Genetic dissection of melanoma pathways in the mouse

The frequent loss of the INK4a/ARF locus, encoding for both p16(INK4a) and p19(ARF) in, human melanoma, raises the question as to which INK4a/ARF gene product functions to suppress melanoma-genesis in vivo. Studies in the mou se have shown that activated RAS mutation can cooperate with INK4a(Delta2/3 ) deficiency (null for both p16(INK4a) and P19(ARF)) to promote development of melanoma, and these melanomas retain wild-type p53. Given the functiona l link between p19(ARF) and p53, we have shown shown that activated RAS can also cooperate with p53 deficiency to produce melanoma in the mouse Moreov er, genome-wide analysis of RAS-induced p53 mutant melanomas reveals altera tions of key components governing RB-regulated G1/S transition, such as c-M yc. These experimental findings suggest that both RE and p53 pathways funct ion to suppress melanocyte transformation in vivo in the mouse.