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Nat Rev Mol Cell Biol. 2018 Jan;19(1):4-19. doi: 10.1038/nrm.2017.73. Epub 2017 Aug 30.

Regulation of heat shock transcription factors and their roles in physiology and disease.

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Department of Pharmacology and Cancer Biology, Duke University School of Medicine.
Department of Biochemistry, Duke University School of Medicine.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.


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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