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有反应 调节对细胞至关重要的转录事件的衍生物 分化、发育和稳态。 核受体 甲状腺激素 (TR) 和视黄酸 (RAR) 是配体依赖性的 可以激活也可以抑制的转录调节因子 （沉默）目标基因表达。 该基因的作用机制 激活和抑制尚未完全理解，但它们是关键 阐明激素作用机制和生理反应 激素和维生素刺激。 异常的、本质性的镇压 RAR 和 TR 可能会阻碍细胞分化并诱导致癌 转变。 因此，了解其机制 未配体受体的转录抑制将 有助于了解正常体内平衡和 某些疾病状态。 最近，鉴定并克隆了 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 由未配体核受体介导的事件。 通过表征 RAR 和 TR (SMRT) 的沉默介体的功能，我们的 实验室继续研究信号通路 由核受体-辅阻遏物复合物介导。 在这个 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检验以下假设： 核受体相互作用对于 SMRT 发挥作用至关重要 辅阻遏物。 我们还将表征转录 SMRT 的抑制域并进一步检验以下假设： 转录抑制对于 SMRT 发挥作用也至关重要 辅阻遏物。 最后，我们已经开始并将继续筛选 并通过酵母二元表征新型 SMRT 相互作用蛋白 混合动力系统。 特别是，两个新颖的、特定的 SMRT 相互作用 已鉴定出可能发挥重要作用的蛋白质 SMRT 核受体信号传导。 我们坚信，这些 研究将显着提高基础知识 了解转录调控的分子机制 核受体和辅阻遏物，以及提供的结果 对正常荷尔蒙反应调节的新见解 激素相关的致癌过程和疾病。