Uncoupling cancer mutations reveals critical timing of p53 loss in sarcomagenesis
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main article
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Author(s)
Young, Nathan P.
Crowley, Denise G.
Jacks, Tyler E
Date Issued
April 2011
Journal
Cancer Research
Publisher
American Association for Cancer Research
Citation
Young, N. P., D. Crowley, and T. Jacks. “Uncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis.” Cancer Research 71 (2011): 4040-4047.
Version
Author's final manuscript
Abstract
It is well accepted that cancer develops following the sequential accumulation of multiple alterations, but how the temporal order of events affects tumor initiation and/or progression remains largely unknown. Here, we describe a mouse model that allows for temporally distinct cancer mutations. By integrating a Flp-inducible allele of K-ras[superscript G12D] with established methods for Cre-mediated p53 deletion, we were able to separately control the mutation of these commonly associated cancer genes in vitro and in vivo. We show that delaying p53 deletion relative to K-ras[superscript G12D] activation reduced tumor burden in a mouse model of soft-tissue sarcoma, suggesting that p53 strongly inhibits very early steps of transformation in the muscle. Furthermore, using in vivo RNA interference, we implicate the p53 target gene p21 as a critical mediator in this process, highlighting cell-cycle arrest as an extremely potent tumor suppressor mechanism.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike 3.0
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DOI of Published Version
https://doi.org/10.1158/0008-5472.can-10-4563
