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 mouse 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 functional 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 Moreover, genome-wide analysis of RAS-induced p53 mutant melanomas reveals alterations of key components governing RB-regulated G1/S transition, such as c-Myc. These experimental findings suggest that both RE and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.