Abstract
Heat shock factor 1 (HSF1) is the master regulator of the heat shock response in eukaryotes, a very highly conserved protective mechanism. HSF1 function increases survival under a great many pathophysiological conditions. How it might be involved in malignancy remains largely unexplored. We report that eliminating HSF1 protects mice from tumors induced by mutations of the RAS oncogene or a hot spot mutation in the tumor suppressor p53. In cell culture, HSF1 supports malignant transformation by orchestrating a network of core cellular functions including proliferation, survival, protein synthesis, and glucose metabolism. The striking effects of HSF1 on oncogenic transformation are not limited to mouse systems or tumor initiation; human cancer lines of diverse origins show much greater dependence on HSF1 function to maintain proliferation and survival than their nontransformed counterparts. While it enhances organismal survival and longevity under most circumstances, HSF1 has the opposite effect in supporting the lethal phenomenon of cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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9,10-Dimethyl-1,2-benzanthracene
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Animals
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Carcinogens
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Expression Regulation, Neoplastic*
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Genotype
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Glucose / metabolism
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Heat Shock Transcription Factors
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Humans
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Methylnitronitrosoguanidine
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mutation
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Phenotype
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Protein Biosynthesis
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Proto-Oncogene Proteins c-sis / genetics
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Proto-Oncogene Proteins c-sis / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Signal Transduction / genetics
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Skin / metabolism*
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Skin / pathology
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Skin Neoplasms / chemically induced
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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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Tetradecanoylphorbol Acetate
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Time Factors
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transduction, Genetic
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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Carcinogens
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DNA-Binding Proteins
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HSF1 protein, human
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Heat Shock Transcription Factors
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Hsf1 protein, mouse
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Proto-Oncogene Proteins c-sis
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RNA, Small Interfering
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Transcription Factors
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Tumor Suppressor Protein p53
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Methylnitronitrosoguanidine
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9,10-Dimethyl-1,2-benzanthracene
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ras Proteins
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Glucose
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Tetradecanoylphorbol Acetate