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Regulation of heat shock transcription factors and their roles in physiology and disease
Nature Reviews Molecular Cell Biology ( IF 112.7 ) Pub Date : 2017-08-30 , DOI: 10.1038/nrm.2017.73
Rocio Gomez-Pastor , Eileen T. Burchfiel , Dennis J. Thiele

The heat shock transcription factors (HSFs) were discovered over 30 years ago as direct transcriptional activators of genes regulated by thermal stress, encoding heat shock proteins. The accepted paradigm posited that HSFs exclusively activate the expression of protein chaperones in response to conditions that cause protein misfolding by recognizing a simple promoter binding site referred to as a heat shock element. However, we now realize that the mammalian family of HSFs comprises proteins that independently or in concert drive combinatorial gene regulation events that activate or repress transcription in different contexts. Advances in our understanding of HSF structure, post-translational modifications and the breadth of HSF-regulated target genes have revealed exciting new mechanisms that modulate HSFs and shed new light on their roles in physiology and pathology. For example, the ability of HSF1 to protect cells from proteotoxicity and cell death is impaired in neurodegenerative diseases but can be exploited by cancer cells to support their growth, survival and metastasis. These new insights into HSF structure, function and regulation should facilitate the development tof new disease therapeutics to manipulate this transcription factor family.



中文翻译:

热休克转录因子的调节及其在生理和疾病中的作用

热激转录因子(HSF)于30年前被发现,是受热应激调节的编码热激蛋白的基因的直接转录激活因子。公认的范例是,HSF通过识别简单的启动子结合位点(称为热激元件)来响应引起蛋白质错误折叠的条件,专门激活蛋白质伴侣的表达。但是,我们现在意识到,HSF的哺乳动物家族包含独立或共同驱动组合基因调控事件的蛋白,这些事件在不同情况下激活或抑制转录。在我们对HSF结构的理解上取得了进步,翻译后修饰和HSF调控的靶基因的广度揭示了激动人心的新机制,可调节HSF,并阐明其在生理学和病理学中的作用。例如,HSF1保护细胞免受蛋白毒性和细胞死亡的能力在神经退行性疾病中受损,但癌细胞可以利用其来支持其生长,存活和转移。这些对HSF结构,功能和调节的新见解应有助于开发新的疾病疗法以操纵该转录因子家族。

更新日期:2017-09-12
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