TUMOR-DERIVED P16 ALLELES ENCODING PROTEINS DEFECTIVE IN CELL-CYCLE INHIBITION

THE cyclin-dependent kinase inhibitor p16 is a candidate tumour-suppre ssor protein that maps to a genomic locus strongly associated with fam ilial melanoma and other tumour types(1-3). Screening of primary tumou rs and linkage analysis of familial melanoma pedigrees have identified many potential mutations in p16, but the functional significance of t hese sequence variants has remained unclear(1,3-9). We report here tha t p16 can act as a potent and specific inhibitor of progression throug h the G1 phase of the cell cycle, and we demonstrate that several tumo ur-derived alleles of p16 encode functionally compromised proteins. Th e ability of p16 to arrest cell-cycle progression generally correlates with inhibition of cyclin D1/Cdk4 kinase activity irt vitro, with two exceptions among the alleles tested. In vivo, the presence of functio nal retinoblastoma protein appears to be necessary but may not be suff icient to confer full sensitivity to p16-mediated growth arrest. Our r esults provide support for the notion that p16 is an important cell-cy cle regulator whose inactivation contributes to the outgrowth of human tumours.