Tissue-specific p19[superscript Arf] regulation dictates the response to oncogenic K-ras
Year: 2010
Type: article
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-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.
Authors: Nathan P. Young, Tyler Jacks
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1517628566