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ActivatingBRAFmutations and loss of wild-typeINK4Aexpression both occur at high frequencies in melanomas. Here, we present evidence thatBRAFandINK4Ahave different effects on melanogenesis, a marker of melanocytic differentiation. Human melanoma cell line 624Mel harbors mutations in bothBRAFandINK4A.Thein vitroandin vivogrowth of these cells was inhibited by either reduced expression of mutantBRAFusing stable retroviral RNA interference (RNAi) or retrovirus-mediated stable expression of wild-typeINK4AcDNA. Consistent with the observed growth inhibition, phosphorylation of S780 and S795 in pRB, both CDK4/6 targets, was suppressed in cells expressing either mutantBRAFRNAi or wild-typeINK4A.Interestingly, melanoma cells expressing mutantBRAFRNAi had increased pigmentation, produced more mature melanosomes and melanin and expressed higher levels of tyrosinase and tyrosinase-related protein-1, whereas melanogenesis was not induced by wild-typeINK4A.We found that the melanocyte lineage-specific master control protein microphthalmia-associated transcription factor was upregulated by inhibition of mutantBRAF,which may be the cause for the melanogenic effect ofBRAFRNAi. The results suggest that, although bothBRAFandINK4Alesions promote cell growth and tumor formation, mutantBRAFmay also induce dedifferentiation in melanoma cells. © 2005 Wiley-Liss, Inc.