Steroid and nuclear receptors respond to hormones and vitamin derivatives to regulate transcriptional events critical for cell differentiation, development and homeostasis. The nuclear receptors for thyroid hormone (TR) and retinoid acid (RAR) are ligand-dependent transcriptional regulators that can activate as well as repress (silence) target gene expression. The mechanisms of such gene activation and repression are not fully understood, but are keys to elucidate mechanisms of hormone action and physiological responses to hormone and vitamin stimuli. Abnormal, constitutive repression by RAR and TR may block cell differentiation and induce oncogenic transformation. Therefore, understanding the mechanisms of transcriptional repression by the unliganded receptors will contribute to fundamental knowledge of both normal homeostasis and certain disease states. Recently, the identification and cloning of the first nuclear receptor corepressors by the applicant and others have provided novel molecular tools to dissect such gene repression events mediated by unliganded nuclear receptors. By characterizing functions of the silencing mediator for RAR and TR (SMRT), our laboratory have continued to investigate the signaling pathways mediated by the nuclear receptor-corepressor complexes. In this study, we will define and characterize the minimal receptor interacting domains of SMRT and extensively test the hypothesis that nuclear receptor interaction is essential for SMRT to function as a corepressor. We will also characterize the transcriptional repression domains of SMRT and further examine the hypothesis that transcriptional repression is also essential for SMRT to function as a corepressor. Finally, we have started and will continue to screen and characterize novel SMRT-interacting proteins by the yeast two- hybrid system. In particular, two novel, specific SMRT-interacting proteins have been identified that are likely to play important role in SMRT-nuclear receptor signaling. We strongly believe that these studies will significantly advance the fundamental knowledge in understanding molecular mechanisms of transcriptional regulation by nuclear receptors and the corepressors, and the results in provide new insights into regulation of normal hormonal responses and also hormone-related oncogenic processes and diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Endocrinology Study Section (END)
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Margolis, Ronald N
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Li, Chia-Wei; Dinh, Gia Khanh; Chen, J Don (2009) Preferential physical and functional interaction of pregnane X receptor with the SMRTalpha isoform. Mol Pharmacol 75:363-73
Zhang, Aihua; Li, Chia-Wei; Chen, J Don (2007) Characterization of transcriptional regulatory domains of ankyrin repeat cofactor-1. Biochem Biophys Res Commun 358:1034-40
Zhang, Aihua; Li, Chia-Wei; Tsai, Shih-Chieh et al. (2007) Subcellular localization of ankyrin repeats cofactor-1 regulates its corepressor activity. J Cell Biochem 101:1301-15
Johnson, David R; Li, Chia-Wei; Chen, Liuh-Yow et al. (2006) Regulation and binding of pregnane X receptor by nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT). Mol Pharmacol 69:99-108
Zhang, Aihua; Yeung, Percy Luk; Li, Chia-Wei et al. (2004) Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. J Biol Chem 279:33799-805
Johnson, David R; Lovett, Jeanne M; Hirsch, Michael et al. (2004) NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. Biochem Biophys Res Commun 318:714-8
Liu, Jilin; Li, Hui; Burstein, Sumner H et al. (2003) Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol 63:983-92
Liao, Guoqing; Chen, Liuh-Yow; Zhang, Aihua et al. (2003) Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. J Biol Chem 278:5052-61
Ghosh, Jagadish C; Yang, Xiaofang; Zhang, Aihua et al. (2002) Interactions that determine the assembly of a retinoid X receptor/corepressor complex. Proc Natl Acad Sci U S A 99:5842-7
Liu, Zheng; Auboeuf, Didier; Wong, Jiemin et al. (2002) Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A 99:7940-4

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