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.

核受体介导许多调节的激素作用 人类和更高的重要生理过程 真核生物。 亲脂激素与 核受体会触发构象变化 受体导致受体转录激活 和靶基因刺激。最近的研究导致了 发现几个可以调节的核受体辅助因子 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 已经确定了核受体辅助因子类别： 通过 增强的非配体受体和共激活剂 配体受体转录激活。 事件 据信激素结合会触发 来自受体的核心和共激活因子的募集 到受体。 申请人的实验室最近有 确定并克隆了核受体的新成员 共激活因子家庭称为Rac3，也称为AIB1， P/CIP，ACTR和TRAM-1。 RAC3的序列密切相关 对于SRC-1和TIF2，两个最有效的核受体 共激活因子。 目前，Rac3在 激素信号仍然不清楚，但重要的是，Rac3是 发现与CBP/P300在体内紧密相关，并且是 在几个人类癌细胞中过表达，这表明至关重要 RAC3在调节细胞生长和增殖中的作用。 为了更好地了解RAC3动作的机制和 它在激素信号传导中的作用，在这项研究中，我们将继续 研究的结构和功能关系 RAC3蛋白。 我们还将调查Rac3在 视黄酸（RA）介导的干细胞分化和对照 基因表达。 最后，我们将识别并表征 新的RAC3相互作用蛋白，从而实质上扩展 我们对RAC3生物的生物学功能的理解 细胞。 这些研究对理解至关重要 核受体共激活剂RAC3及其的功能 在激素信号传导中的作用。 之间的功能相互作用 核受体和共激活因子将作为模型 了解其他转录的转录调节 激活剂。 这个项目代表了我们的重要方面 长期方向和结果将为 开发可以控制激素的未来治疗剂 受调节和 - 调节的细胞生长和增殖。