COFACTORS AND NUCLEAR HORMONE RECEPTOR FUNCTION

辅助因子和核激素受体功能

• 批准号: 6342516
• 负责人: Martin L. Privalsky
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-20 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342516
• 关键词: Saccharomyces cerevisiae; biological signal transduction; cell nucleus; chromatin; cofactor; hormone receptor; hormone regulation /control mechanism; receptor binding; receptor expression; retinoid binding proteins; site directed mutagenesis; transcription factor; transcription termination; yeast two hybrid system

We wish to better understand how nuclear hormone receptors participate in signal transduction in normal cells, and the lesions in this process that lead to disease. Nuclear hormone receptors are transcription factors that regulate gene expression in response to small lipophil ligands, such as steroids, thyroid hormones, and retinoids. Nuclear hormone receptors regulate key aspects of normal metazoan reproduction, proliferation, differentiation, and homeostasis; aberrant receptors are causal factors in a variety of human endocrine and neoplastic disorders. Many nuclear hormone receptors exhibit bimodal transcriptional properties, and can either repress or activate gene expression. Transcriptional repression is least understood of these effects. Recently, we and other have identified a family of "co-repressors" (variously detonated TRACs, SMRT, N-CoR, or RIP13) that physically associate with nuclear hormone receptors and appear necessary for transcriptional silencing by these receptors. Our primary goal is to determine the roles of these co- repressors in receptor-mediated gene regulation. Specifically: 1. We will determine how co-repressors interact with receptors, and the manner in which the interaction is regulated. 2. We will determine how co-repressors interaction with other regulatory pathways that are know to modulate receptor function. 3. We will also elucidate how co-repressors, together with the receptor itself, interact with the transcriptional machinery and with chromatin to mediate transcriptional silencing. 4. We will determine the roles co-repressors play in human endocrine and neoplastic disorders. As a secondary goal we will also characterize an additional series of potentially novel effectors and/or modulators of nuclear hormone receptor action that we have recently identified. The results from these experiments will contribute to our understanding of the molecular basis behind hormone receptor function in both the normal and the diseased organism.

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