Tissue-specific p19 Arf regulation dictates the response to oncogenic K-ras
Open Access
- 17 May 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (22), 10184-10189
- https://doi.org/10.1073/pnas.1004796107
Abstract
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-rasG12D in vivo has not been examined. Using compound mutant mice containing the ArfGFP reporter and the spontaneously activating K-rasLA2 allele, we have uncovered dramatic tissue specificity of K-rasG12D-dependent p19Arf up-regulation. Lung tumors, which can arise in the presence of functional p19Arf, rarely display p19Arf induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19Arf-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 p19Arf induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.Keywords
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