Tissue-specific p19[superscript Arf] regulation dictates the response to oncogenic K-ras
Author(s)
Young, Nathan P.; Jacks, Tyler E
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The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras[superscript G12D] in vivo has not been examined. Using compound mutant mice containing the Arf[superscript GFP] reporter and the spontaneously activating K-ras[superscript LA2] allele, we have uncovered dramatic tissue specificity of K-ras[superscript G12D]-dependent p19[superscript Arf] up-regulation. Lung tumors, which can arise in the presence of functional p19[superscript Arf], rarely display p19[superscript Arf] induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19[superscript Arf]-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19[superscript Arf] induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.
Date issued
2010-05Department
Koch Institute for Integrative Cancer Research at MITJournal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Young, N. P., and T. Jacks. “Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras.” Proceedings of the National Academy of Sciences 107, no. 22 (June 1, 2010): 10184-10189.
Version: Final published version
ISSN
0027-8424
1091-6490