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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

ABSTRACT: Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

SUBMITTER: Kourtis N

PROVIDER: S-EPMC4401662 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

Kourtis Nikos N Moubarak Rana S RS Aranda-Orgilles Beatriz B Lui Kevin K Aydin Iraz T IT Trimarchi Thomas T Darvishian Farbod F Salvaggio Christine C Zhong Judy J Bhatt Kamala K Chen Emily I EI Celebi Julide T JT Lazaris Charalampos C Tsirigos Aristotelis A Osman Iman I Hernando Eva E Aifantis Iannis I

Nature cell biology 20150301 3

Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FB ...[more]

PMID: 25720964

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Project description:Background: Cardiac diseases remain one of the leading causes of death globally, often linked to ischemic conditions that can affect cellular homeostasis and metabolism, which can lead to the development of cardiovascular dysfunction. Considering the effect of ischemic cardiomyopathy on the global population, it is vital to understand the impact of ischemia on cardiac cells and how ischemic conditions change different cellular functions through post-translational modification of cellular proteins. Methods: To understand the cellular function and fine-tuning during stress, we established an ischemia model using neonatal rat ventricular cardiomyocytes. Further, the level of cellular acetylation was determined by Western blotting and affinity chromatography coupled with liquid chromatography-mass spectroscopy. Results: Our study found that the level of cellular acetylation significantly reduced during ischemic conditions compared to normoxic conditions. Further, in mass spectroscopy data, 179 acetylation sites were identified in the proteins in ischemic cardiomyocytes. Among them, acetylation at 121 proteins was downregulated, and 26 proteins were upregulated compared to the control groups. Differentially, acetylated proteins are mainly involved in cellular metabolism, sarcomere structure, and motor activity. Additionally, a protein enrichment study identified that the ischemic condition impacted two major biological pathways: the acetyl-CoA biosynthesis process from pyruvate and the tricarboxylic acid cycle by deacetylation of the associated proteins. Moreover, most differential acetylation was found in the protein pyruvate dehydrogenase complex. Conclusions: Understanding the differential acetylation of cellular protein during ischemia may help to protect against the harmful effect of ischemia on cellular metabolism and cytoskeleton organization. Additionally, our study can help to understand the fine-tuning of proteins at different sites during ischemia.

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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

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FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

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FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

Publications

FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.

FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification.