Abstract
Intrinsic stress response pathways are frequently mobilized within tumor cells. The mediators of these adaptive mechanisms and how they contribute to carcinogenesis remain poorly understood. A striking example is heat shock factor 1 (HSF1), master transcriptional regulator of the heat shock response. Surprisingly, we found that loss of the tumor suppressor gene neurofibromatosis type 1 (Nf1) increased HSF1 levels and triggered its activation in mouse embryonic fibroblasts. As a consequence, Nf1-/- cells acquired tolerance to proteotoxic stress. This activation of HSF1 depended on dysregulated MAPK signaling. HSF1, in turn, supported MAPK signaling. In mice, Hsf1 deficiency impeded NF1-associated carcinogenesis by attenuating oncogenic RAS/MAPK signaling. In cell lines from human malignant peripheral nerve sheath tumors (MPNSTs) driven by NF1 loss, HSF1 was overexpressed and activated, which was required for tumor cell viability. In surgical resections of human MPNSTs, HSF1 was overexpressed, translocated to the nucleus, and phosphorylated. These findings reveal a surprising biological consequence of NF1 deficiency: activation of HSF1 and ensuing addiction to this master regulator of the heat shock response. The loss of NF1 function engages an evolutionarily conserved cellular survival mechanism that ultimately impairs survival of the whole organism by facilitating carcinogenesis.
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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Active Transport, Cell Nucleus
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Animals
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Cell Line, Tumor / metabolism
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Cell Transformation, Neoplastic / genetics*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Genes, Neurofibromatosis 1*
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Heat Shock Transcription Factors
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Hot Temperature
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Humans
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Leupeptins / toxicity
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MAP Kinase Signaling System
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Macrolides / toxicity
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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NIH 3T3 Cells
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nerve Sheath Neoplasms / pathology
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Neurofibromin 1 / deficiency*
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Neurofibromin 1 / physiology
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Phosphorylation
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Protein Processing, Post-Translational
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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RNA, Small Interfering / pharmacology
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Withanolides / toxicity
Substances
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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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Leupeptins
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Macrolides
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Neoplasm Proteins
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Neurofibromin 1
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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Transcription Factors
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Withanolides
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monorden
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withaferin A
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde