Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis
Name
Dai, Chengkai, et al. -Loss of Tumor Suppressor Nf1 Activates Hsf1 to Promote Carcinogenesis.- JCI 122(2012)3742-54..pdf
Size
18.97 MB
Format
Adobe PDF
Checksum (MD5)
759fc275b4ddaf217574ae883da8992d
Author(s)
Dai, Chengkai
Santagata, Sandro
Tang, Zijian
Shi, Jiayuan
Cao, Junxia
Kwon, Hyoungtae
Bronson, Roderick T.
Whitesell, Luke
Lindquist, Susan
Date Issued
September 2012
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Citation
Dai, Chengkai, Sandro Santagata, Zijian Tang, Jiayuan Shi, Junxia Cao, Hyoungtae Kwon, Roderick T. Bronson, Luke Whitesell, and Susan Lindquist. “Loss of Tumor Suppressor NF1 Activates HSF1 to Promote Carcinogenesis.” J. Clin. Invest. 122, no. 10 (October 1, 2012): 3742–3754.
Version
Author's final manuscript
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[superscript –/–] 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1172/jci62727
