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Sensor Mechanisms of HSF Activation

HSF 激活的传感器机制

基本信息

批准号：
8468101
负责人：
EVGENY A NUDLER
金额：
$ 39.32万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468101
关键词：
Address Antibiotic Therapy Antibiotics Biochemical Biological Assay Cell physiology Cells Chemicals Chickens Competence Complex DNA Binding Data Defense Mechanisms Drosophila genus Drug Targeting Electron Microscopy Elongation Factor Ensure Eukaryota Family Functional RNA Gene Expression Regulation Genes Genetic Genomics Goals Guanosine Triphosphate HSF1 Heat shock proteins Heat-Shock Proteins 70 Heat-Shock Response Heat-Shock Transcription Factor 2 Inflammation Investigation Ischemia Location Malignant Neoplasms Mammals Maps Mass Spectrum Analysis Mediating Methods Modification Molecular Molecular Chaperones Nitric Oxide Synthase Nucleotides Oxidation-Reduction Pattern Phosphorylation Physiological Play Protein Disulfide Isomerase Proteins RNA Regulation Reperfusion Therapy Research Roentgen Rays Role Site Stimulus Structure Techniques Temperature Temperature Sense Testing Transactivation Translational Activation Translations Vertebrates Work X-Ray Crystallography base biological adaptation to stress chromatin immunoprecipitation crosslink heat shock transcription factor in vivo intermolecular interaction macrophage member monomer multidisciplinary novel nuclease promoter research study response sensor stressor translation factor

项目摘要

DESCRIPTION (provided by applicant): The heat shock (HS) response is the primary cellular defense mechanism against adverse environmental conditions. The hallmark of the HS response is the rapid and robust induction of HS genes, many of which encoding molecular chaperones. Heat shock proteins (HSPs) have been also implicated in a variety of pathological situations including cancer, ischemia/reperfusion, inflammation, etc. In eukaryotes the HS gene regulation occurs mainly at the transcriptional level by a family of heat shock transcription factors (HSFs), among which HSF1 is the master regulator. HSF1 is constitutively expressed in vertebrates as inactive monomer under tight negative regulation. Rapid and robust post- translational activation of HSF1 occurs in response to HS conditions and other stressors. Activation of HSF1 involves trimerization and acquisition of the DNA-binding activity, changes in phosphorylation pattern and acquisition of transactivation competence. Despite extensive research, the mechanism of HSF1 activation, especially at the trimerization step, remained elusive. During our extensive preliminary work we have identified two cellular factors that are essential for HSF1 activation: translation elongation factor eEF1A and a novel large non-coding RNA termed HSR1. HSR1 is shown to serve as a cellular thermosensor, whereas eEF1A serves a general sensor of protein integrity. The long-term objective of the present proposal is to provide a comprehensive physiological and mechanistic description of HSF1 activation and its regulation by HSR1/eEF1A sensor machinery. Specifically we propose to perform extensive structure-function characterization of HSF1-eEF1A- HSR1 ternary complex and unravel the mechanism underlying HSF activation by HSR1/eEF1A in response to various types of physical and chemical stressors in mammalian and Drosophila cells.

描述(由申请人提供)：热休克(HS)反应是抵抗不利环境条件的主要细胞防御机制。HS反应的特点是HS基因的快速而强大的诱导，其中许多编码分子伴侣。热休克蛋白(HSPs)也参与了多种病理情况，包括癌症、缺血/再灌注、炎症等。在真核生物中，HS基因的调控主要是由一类热休克转录因子(HSFs)在转录水平上进行的，其中HSF1是主要的调节因子。HSF1在脊椎动物中以非活性单体的形式在严格的负调控下结构性表达。HSF1的翻译后快速而强劲的激活发生在HS条件和其他应激源的反应中。HSF1的激活包括DNA结合活性的三聚化和获得、磷酸化模式的改变和反式激活能力的获得。尽管进行了广泛的研究，但HSF1的激活机制，特别是在三聚化步骤中的激活机制，仍然难以捉摸。在我们广泛的前期工作中，我们已经确定了两个对HSF1激活至关重要的细胞因子：翻译延长因子eEF1A和一种新的被称为HSR1的大的非编码RNA。HSR1被证明是细胞温度传感器，而eEF1A则是蛋白质完整性的一般传感器。本提案的长期目标是为HSF1的激活及其由HSR1/eEF1A传感器机制的调节提供一个全面的生理和机制描述。具体地说，我们建议对HSF1-eEF1A-HSR1三元复合体进行广泛的结构-功能表征，并揭示HSR1/eEF1A在哺乳动物和果蝇细胞中响应各种物理和化学应激源而激活HSF的机制。