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

ABSTRACT: 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.

SUBMITTER: Gomez-Pastor R

PROVIDER: S-EPMC5794010 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Gomez-Pastor Rocio R Burchfiel Eileen T ET Thiele Dennis J DJ

Nature reviews. Molecular cell biology 20170830 1

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 tha ...[more]

PMID: 28852220

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Project description:BackgroundRegulation of transcriptional activity of heat shock factor-1 (HSF1) is widely thought to be the main point of control for heat shock protein (Hsp) expression.ResultsGlutamine increases Hsf1 gene transcription in a C/EBP?-dependent manner and up-regulates HSF1 activity.ConclusionGlutamine is an activator for both HSF1 expression and transactivation.SignificanceGlutamine-induced HSF1 expression provides a novel mechanistic frame for HSF1-Hsp axis regulation. Heat shock transcription factor-1 (HSF1) is the master regulator for cytoprotective heat shock protein (Hsp) expression. It is widely thought that HSF1 expression is non-inducible, and thus the key control point of Hsp expression is regulation of the transactivation activity of HSF1. How HSF1 expression is regulated remains unknown. Herein we demonstrate that glutamine (Gln), a preferred fuel substrate for the gut, enhanced Hsp expression both in rat colonic epithelium in vivo and in cultured non-transformed young adult mouse colonic epithelial cells. This was associated with up-regulation of the transactivation activity of HSF1 via increased HSF1 trimerization, nuclear localization, DNA binding, and relative abundance of activating phosphorylation at Ser-230 of HSF1. More intriguingly, Gln enhanced HSF1 protein and mRNA expression and Hsf1 gene promoter activity. Within the -281/-200 region of the Hsf1 promoter, deletion of the putative CCAAT enhancer-binding protein (C/EBP) binding site abolished the HSF1 response to Gln. C/EBP? was further shown to bind to this 82-bp sequence both in vitro and in vivo. Gln availability strikingly altered the ratio of C/EBP? inhibitory and active isoforms, i.e. liver-enriched inhibitory protein and liver-enriched activating protein. Liver-enriched inhibitory protein and liver-enriched activating protein were further shown to be an independent repressor and activator, respectively, for Hsf1 gene transcription, and the relative abundance of these two C/EBP? isoforms was demonstrated to determine Hsf1 transcription. We show for the first time that Gln not only enhances the transactivation of HSF1 but also induces Hsf1 expression by activating its transcription in a C/EBP?-dependent manner.

Dataset Information

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

Publications

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

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