MOLECULAR ACTIONS OF NUCLEAR RECEPTOR COREPRESSOR SMRT

类固醇和核受体对激素和维生素的反应 调节对细胞至关重要的转录事件的衍生物 分化、发育和动态平衡。核受体 因为甲状腺激素(TR)和维甲酸(RAR)是配体依赖的 既能激活又能抑制的转录调节因子 (沉默)靶基因表达。这类基因的作用机制 激活和抑制并不是完全理解的，但它们是 阐明激素的作用机制和生理反应 激素和维生素的刺激物。反常的、结构性的压制 RAR和TR可能阻断细胞分化并诱导肿瘤发生 转型。因此，理解这一机制 未连接受体对转录的抑制作用 有助于了解正常的动态平衡和 某些疾病状态。近年来，该基因的鉴定和克隆 申请者和其他人的第一个核受体辅阻遏物 为分析这种基因抑制提供了新的分子工具 未连接的核受体介导的事件。通过刻画 RAR和TR(SMRT)沉默调节器的功能，OUR 实验室一直在继续研究信号通路 由核受体-辅阻遏物复合体介导。在这 研究中，我们将定义和表征最小受体 SMRT的相互作用域，并广泛检验假设 核受体相互作用是SMRT发挥作用的关键 辅酶抑制因子。我们还将描述转录的 SMRT的抑制结构域，并进一步检验以下假设 转录抑制也是SMRT发挥作用的关键 一种核心抑制因子。最后，我们已经开始并将继续筛选 并利用酵母双功能菌株鉴定了新型SMRT相互作用蛋白 混合系统。尤其是两种新颖、特定的SMRT相互作用 已经确定了可能起重要作用的蛋白质 在SMRT-核受体信号转导中。我们坚信，这些 研究将极大地促进基础知识的发展 了解转录调控的分子机制 核受体和辅抑制子，其结果提供了 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。

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.