MOLECULAR ACTIONS OF NUCLEAR RECEPTOR COREPRESSOR SMRT

核受体 CorePressor SMRT 的分子作用

• 批准号: 6524609
• 负责人: J DON CHEN
• 金额: $ 7.33万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-15 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524609
• 关键词: cofactor; gene induction /repression; genetic transcription; hormone receptor; hormone regulation /control mechanism; membrane proteins; nuclear membrane; point mutation; protein structure function; receptor expression; recombinant proteins; retinoid binding proteins; site directed mutagenesis; thyroid hormones; transcription factor; yeast two hybrid system

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.

类固醇和核受体对激素和维生素反应 衍生物调节转录事件至关重要 分化，发展和稳态。 核受体 对于甲状腺激素（TR）和视乙酸（R​​AR）是配体依赖性的 可以激活和压抑的转录调节器 （静音）靶基因表达。 这种基因的机制 激活和抑制尚未完全理解，而是关键 阐明激素作用的机制和生理反应 激素和维生素刺激。 异常，构成抑制 RAR和TR可能会阻止细胞分化并诱导致癌 转型。 因此，了解机制 非配体受体的转录抑制作用将 有助于正常稳态和 某些疾病状态。 最近，识别和克隆 申请人和其他人的第一个核受体核心器 已经提供了新颖的分子工具来剖析这种基因抑制 由非配体核受体介导的事件。 通过表征 RAR和TR（SMRT）的沉默中介器的功能，我们 实验室继续研究信号通路 由核受体 - 孔子复合物介导。 在这个 研究，我们将定义和表征最小的受体 SMRT的相互作用领域，并广泛检验了以下假设 核受体相互作用对于SMRT起作用至关重要 CorePressor。 我们还将表征转录 SMRT的镇压领域，并进一步研究了以下假设 转录抑制对于SMRT的作用也是必不可少的 一个核心。 最后，我们已经开始并将继续筛选 并通过酵母两种酵母来表征新颖的SMRT相互作用蛋白 混合系统。 特别是两个新颖的特定SMRT相互作用 已经确定了可能起重要作用的蛋白质 在SMRT核受体信号中。 我们坚信这些 研究将大大提高基本知识 了解转录调控的分子机制 核受体和核心器，结果提供 对正常荷尔蒙反应调节的新见解以及 与激素有关的致癌过程和疾病。