Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a 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 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.
Delmas
Véronique
V
Developmental Genetics of Melanocytes, UMR 146, Centre National de Recherche Scientifique-Institut Curie, 91405 Orsay Cedex, France.
Beermann
Friedrich
F
Martinozzi
Silvia
S
Carreira
Suzanne
S
Ackermann
Julien
J
Kumasaka
Mayuko
M
Denat
Laurence
L
Goodall
Jane
J
Luciani
Flavie
F
Viros
Amaya
A
Demirkan
Nese
N
Bastian
Boris C
BC
Goding
Colin R
CR
Larue
Lionel
L
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
D019941:Cyclin-Dependent Kinase Inhibitor p16; D051176:beta Catenin; D008156:Luciferases; D001616:beta-Galactosidase