Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras.
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(G12D) in vivo has not been examined. Using compound mutant mice containing the Arf(GFP) reporter and the spontaneously activating K-ras(LA2) allele, we have uncovered dramatic tissue specificity of K-ras(G12D)-dependent p19(Arf) up-regulation. Lung tumors, which can arise in the presence of functional p19(Arf), rarely display p19(Arf) induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19(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(Arf) induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.
Young
Nathan P
NP
Koch Institute for Integrative Cancer Research and Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jacks
Tyler
T
D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009928:Organ Specificity; D034622:RNA Interference; D000071796:SMARCB1 Protein; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
C417743:Cdkn2a protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse