Regulation of heat shock transcription factors and their roles in physiology and disease.
Regulation of heat shock transcription factors and their roles in physiology and disease.
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DOI：
10.1038/nrm.2017.73
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Thiele DJ
中科院分区：
文献类型：
--
作者：
Gomez-Pastor R;Burchfiel ET;Thiele DJ
热休克转录因子（heat shock transcription factors，HSFs）是近30年来发现的一类热应激基因的直接转录激活因子，编码热休克蛋白。公认的范式假定，HSF专门激活蛋白伴侣的表达，以响应通过识别被称为热休克元件的简单启动子结合位点而引起蛋白质错误折叠的条件。然而，我们现在认识到，哺乳动物家族的HSF包括蛋白质，独立地或一致地驱动组合基因调控事件，在不同的情况下激活或抑制转录。我们对HSF结构、翻译后修饰和HSF调节靶基因的广度的理解的进展揭示了令人兴奋的调节HSF的新机制，并揭示了它们在生理学和病理学中的作用。例如，HSF 1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，但可以被癌细胞利用以支持其生长、存活和转移。这些对HSF结构、功能和调控的新认识将有助于开发新的疾病治疗方法来操纵这个转录因子家族。
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.
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