Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition

Abstract

THE cyclin-dependent kinase inhibitor p16 is a candidate tumour-suppressor protein that maps to a genomic locus strongly associated with familial melanoma and other tumour types ^1–3. Screening of primary tumours and linkage analysis of familial melanoma pedigrees have identified many potential mutations in p16, but the functional significance of these sequence variants has remained unclear^1,3–9. We report here that pi6 can act as a potent and specific inhibitor of progression through the Gl phase of the cell cycle, and we demonstrate that several tumour-derived alleles of p16 encode functionally compromised proteins. The ability of p16 to arrest cell-cycle progression generally correlates with inhibition of cyclin Dl/Cdk4 kinase activity in vitro, with two exceptions among the alleles tested. In vivo, the presence of functional retino-blastoma protein appears to be necessary but may not be sufficient to confer full sensitivity to p!6-mediated growth arrest. Our results provide support for the notion that pi6 is an important cell-cycle regulator whose inactivation contributes to the outgrowth of human tumours.