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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 2

NF1 loss activates HSF1 via elevated MAPK signaling.

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NF1 loss activates HSF1 via elevated MAPK signaling.
(A and B) Cytoplasm...
(A and B) Cytoplasmic and nuclear fractions were prepared from immortalized MEFs after overnight treatment with DMSO or 10 μM U0126. Blotting for cytoplasmic lactate dehydrogenase (LDH) and nuclear lamins A/C confirmed appropriate fractionation. (C and D) HSF1 was activated in primary Nf1-knockout MEFs. (E) MEK inhibition impaired HSF1 transcriptional activity. EGFP or HSF1 plasmids were transfected with pHSE–firefly luciferase reporter plasmid and pCMV–renilla luciferase plasmid into HEK293T cells. After 1 day, cells were treated with DMSO or 20 μM U0126 overnight. Firefly luciferase signals were normalized against renilla luciferase signals (mean ± SD; n = 6). (F) Dominant-negative MEK1 impaired p-Ser326. EGFP or MEK1AA plasmid was transfected into HEK293T cells; after 3 days, cells were harvested for immunoblotting. (G) Dominant-negative MEK1 impaired HSF1 transcriptional activity. In HEK293T cells, EGFP or MEK1AA plasmid was transfected with the luciferase reporter plasmids. HSF1 plasmid was further cotransfected with either EGFP or MEK1AA plasmid. 3 days after transfection, luciferase signals were measured (mean ± SD; n = 4). (H) Proteasomal inhibition caused HSF1 protein accumulation. MEFs were treated with DMSO or MG132 overnight. (I) HSF1 polyubiquitination was suppressed in Nf1-knockdown cells and reestablished after MEK inhibition. MEFs were treated with either DMSO or 20 μM U0126 overnight, and whole cell lysates were immunoprecipitated for HSF1. Normal rat IgG served as the control. Precipitates were immunoblotted for polyubiquitinated conjugates and HSF1. LC, light chain; WLC, whole cell lysates. P values were determined by Student’s t test.

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

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