Analysis of roles of heat shock transcription factors in cell protection and its physiological roles

众所周知，当细胞在亚致死温度下预先孵育时，细胞可以在致命温度下存活。这种现象被称为“诱导耐热性”，由热休克转录因子(HSFs)调节。在本研究项目中，我们发现了HSF1控制的两种新的细胞保护机制。首先，鸡B淋巴细胞中的热休克蛋白1和热休克蛋白3上调正常生长细胞中热休克蛋白90α的表达。此外，Hsp90还稳定了从G_2向M期转变所必需的CDc2蛋白。其次，HSF1不依赖于热休克基因的激活，而是保护细胞免受各种压力的伤害。HSF1可能调控热休克基因以外的未知靶基因，为了了解HSFs的生理作用，我们分析了HSF4和HSF1突变的小鼠。我们发现HSF4对晶状体的发育是必不可少的。HSF4在晶状体中的表达缺失会导致白内障的进展。另有研究表明，HSF4基因突变与遗传性白内障有关。我们还发现，HSF1促进了热应激下的雄性生殖细胞的凋亡。HSF1激活了一个新的热休克基因T细胞死亡相关基因51(TDAG51)，它是一种促凋亡基因，对T细胞杂交瘤中Fas的表达是必不可少的。在HSF1基因缺失的小鼠中，TDAG51和Fas的诱导在热休克反应中是缺乏的。因此，我们确定了一种新的HSF1介导的精子发生质量控制机制。

It is well known that cells can survive against an exposure to lethal temperatures when cells are pre-incubated at sublethal high temperatures. This phenomenon is called "induced thermotolerance", and is regulated by heat shock transcription factors (HSFs). In this research project, we uncovered novel two mechanisms of cell protection controlled by HSF1. First, HSF1 and HSF3 in chicken B lymphocytes up-regulate Hsp90α expression in normally growing cells. Furthermore, Hsp90 stabilizes Cdc2 protein that is essential for G_2 to M phase transition. Second, HSF1 is protecting cell death against various kinds of stresses independently of the activation of heat shock genes. HSF1 may regulate unknown target genes other than heat shock genes.To understand physiological roles of HSFs, we analyzed mice mutated in HSF4 and HSF1. We found that HSF4 is essential for lens development. The lack of HSF4 expression in the lens results in progression of cataract. It was also reported from other group that mutation of HSF4 gene is associated with hereditary cataract. We also found that HSF1 promotes apoptosis of male germ cells exposed to thermal stress. HSF1 activates a novel heat shock gene T-cell death-associated gene 51 (TDAG51) that is a pro-apoptotic gene, and is essential for Fas expression in T cell hybridoma. The induction of TDAG51 as well as Fas in response to heat shock was lacking in the testis in HSF1-null mice. Thus, we identified a novel HSF1-mediated quality control mechanism in spermatogenesis.