Dynamic signaling by intracellular hormone receptors

描述（由申请人提供）：本项目的长期目标是了解动态转录复合物的目的和促进所用结构解离的机制。要使用的一般策略是专注于细胞内激素受体（IR）介导的转录，它使用一系列的蛋白质，以达到一个功能性终点，并研究所招募的复合物的主动拆卸的要求。例如，在激素结合IR之后，在基因组应答元件处使多个结构成核，其协调作用导致特异性mRNA转录物的产生。虽然复合物在体外是长寿命的，但在体内结构是高度动态的（t1/2 < 4秒）。快速的IR动力学可以促进所用蛋白质之间的有效转换，并且可以允许IR有效地感测激素水平-这些活动中的缺陷可能导致无数疾病。因此，动态作用是IR信号转导的关键特征。拟议的研究将集中在分子伴侣在促进IR转导途径中的作用，包括通过转录结构传递信号和对激素水平变化的反应。 为了解决p23和Hsp 90分子伴侣改变包括IR在内的选择性转录因子的DNA结合状态以及某些共激活因子可以稳定DNA结合状态的前提，设想了三个目标：1）确定伴侣促进的转录因子动力学的机制; 2）检查伴侣介导的转录复合物之间的转换; 3）研究辅助因子对GR核转录的影响。 基因调控，特别是由IR调节的事件，已经涉及广泛的疾病，包括癌症，炎症和高血压;这些疾病中的许多可以使用IR的配体来控制。对于IR配体作为治疗剂的使用来说，当务之急是同源受体对配体应用和撤回的适当和及时的响应。因此，了解IR控制基因调控的机制，特别是决定反应时间的事件，对健康以及检测、治疗和治愈疾病具有重要意义。

DESCRIPTION (provided by applicant): The long-term objectives of this project are to understand the purpose of dynamic transcription complexes and the mechanisms that promote dissociation of the employed structures. The general strategy to be used is to focus on intracellular hormone receptor (IR) mediated transcription, which uses a series of proteins to reach a functional endpoint, and to study the requirement for active disassembly of the recruited complexes. For example, following hormone binding IRs nucleate multiple structures at genomic response elements whose coordinated actions lead to the production of specific mRNA transcripts. Though the complexes are long-lived in vitro, in vivo the structures are highly dynamic (t1/2 < 4 sec). The rapid IR kinetics may facilitate efficient transitions between the employed proteins and may permit effective sensing of hormone levels by IRs--defects in these activities may contribute to a myriad of diseases. Hence, dynamic action is a critical feature for IR signal transduction. The proposed studies will focus on the roles of molecular chaperones in promoting IR transduction pathways including conveying the signal through transcription structures and reacting to changes in hormone levels. To address the premise that the p23 and Hsp90 molecular chaperones alter the DNA binding state of select transcription factors including IRs and that certain coactivators can stabilize the DNA bound state three goals are envisioned: 1) Determine the mechanism of chaperone-promoted transcription factor dynamics; 2) Examine the chaperone-mediated transitions between transcription complexes; 3) Study the effect of cofactors on GR-nucleated transcription. Gene regulation, particularly events modulated by IRs, has been implicated in a wide range of diseases including cancer, inflammation and hypertension; many of these diseases can be controlled using ligands to IRs. Imperative for the use of IR ligands as therapeutic agents, is an appropriate and timely response by the cognate receptor to ligand application and withdrawal. Thus, understanding the mechanisms that govern gene regulation by IRs, particularly events that dictate response times, has important implications for health, and for detecting, treating, and curing disease.