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Regulation of HSF1 and HSF2 by SUMO-1 Modification

SUMO-1 修饰对 HSF1 和 HSF2 的调节

基本信息

批准号：
7271321
负责人：
Kevin D Sarge
金额：
$ 27.03万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7271321
关键词：
Affinity Alzheimer&apos s Disease Binding Cell Aging Cell Death Cells Complex Condition DNA Binding DNA Binding Domain Disease Elements Enzymes Event Exposure to Fostering Gene Expression Genes Genetic Transcription Goals Heat shock proteins Heat-Shock Response Heat-Shock Transcription Factor 2 Human Huntington Disease Lysine Mediating Modeling Modification Molecular Molecular Chaperones N-terminal Nuclear Parkinson Disease Phosphorylation Positioning Attribute Proline Proteins Rate Regulation Relative (related person)Role Serine Site Stress Testing Thinking Transactivation Transcription Factor TFIIB Transcription Regulatory Protein Translating UC01 Ubiquitin Ubiquitination base caspase-3 cell age heat shock transcription factor human Huntingtin protein in vivo monomer prevent promoter protein aggregation protein expression protein folding protein misfolding

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this application is to elucidate the mechanism(s) that regulate stress-induced and constitutive expression of heat shock proteins (hsps), which are critical not only for the cell's ability to survive exposure to stress conditions but also for normal protein folding in non-stressed cells. The stress-inducible vs. constitutive activities of the transcriptional regulatory proteins HSF1 and HSF2 are critical for this stress-activated and basal hsp gene expression, but how their differentially-regulated activities are controlled is unknown. In the search for this mechanism, we have identified differential regulation of SUMO-1 modification of HSF 1 and HSF2 leading to stress-induced and constitutive activation, respectively. We propose that SUMO-1 modification of HSFs is pre-requisite for their transcriptional activities at the levels of their ability to interact with promoters of hsp genes (DNA-binding activities), for assembly of transcription complexes with other factors on these promoters (transactivation potential), and for their protection against degradation. In this application we will 1) determine the functional consequences of SUMO-1 modification for the DNA-binding and transactivation activities of HSF 1 and HSF2, 2) characterize the role of this modification in regulating the turnover of HSF1 and HSF2, and 3) identify the mechanism(s) which mediate the differential regulation of stress-induced vs. constitutive SUMO-1 modification of HSF1 and HSF2, determine the significance of HSF sumoylation for protein misfolding in vivo, and determine whether sumoylation of HSFs is altered by cellular aging. Results from the proposed studies will define the basis of the differential regulation of HSF 1 and HSF2 leading to stress-induced and constitutive expression of heat shock proteins, and may provide a strategy for manipulating cellular heat shock protein expression, a promising potential treatment of diseases caused by protein misfolding/aggregation such as Parkinson's, Huntington's, and Alzheimer's Disease.

描述（由申请人提供）：本申请的长期目标是阐明调节应激诱导和热休克蛋白（hsps）组成表达的机制，热休克蛋白（hsps）不仅对细胞在应激条件下存活的能力至关重要，而且对非应激细胞中的正常蛋白质折叠也至关重要。转录调节蛋白HSF1和HSF2的胁迫诱导活性与构成活性对这种应激激活的基础hsp基因表达至关重要，但它们的差异调节活性是如何被控制的尚不清楚。在寻找这一机制的过程中，我们已经确定了hsf1和HSF2的SUMO-1修饰的差异调节，分别导致应力诱导和本构激活。我们认为，在与热休克蛋白基因启动子相互作用（dna结合活性）的水平上，热休克蛋白的SUMO-1修饰是其转录活性的先决条件，在这些启动子上与其他因子组装转录复合物（反活化电位），并保护其免受降解。在本应用中，我们将1)确定SUMO-1修饰对HSF1和HSF2的dna结合和转激活活性的功能后果，2)表征该修饰在调节HSF1和HSF2的周转中的作用，以及3)确定介导HSF1和HSF2的应激诱导与构成性SUMO-1修饰差异调节的机制，确定HSF SUMO-1修饰对体内蛋白质错误折叠的意义。并确定hsf的sumo化是否会因细胞老化而改变。这些研究的结果将确定hsf1和HSF2导致应激诱导和组成性热休克蛋白表达的差异调控的基础，并可能提供操纵细胞热休克蛋白表达的策略，这是由蛋白质错误折叠/聚集引起的疾病（如帕金森病、亨廷顿病和阿尔茨海默病）的有希望的潜在治疗方法。