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）反应是针对不利环境条件的主要细胞防御机制。 HS 反应的标志是 HS 基因的快速而有力的诱导，其中许多基因编码分子伴侣。热休克蛋白 (HSP) 还与多种病理情况有关，包括癌症、缺血/再灌注、炎症等。在真核生物中，热休克蛋白 (HSP) 基因调控主要发生在热休克转录因子 (HSF) 家族的转录水平上，其中HSF1为主调节器。 HSF1 在脊椎动物中以非活性单体的形式在严格的负调控下组成型表达。 HSF1 的快速而强大的翻译后激活是响应 HS 条件和其他应激源而发生的。 HSF1 的激活涉及三聚化和 DNA 结合活性的获得、磷酸化模式的变化以及反式激活能力的获得。尽管进行了广泛的研究，HSF1 激活的机制，特别是在三聚化步骤，仍然难以捉摸。在我们广泛的前期工作中，我们已经确定了 HSF1 激活所必需的两个细胞因子：翻译延伸因子 eEF1A 和一种称为 HSR1 的新型大非编码 RNA。 HSR1 被证明可用作细胞热传感器，而 eEF1A 可用作蛋白质完整性的通用传感器。本提案的长期目标是提供 HSF1 激活及其通过 HSR1/eEF1A 传感器机制的调节的全面生理和机制描述。具体来说，我们建议对 HSF1-eEF1A-HSR1 三元复合物进行广泛的结构功能表征，并揭示 HSR1/eEF1A 响应哺乳动物和果蝇细胞中各种类型的物理和化学应激源激活 HSF 的机制。