-Authors: Eric L Carter, Nirupama Gupta, Stephen W RagsdaleAbstract:Abstract Rev-erbα and Rev-erbβ are heme-binding Nuclear Receptors (NRs) that repress the transcription of genes involved in regulating metabolism, inflammation and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erbα recruits Nuclear Receptor Corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases affinity of the ligand-binding domain (LBD) of Rev-erbs for NCoR1 peptides. One explanation for this discrepancy is that the LBD and NCoR1 peptides used for in vitro studies cannot replicate key features of the full-length proteins used in cellular studies. However, combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erbβ (FLRev-erbβ) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo- and heme- replete FLRev-erbβ:DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erbβ-NCoR1 complex. The interaction between FLRev-erbβ and NCoR1 as well as Rev-erbβ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating degradation of Rev-erbβ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10-6 s-1) for heme dissociation from Rev-erbβ, rules out a prior proposal that Rev-erbβ acts as an intracellular heme sensor.
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high affinity heme binding to a heme regulatory motif on the Nuclear Receptor rev erbβ leads to its degradation and indirectly regulates its interaction with Nuclear Receptor Corepressor
Journal of Biological Chemistry, 2016Co-Authors: Eric L Carter, Nirupama Gupta, Stephen W RagsdaleAbstract:Rev-erbα and Rev-erbβ are heme-binding Nuclear Receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erbα recruits Nuclear Receptor Corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erbβ (FLRev-erbβ) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo- and heme-replete FLRev-erbβ·DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erbβ·NCoR1 complex. The interaction between FLRev-erbβ and NCoR1 as well as Rev-erbβ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erbβ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10(-6) s(-1)) of heme dissociation from Rev-erbβ rules out a prior proposal that Rev-erbβ acts as an intracellular heme sensor.
