Invasive melanoma in Cdk4-targeted mice

Many human tumors harbor mutations that result in deregulation of Cdk4 acti vity. Most of these mutations involve overexpression of D-type cyclins and inactivation of INK4 inhibitors. In addition, a mutation in the Cdk4 protei n has been described in patients with familial melanoma (Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., et al. (1995) Science 269, 128 1-1284; Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., et a l. (11996) Nat. Genet. 12, 97-99). This mutation, R24C, renders the Cdk4 pr otein insensitive to inhibition by INK4 proteins including p16(INK4a), a ma jor candidate for the melanoma susceptibility locus. Here we show that knoc k-in mice expressing a Cdk4 R24C allele are highly susceptible to melanoma development after specific carcinogenic treatments. These tumors do not hav e mutations in the p19(ARF)/p53 pathway, suggesting a specific involvement of the p16(INK4a)/ Cdk41/Rb pathway in melanoma development. Moreover, by u sing targeted mice deficient for other INK4 inhibitors, we show that deleti on of p18(INK4c) but not of p15(INK4b) confers proliferative advantage to m elanocytic tumor growth. These results provide an experimental scenario to study the role of Cdk4 regulation in melanoma and to develop novel therapeu tic approaches to control melanoma progression.