Dynamic signaling by intracellular hormone receptors

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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.