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Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis
Chengkai Dai, … , Luke Whitesell, Susan Lindquist
Chengkai Dai, … , Luke Whitesell, Susan Lindquist
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3742-3754. https://doi.org/10.1172/JCI62727.
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Research Article Oncology Article has an altmetric score of 1

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

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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.

Authors

Chengkai Dai, Sandro Santagata, Zijian Tang, Jiayuan Shi, Junxia Cao, Hyoungtae Kwon, Roderick T. Bronson, Luke Whitesell, Susan Lindquist

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Figure 1

Genetic compromise of NF1 induces the heat shock response.

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Genetic compromise of NF1 induces the heat shock response.
(A) Whole cel...
(A) Whole cell–based screen of a heat shock–oriented shRNA library. Heat shock reporter NIH3T3 cells arrayed in a 384-well format were infected with lentiviral constructs designed to target 175 candidate genes. 5 days later, reporter activation was measured by luciferase assay. The mean Z score calculated from 2 biological replicates per construct is plotted as a measure of activation relative to the entire population of wells assayed. 2 independent Nf1-targeted shRNAs that strongly activate the heat shock reporter are highlighted in bold. (B) Nf1 knockdown increased HSP72 expression in an immortalized MEF cell line. MEFs were stably transduced with shRNA39 and shRNA42, which target different regions of the Nf1 mRNA, and a scrambled control shRNA (Scr). NF1 and HSP72 protein levels were examined by immunoblotting. (C) Nf1 knockdown transcriptionally activates the heat shock response. Transcript levels of chaperones in Nf1-knockdown MEFs were measured by 2-step real-time quantitative RT-PCR technique. Transcript levels relative to cells transduced with scrambled control shRNA for each gene are expressed as fold changes (mean ± SD, n = 3 or 4). *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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