p16(INK4a) expression and cooperates with N-Ras in melanoma development

Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16(Ink4a) gene. Melanomas also frequently exhibit constitutive activation of the Wnt/beta-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized beta-catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized beta-catenin bypasses the requirement for p16Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.C1 Inst Curie, CNRS, UMR 146, F-91405 Orsay, France.Swiss Inst Expt Canc Res, Natl Ctr Competence Res Mol Oncol, CH-1066 Epalinges, Switzerland.Ecole Polytech Fed Lausanne, Sch Sci, CH-1066 Epalinges, Switzerland.Marie Curie Res Inst, Signalling & Dev Lab, Surrey RH8 OTL, England.Univ Calif San Francisco, Ctr Comprehens Canc, Dept Dermatol, San Francisco, CA 94143 USA.Univ Calif San Francisco, Ctr Comprehens Canc, Dept Pathol, San Francisco, CA 94143 USA.Pamukkale Univ, Tip Fak, Patol Anabilim Dali, TR-20003 Kinikli Denizli, Turkey