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

热激转录因子的细胞保护作用及其生理作用分析

基本信息

批准号：
13480231
负责人：
NAKAI Akira
金额：
$ 8.45万
依托单位：
YAMAGUCHI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

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.

众所周知，当细胞在余生的高温下预孵育时，细胞可以在暴露于致命温度的情况下生存。该现象称为“诱导的热耐耐能力”，受热冲击转录因子（HSF）的调节。在这个研究项目中，我们发现了由HSF1控制的新型细胞保护机制。首先，鸡B淋巴细胞中的HSF1和HSF3在正常生长的细胞中上调HSP90α表达。此外，HSP90稳定Cdc2蛋白，这对于G_2到M相跃迁至关重要。其次，HSF1独立于热休克基因的激活而保护细胞死亡免受各种应力。 HSF1可能调节热休克基因以外的未知靶基因。为了了解HSF的身体作用，我们分析了在HSF4和HSF1中突变的小鼠。我们发现HSF4对于晶状体开发至关重要。晶状体中缺乏HSF4表达会导致白内障的进展。也有其他群体据报道，HSF4基因的突变与遗传性白内障有关。我们还发现，HSF1促进了暴露于热应激的男性生殖细胞的凋亡。 HSF1激活了一种新型的热休克基因T细胞死亡相关基因51（TDAG51），该基因是促凋亡基因，对于T细胞杂交瘤中FAS的表达至关重要。 HSF1-NULL小鼠的睾丸缺乏TDAG51的诱导和FAS的诱导以及FAS的响应。这是我们确定了一种新型的HSF1介导的质量控制机制，使其在精子发生中。