Heat Shock Transcription Factor Function and Regulation

描述(由申请人提供)： 所有的生物和细胞都暴露在应激条件下，无论是环境温度升高的结果还是有毒化合物的结果，以响应通过正常的线粒体呼吸产生的活性氧物种、药物、感染和炎症、正常的细胞生长和分裂或其他生理或病理生理条件。暴露在压力下会导致细胞周期的扰动，基因表达的戏剧性重新编程和细胞内稳态控制，以及蛋白质的展开和沉积。无法建立适当的应激反应与中风和缺血-再灌注损伤、癌症、衰老、生物体生长、发育、不孕和以蛋白质聚集和沉积为特征的神经退行性疾病有关。真核细胞通过诱导热休克蛋白(HSPs)的合成来响应胁迫条件，热休克蛋白参与蛋白质的折叠、运输、降解以及信号转导蛋白和转录因子的成熟和激活。在这一应用中，我们概述了热休克转录因子(HSFs)诱导HSP表达的研究，HSFs是从酵母到人类保守的应激反应转录因子。首先，哺乳动物HSF1感受压力的机制将被阐明。其次，将识别调节哺乳动物HSF1应激激活的细胞因子，并确定它们的作用机制。第三，将对酵母HSF靶基因进行全基因组鉴定。酵母HSF靶基因调控网络将被分析为理解HSF应激反应的广泛生物学意义的范例，这些研究将外推到哺乳动物HSF1靶基因的识别。HSPs具有保护机体免受中风和缺血再灌注损伤的功能，而HSF1的激活已被证明抑制蛋白质聚集，类似于神经退行性疾病中的发现。因此，了解hsf1如何感知和响应压力，以及在压力过程中被激活的靶基因，具有重要意义。

DESCRIPTION (provided by applicant): All organisms and cells are exposed to stressful conditions, whether a consequence of elevations in environmental temperatures or toxic compounds, in response to reactive oxygen species generated through normal mitochondrial respiration, pharmacological agents, infection and inflammation, normal cell growth and division or other physiological or pathophysiological conditions. Exposure to stress results in perturbations in the cell cycle, dramatic reprogramming of gene expression and cellular homeostatic controls and in the unfolding and deposition of proteins. The inability to mount appropriate stress responses is associated with stroke and ischemia-reperfusion injury, cancer, aging, defects in organismal growth, development, infertility and in neurodegenerative diseases characterized by protein aggregation and deposition. Eukaryotic cells respond to stress conditions by inducing the synthesis of heat shock proteins (Hsps), which function in protein folding, trafficking, degradation and in the maturation and activation of signal transduction proteins and transcription factors. In this application we outline studies on the induction of Hsp expression by Heat Shock Transcription Factors (HSFs), stress-responsive transcription factors conserved from yeast to humans. First, the mechanisms by which mammalian HSF1 senses stress will be elucidated. Secondly, cellular factors that modulate mammalian HSF1 stress activation will be identified and their mechanisms of action ascertained. Third, a genome wide identification of yeast HSF target genes will be carried out. Yeast HSF target gene regulatory networks will be analyzed as a paradigm for understanding the broad biological significance of the HSF stress response, and these studies will be extrapolated to the identification of mammalian HSF1 target genes. Hsps function to protect organisms from stroke and ischemia reperfusion injury, and activation of HSF1 has been shown to suppress protein aggregation similar to that found in neurodegenerative disease. Therefore, understanding how HSF1 senses and responds to stress, and the target genes activated during stress, have important