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。 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，并研究活性蛋白质的需求。 分解所募集的复合物。例如，在激素结合IR之后， 基因组反应元件的结构，其协调作用导致产生特定的 mRNA转录物。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IR动力学可促进所用蛋白质之间的有效转变， 可能允许IR有效地感知激素水平，这些活动的缺陷可能有助于 无数的疾病。因此，动态作用是IR信号转导的关键特征。拟议 研究将集中在分子伴侣在促进IR转导途径中的作用， 通过转录结构传递信号并对激素水平的变化做出反应。 为了解决p23和Hsp 90分子伴侣改变DNA结合状态的前提， 选择包括IR在内的转录因子，某些辅激活因子可以稳定DNA结合 本论文的研究目标有三：1）确定分子伴侣促进转录因子的作用机制 动力学; 2）检查转录复合物之间的伴侣介导的转换; 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，与广泛的疾病有关。 包括癌症、炎症和高血压;这些疾病中的许多都可以用配体来控制 到IR。对于IR配体作为治疗剂的使用来说，当务之急是适当和及时的反应， 同源受体对配体的应用和撤回。因此，了解 通过IR控制基因调节，特别是决定反应时间的事件，具有重要的意义 用于健康，用于检测，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.