Dynamic signaling by intracellular hormone receptors

细胞内激素受体的动态信号传导

• 批准号: 7368614
• 负责人: Brian C Freeman
• 金额: $ 4.82万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7368614
• 关键词: ATP phosphohydrolase; Address; Behavior; Binding; Biochemical; Biological; Biological Assay; Cells; Complex; DNA Binding; DNA-Directed RNA Polymerase; Disease; Dissociation; End Point; Engineering; Equilibrium; Esthesia; Event; Fluorescence; Gene Expression Regulation; Genetic Transcription; Genomics; Goals; Health; Hormone Receptor; Hormones; Hypertension; In Vitro; Inflammation; Kinetics; Lead; Life; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Molecular Chaperones; Monitor; Nuclear; P23; Pathway interactions; Production; Property; Proteins; Purpose; RNA Polymerase II; Range; Reaction Time; Receptor Signaling; Recruitment Activity; Regulation; Response Elements; Role; Run-On Assays; Series; Signal Transduction; Structure; Testing; Therapeutic Agents; Transcript; Withdrawal; cofactor; in vivo; insight; mutant; promoter; receptor; research study; response; scaffold; transcription factor; transcription factor TFIIF

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.

这个项目的长期目标是了解动态转录复合物的目的