REGULATION AND FUNCTION OF NUCLEAR RECEPTOR COACTIVATORS

核受体共激活剂的调节和功能

• 批准号: 6150608
• 负责人: J DON CHEN
• 金额: $ 18.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150608
• 关键词: biological signal transduction; cell differentiation; gene expression; genetic transcription; hormone regulation /control mechanism; laboratory rabbit; nuclear membrane; protein protein interaction; protein structure function; receptor; stem cells

Nuclear receptors mediate many hormone actions that regulate important physiological processes in human and in higher eukaryotic organisms. The binding of the lipophilic hormones to nuclear receptors triggers conformational changes in the receptors, leading to transcriptional activation of the receptors and target gene stimulation. Recent studies have led to the discovery of several nuclear receptor cofactors that can modulate the transcriptional activity of nuclear receptors. These cofactors are potential regulators of hormone actions. Two main classes of nuclear receptor cofactors have been identified: corepressors that promote transcriptional repression by unliganded receptors and coactivators that enhance transcriptional activation by liganded receptors. The event of hormone-binding is believed to trigger dissociation of corepressors from the receptors and recruitment of coactivators to the receptors. The applicant's laboratory has recently identified and cloned a new member of the nuclear receptor coactivator family termed RAC3, which is also known as AIB1, p/CIP, ACTR, and TRAM-1. The sequence of RAC3 is closely related to that of SRC-1 and TIF2, two most potent nuclear receptor coactivators. Currently, the biological relevance of RAC3 in hormone signaling is still unclear, but importantly, RAC3 was found to associate strongly with CBP/p300 in vivo and to be overexpressed in several human cancer cells, suggesting a crucial role of RAC3 in the regulation of cell growth and proliferation. In order to better understand the mechanism of RAC3 action and its role in hormone signaling, in this study we will continue to investigate the structural and functional relationship of the RAC3 protein. We will also investigate the role of RAC3 in retinoic acid (RA)-mediated stem cell differentiation and control of gene expression. Finally, we will identify and characterize new RAC3-interacting proteins, thereby substantially expanding our understanding of the biological function of RAC3 in living cells. Together, these studies are critical for understanding the function of the nuclear receptor coactivator RAC3 and its role in hormone signaling. The functional interaction between nuclear receptors and coactivators will serve as a model for understanding transcriptional regulation of other transcriptional activators. This project represents an important aspect of our long-term directions and the results will provide insights for development of future therapeutics that can control hormone- regulated and -dysregulated cell growth and proliferation.

核受体介导许多激素作用， 在人类和高等生物中重要的生理过程 真核生物 亲脂性激素与 核受体触发了 受体，导致受体的转录激活 和靶基因刺激。最近的研究表明， 发现几种核受体辅因子， 核受体的转录活性。 这些 辅因子是激素作用的潜在调节剂。 两个主要 核受体辅因子的种类已被鉴定： 辅阻遏物，其促进转录抑制， 非配体受体和辅激活因子， 配体受体的转录激活。 的情况 据信，蛋白结合引发了 来自受体的辅阻遏物和辅激活物的募集 到受体。 申请人的实验室最近 鉴定并克隆了一个核受体的新成员 称为RAC 3的辅激活因子家族，也称为AIB 1， p/CIP、ACTR和TRAM-1。 RAC 3的序列密切相关 SRC-1和TIF 2，两种最有效的核受体 辅活化剂 目前，RAC 3的生物学相关性， 激素信号仍然不清楚，但重要的是，RAC 3是 在体内发现与CBP/p300密切相关， 在几种人类癌细胞中过度表达，这表明 RAC 3在细胞生长和增殖调节中的作用。 为了更好地理解RAC 3的作用机制， 它在激素信号中的作用，在这项研究中，我们将继续 研究结构和功能的关系， RAC 3蛋白。 我们还将研究RAC 3在以下方面的作用： 维甲酸（RA）介导的干细胞分化和调控 的基因表达。 最后，我们将识别和描述 新的RAC 3相互作用蛋白，从而大大扩展 我们对RAC 3在生活中的生物学功能的理解 细胞 总之，这些研究对于理解 核受体辅激活子RAC 3的功能及其对细胞凋亡的影响 在激素信号中的作用。 之间的功能互动 核受体和辅激活因子将作为模型， 理解其他转录调控 活化剂。 这个项目代表了我们的一个重要方面 长期的方向和结果将提供见解， 未来的治疗方法可以控制激素的发展， 调节和失调的细胞生长和增殖。