title: Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development.
abstract: 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 p16(Ink4a) promoter. Significantly, in a novel mouse model for melanoma, stabilized beta-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.
authors.affiliation: Developmental Genetics of Melanocytes, UMR 146, Centre National de Recherche Scientifique-Institut Curie, 91405 Orsay Cedex, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Delmas
authors.forename: Friedrich
authors.initials: F
authors.lastname: Beermann
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinozzi
authors.forename: Suzanne
authors.initials: S
authors.lastname: Carreira
authors.forename: Julien
authors.initials: J
authors.lastname: Ackermann
authors.forename: Mayuko
authors.initials: M
authors.lastname: Kumasaka
authors.forename: Laurence
authors.initials: L
authors.lastname: Denat
authors.forename: Jane
authors.initials: J
authors.lastname: Goodall
authors.forename: Flavie
authors.initials: F
authors.lastname: Luciani
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.forename: Nese
authors.initials: N
authors.lastname: Demirkan
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D020868:Gene Silencing; D011905:Genes, ras; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D014162:Transfection; D051176:beta Catenin / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D051176:beta Catenin; D008156:Luciferases; D001616:beta-Galactosidase