Dynamic signaling by intracellular hormone receptors

这个项目的长期目标是了解动态转录复合体的目的 以及促进所用结构解离的机制。 要使用的一般策略是关注细胞内激素受体(IR)介导的转录， 它使用一系列蛋白质来达到功能终点，并研究活性的需求 拆解招募的建筑群。例如，以下激素结合红外光谱成核多次 基因组反应元件的结构，其协调作用导致产生特定的 信使核糖核酸转录。虽然这些化合物在体外寿命很长，但在体内的结构是高度动态的 (t1/2&lt；4秒)快速的红外动力学可以促进所使用的蛋白质和 可能允许IRS有效地检测激素水平。这些活动中的缺陷可能会导致 无数的疾病。因此，动态作用是红外信号转导的一个重要特征。建议数 研究重点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，并对激素水平的变化做出反应。 解决p23和Hsp90分子伴侣改变DNA结合状态的前提 选择包括IRS在内的转录因子，以及某些共激活剂可以稳定DNA结合 国家设想了三个目标：1)确定伴侣促进的转录因子的机制 动力学；2)研究伴侣介导的转录复合体之间的转换；3)研究 辅因子对GR核转录的影响。 基因调控，特别是由IRS调节的事件，与一系列疾病有关 包括癌症、炎症和高血压；这些疾病中的许多可以通过配体来控制 给美国国税局。将IR配体用作治疗剂的当务之急是通过 同源受体对配体的应用和撤除。因此，了解 通过国税局管理基因调控，特别是决定反应时间的事件，具有重要的意义 为了健康，为了检测、治疗和治愈疾病。

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 statethree 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.