Differential roles of heat shock transcription factors

脊椎动物基因组编码热休克因子（HSFs 1-4）家族，其中HSF 1和HSF 3的DNA结合和转录活性在热休克时被激活。HSF 1具有经典热休克因子的性质，并且在暴露于热休克和其他应激条件时表现出DNA结合和转录活性的快速活化，而HSF 3通常在较高温度下活化，并且具有明显的延迟动力学。虽然这些数据表明，HSF 3的功能作为一个多余的应激激活剂，其作用相对于HSF 1，在调节热休克反应，是不确定的。为了解决HSF 3在热休克反应中的作用，通过在禽类淋巴细胞系中通过体细胞重组破坏常驻基因来构建缺乏HSF 3基因的空细胞。缺乏HSF 3，但表达正常水平HSF 1的人结肠癌细胞，通过热休克蛋白的诱导表达，显示出热休克反应的严重降低。 关于我们 enes.因此，缺乏HSF 3的细胞不表现出耐热性。这些结果表明，HSF 3在热休克反应的调控中起主导作用，HSF 4是一种哺乳动物因子，其特点是缺乏一个抑制DNA结合同源三聚体形成的结构域。我们已经确定了人类HSF 4基因的外显子结构，并确定了一个主要的新的异构体，HSF 4 b，除了以前报道的HSF 4a异构体，由选择性RNA剪接，事件。RT-PCR结果显示，小鼠组织中HSF 4 b mRNA的表达量高于HSF 4a，在脑和肺组织中检测到HSF 4 b蛋白。虽然小鼠HSF 4a和HSF 4 b在没有应激的情况下形成三聚体，但这两种同种型表现出不同的转录活性，HSF 4a作为热休克基因组成型表达的抑制剂，而hHSF 4 b作为转录激活剂。此外，HSF 4 b，而不是HSF 4a补充缺乏HSF的酵母细胞的活力缺陷。此外，热休克和其他应激刺激HSF 4 b在酵母和哺乳动物细胞中的靶基因的转录。这些结果表明，HSF 4 mRNA的差异剪接引起组织特异性热休克基因表达的抑制剂和激活剂。少

The vertebrate genome encodes a family of heat shock factors (HSFs 1-4) of which the DNA binding and transcriptional activities of HSF1 and HSF3 are activated upon heat shock. HSF1 has the properties of the classical heat shock factor and exhibits rapid activation of DNA binding and transcriptional activity upon exposure to conditions of heat shock and other stresses, whereas HSF3 is typically activated at higher temperatures and with distinct delayed kinetics. While these data suggest that HSF3 functions as a redundant stress activator, its role relative to HSF1, in the regulation of the heat shock response, was uncertain. To address the role of HSF3 in the heat shock response, null cells lacking the HSF3 gene were constructed by disruption of the resident gene by somatic recombination in an avian lymphoid cell line. Null cells lacking HSF3, yet expressing normal levels of HSF1, exhibited a severe reduction in the heat shock response as measured by inducible expression of heat shock g … More enes. Consequently, cells lacking HSF3 did not exhibit thermotolerance. These results reveal that HSF3 has a dominant role in the regulation of the heat shock response.HSF4 is a mammalian factor characterized by its lack of a suppression domain that modulates formation of DNA-binding homotrimer. We have determined the exon structure of the human HSF4 gene and identified a major new isoform, HSF4b, derived by alternative RNA splicing, events, in addition to a previously reported HSF4a isoform. In mouse tissues HSF4b mRNA was more abundant than HSF4a as examined by RT-PCR, and its protein was detected in the brain and lung. Although both mouse HSF4a and HSF4b form trimers in the absence of stress, these two isoforms exhibit different transcriptional activity, HSF4a acts as an inhibitor of the constitutive expression of heat shock genes, and hHSF4b as a transcriptional activator. Furthermore HSF4b, but not HSF4a complements the viability defect of yeast cells lacking HSF.Moreover heat shock and other stresses stimulate transcription of target genes by HSF4b in both yeast and mammalian cells. These results suggest that differential splicing of HSF4 mRNA gives rise to both an inhibitor and activator of tissue-specific heat shock gene expression. Less