REGULATION AND FUNCTION OF NUCLEAR RECEPTOR COACTIVATORS

核受体介导许多激素活动，调节 人类和高等生物中的重要生理过程 真核生物。亲脂荷尔蒙与 核受体在细胞内触发构象变化 受体，导致受体的转录激活 和靶基因刺激。最近的研究导致了 几种可调节核受体辅因子的发现 核受体的转录活性。这些 辅因子是荷尔蒙活动的潜在调节者。两条主线 核受体辅助因子的种类已经被确定： 通过以下途径促进转录抑制的辅阻遏子 未连接的受体和辅助激活剂可增强 配体受体的转录激活作用。发生的事件 荷尔蒙结合被认为触发了细胞的解离 受体的辅抑制子和辅激活子的募集 到感受器。申请人的实验室最近 鉴定和克隆核受体的一个新成员 辅活化子家族称为RAC3，也被称为AIB1， P/CIP、ACTR和电车-1。RAC3的序列密切相关 SRC-1和TIF2，这两个最强大的核受体 助活剂。目前，RAC3在中国的生物学意义 激素信号仍不清楚，但重要的是，RAC3 在体内被发现与CBP/p300强烈相关，并被认为是 在几个人类癌细胞中过表达，表明一个关键的 RAC3在调节细胞生长和增殖中的作用。 为了更好地了解RAC3的作用机制和 它在激素信号传递中的作用，在这项研究中我们将继续 调查结构和功能的关系 RAC3蛋白。我们还将调查RAC3在 维甲酸(RA)介导的干细胞分化与调控 关于基因表达的。最后，我们将确定和描述 新的RAC3相互作用蛋白，从而大大扩展 我们对RAC3在生活中的生物学功能的理解 细胞。总而言之，这些研究对于理解 核受体辅活化子RAC3的功能及其作用 在荷尔蒙信号中的作用。两国之间的功能互动 核受体和辅助激活剂将成为 了解其他转录因子的转录调控 激活剂。这个项目是我们的一个重要方面 长期方向和结果将为以下方面提供见解 未来可以控制荷尔蒙的疗法的发展- 调节和失调的细胞生长和增殖。

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.