Mutations in the INK4a/ARF Melanoma Susceptibility Locus Functionally Impair p14^ARF

The INK4a/ARF locus encodes two cell cycle regulatory proteins, the cyclin-dependent kinase inhibitor, p16^INK4a, and the p53 activator, p14^ARF. Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Many of these mutations specifically impair p16^INK4a, whereas mutations uniquely targeting p14^ARF are rare. Nevertheless, the importance of p14^ARF has not been excluded because more than 40% of INK4a/ARF alterations affect p16^INK4a and p14^ARF. We now report that p14^ARF is functionally impaired in melanoma kindreds carrying INK4a/ARF mutations. Of the seven INK4a/ARF mutations tested, three altered the subcellular distribution of p14^ARF and diminished the ability of p14^ARF to activate the p53 pathway. This work establishes the importance of p14^ARF in melanoma predisposition.