A P18 MUTANT DEFECTIVE IN CDK6 BINDING IN HUMAN BREAST-CANCER CELLS

Progression from G(1) to the S-phase of the cell cycle is controlled b y a family of low molecular weight cyclin-dependent kinase (CDK) inhib itors. The importance of these proteins in cell growth control is unde rscored by the observation that some members of this family are delete d or mutated in human cancers. For example, the gene encoding the CDK inhibitor p18 is located on a segment of chromosome 1 that is often ab normal in human breast tumors. We have identified an alanine to prolin e substitution at codon 72 of the p18 gene in BT-20 human breast cance r cells. This mutation abrogates the ability of p18 to interact with C DK6 and renders p18 deficient in suppressing cell growth in a colony f ormation assay. Our results suggest that p18 inactivation by point mut ations may contribute to deregulated growth control in certain cell li nes and/or tumors.