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-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development

¹ Developmental Genetics of Melanocytes, UMR 146, Centre National de la Recherche Scientifique (CNRS)-Institut Curie, 91405 Orsay Cedex, France; ² The Swiss Institute for Experimental Cancer Research (ISREC), Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, 1066 Epalinges, Switzerland; ³ Ecole Polytechnique Fédérale de Lausanne (EPFL) School of Sciences, CH-1066 Epalinges, Switzerland; ⁴ Signalling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, United Kingdom; ⁵ Department of Dermatology and Department of Pathology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA; ⁶ Pamukkale Üniversitesi, Tp Fakültesi, Patoloji Anabilim Dal, Knkl-Denizli 20003, Turkey

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/-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized -catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16^Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized -catenin bypasses the requirement for p16^Ink4a 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.

[Keywords: Mitf; Wnt; senescence; development; tumor suppressor; oncogene]]

Received July 23, 2007; revised version accepted September 27, 2007.

E-MAIL lionel.larue{at}curie.fr; FAX 33-1-69-86-71-09.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.450107

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