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^Δ2/3 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 now 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 RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.