MECHANISM OF REGULATION OF HEAT SHOCK GENE EXPRESSION

描述(根据申请者的描述改编)：高温和其他压力 包括接触有毒化学物质会刺激一组 编码所谓的热休克或应激蛋白(HSP)的基因，其中许多 是分子伴侣。这种应激反应的预先激活使细胞， 组织和器官对压力更有抵抗力，并阻止这种反应 增加对压力的敏感性。应激反应的激活可以 预防或减轻脑缺血再灌流损伤及其毒性 化疗药物和炎症反应，并可以增强 免疫系统的响应性。热休克转录因子HSF1 负责应激诱导脊椎动物细胞中的基因激活。在……里面 非应激细胞，HSF1存在于与Hsp90形成的复合体的细胞质中，是 不能与DNA结合。当细胞遇到压力时，蛋白质的速率 去折叠急剧增加，积累的非本地蛋白质 与HSF1竞争与Hsp90的结合。从HSP90释放后，HSF1迅速 形成具有DNA结合活性的同源三聚体络合物，并被转移到 原子核。在三聚化之后，HSF1被转化为转录上的 一种可能由压力调节调节的反应中的活性形式 HSF1中特定丝氨酸和/或苏氨酸残基的磷酸化。在.之后 应激事件，活跃的HSF1被回收。这项研究的目标是 发现三聚体HSF1转化为其转录的机制 Active Form和随后停用HSF1并将其返回到其 非三聚体形式。从这项工作中学到的机械知识将应用于 旨在阐明应力缺陷基础的系统研究 老化细胞和表达普鲁恩的细胞的反应。

DESCRIPTION (adapted from the applicant's description): Heat and other stresses including exposure to noxious chemicals stimulate transcription of a group of genes encoding so-called heat shock or stress proteins (Hsps), many of which are molecular chaperones. Prior activation of this stress response makes cells, tissues, and organs more resistant to stress, and blocking this response increases susceptibility to stress. Activation of the stress response can prevent or mitigate ischemia and reperfusion injury and the toxicity of chemotherapeutic agents and inflammatory responses, and can enhance the responsiveness of the immune system. The heat shock transcription factor HSF1 is responsible for stress-induced gene activation in vertebrate cells. In unstressed cells, HSF1 resides in the cytoplasm in a complex with Hsp90 and is incapable of binding to DNA. When cells encounter stress, the rate of protein unfolding increases dramatically and the accumulating nonnative proteins compete with HSF1 for binding to Hsp90. Upon release from Hsp90, HSF1 rapidly forms a homotrimeric complex with DNA-binding activity and is translocated to the nucleus. Following trimerization, HSF1 is converted to a transcriptionally active form in a reaction that may be mediated by stress-regulated phosphorylation of specific serine and/or threonine residues in HSF1. After a stressful event, active HSF1 is recycled. The goal of this research is to discover the mechanisms for converting trimeric HSF1 to its transcriptionally active form and for subsequently deactivating HSF1 and returning it to its non-trimeric form. Mechanistic knowledge from this work will be applied to systematic studies aimed at elucidating the basis for defects in stress responses in aging cells and cells expressing prions.