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

众所周知，当细胞在亚致死高温下预孵育时，细胞可以抵抗暴露于致死温度而存活。这种现象被称为“诱导的热耐受性”，并由热休克转录因子（HSFs）调节。在这个研究项目中，我们发现了由HSF 1控制的两种新的细胞保护机制。首先，鸡B淋巴细胞中的HSF 1和HSF 3上调正常生长细胞中的Hsp 90 α表达。此外，Hsp90还能稳定Cdc2蛋白，而Cdc2蛋白是G_2期向M期转变所必需的。第二，HSF 1保护细胞免于各种应激，而不依赖于热休克基因的激活。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，HSF 4是必不可少的透镜的发展。透镜中HSF 4表达的缺乏导致白内障的进展。其他研究组也报道HSF 4基因突变与遗传性白内障有关。我们还发现，HSF 1促进暴露于热应激的雄性生殖细胞的凋亡。热休克因子1激活了一个新的热休克基因T细胞死亡相关基因51（TDAG 51），它是一个促凋亡基因，是T细胞杂交瘤中Fas表达所必需的。在HSF1基因敲除小鼠的睾丸中，TDAG51和Fas对热休克反应的诱导是缺乏的。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.