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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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F-Box Proteins / genetics*
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F-Box Proteins / metabolism
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F-Box-WD Repeat-Containing Protein 7
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Female
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Gene Expression Regulation, Neoplastic
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Genes, Reporter
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Glycogen Synthase Kinase 3 / genetics*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HEK293 Cells
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Heat Shock Transcription Factors
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Humans
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Luciferases / genetics
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Luciferases / metabolism
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Melanoma / genetics*
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 3 / genetics*
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Mitogen-Activated Protein Kinase 3 / metabolism
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Molecular Sequence Data
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Neoplasm Metastasis
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Neoplasm Transplantation
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Protein Processing, Post-Translational*
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Sequence Alignment
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Ubiquitin-Protein Ligases / genetics*
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Ubiquitin-Protein Ligases / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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HSF1 protein, human
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Heat Shock Transcription Factors
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Transcription Factors
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Luciferases
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Ubiquitin-Protein Ligases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Mitogen-Activated Protein Kinase 3
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Glycogen Synthase Kinase 3