Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo

Deletion of the INK4a/ARF locus at 9p21 is detected with high frequency in human melanoma. Within a short genomic distance, this locus encodes several proteins with established tumor-suppressor roles in a broad spectrum of cancer types. Several lines of evidence support the view that p10(INKa4) and p19(ARF) exert the tumor-suppressor activities of this locus, although their relative importance in specific cancer types such as melanoma has been less rigorously documented on the genetic level. Here, we exploit a well-defined mouse model of RAS-induced melanomas to examine the impact of germline p16(INK4a) or p19(ARF) nullizygosity on melanoma formation. We demonstrate that loss of either Ink4a/Arf product can cooperate with RAS activation to produce clinically indistinguishable melanomas. In line with the common phenotypic end point, we further show that RAS+ p16(INK4a)-/- melanomas sustain somatic inactivation of p19(ARF)-p53 and, correspondingly, that RAS+ p19(ARF)-/- melanomas experience high-frequency loss of p16(INK4a). These genetic studies provide definitive proof that p16(INK4a), and p19(ARF) cooperate to suppress the development of melanoma in vivo.