Mutations in the INK4a/ARF Melanoma Susceptibility Locus Functionally Impair p14ARF

Abstract

The INK4a/ARF locus encodes two cell cycle regulatory proteins, the cyclin-dependent kinase inhibitor, p16INK4a, and the p53 activator, p14ARF. Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Many of these mutations specifically impair p16INK4a, whereas mutations uniquely targeting p14ARF are rare. Nevertheless, the importance of p14ARF has not been excluded because more than 40% of INK4a/ARF alterations affect p16INK4a and p14ARF. We now report that p14ARF is functionally impaired in melanoma kindreds carrying INK4a/ARF mutations. Of the seven INK4a/ARF mutations tested, three altered the subcellular distribution of p14ARF and diminished the ability of p14ARF to activate the p53 pathway. This work establishes the importance of p14ARF in melanoma predisposition. Show more