THE TUMOR-SUPPRESSOR GENE-PRODUCT APC BLOCKS CELL-CYCLE PROGRESSION FROM G(0)/G(1) TO S-PHASE

The APC gene is mutated in familial adenomatous polyposis (FAP) as well as in sporadic colorectal tumours, The product of the APC gene is a 300 kDa cytoplasmic protein associated with the adherence junction protein catenin, Here we show that overexpression of APC blocks serum-induced cell cycle progression from G(0)G(1) to the S phase. Mutant APCs identified in FAP and/or colorectal tumours were less inhibitory and partially obstructed the activity of the normal APC, The cell-cycle blocking activity of APC was alleviated by the overexpression of cyclin E/CDK2 or cyclin D1/CDK4. Consistent with this result, kinase activity of CDK2 was significantly down-regulated in cells overexpressing APC although its synthesis remained unchanged, while CDK4 activity was barely affected. These results suggest that APC may play a role in the regulation of the cell cycle by negatively modulating the activity of cyclin-CDK complexes.