MOLECULAR ACTIONS OF NUCLEAR RECEPTOR COREPRESSOR SMRT

类固醇和核受体对激素和维生素 调节细胞关键转录事件的衍生物 分化、发育和体内平衡。 核受体 甲状腺激素（TR）和维甲酸（RAR）是配体依赖性的 转录调节因子既能激活也能抑制 （沉默）靶基因表达。 这种基因的作用机制 激活和抑制尚未完全理解，但它们是 阐明激素的作用机制和生理反应， 激素和维生素刺激。 异常的，结构性抑制， RAR和TR可阻断细胞分化并诱导肿瘤发生， 转型 因此，了解 非配体受体的转录抑制将 有助于了解正常体内平衡的基本知识， 某些疾病状态。 最近，鉴定和克隆 申请人和其他人的第一个核受体辅阻遏物 提供了新的分子工具来剖析这种基因抑制 非配体核受体介导的事件。 通过表征 RAR和TR的沉默介体（SMRT）的功能，我们 实验室继续研究信号通路 由核受体-辅阻遏物复合物介导。 在这 研究中，我们将定义和表征最小受体 SMRT的相互作用域，并广泛测试假设， 核受体相互作用是SMRT发挥作用所必需的。 辅阻遏物 我们还将描述转录 抑制结构域的SMRT，并进一步检查的假设， 转录抑制对于SMRT发挥作用也是必不可少的， 辅阻遏物 最后，我们已经开始并将继续筛选 和表征新的SMRT相互作用蛋白的酵母双- 混合系统 特别是，两个新的，具体的SMRT相互作用 已经鉴定出了一些蛋白质， 在SMRT-核受体信号传导中。 我们坚信，这些 研究将大大推进基础知识， 理解转录调控的分子机制， 核受体和辅阻遏物，结果提供了 调节正常激素反应的新见解， 肿瘤相关的致癌过程和疾病。

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.