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Baeg, GH, Matsumine, A, Kuroda, T, Bhattacharjee, RN, Miyashiro, I, Toyoshima, K and Akiyama, T (1995) The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. EMBO J. 14:5618-25
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 G0/G1 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.
3T3 Cells; Adenomatous Polyposis Coli Protein; Animals; Base Sequence; CDC2-CDC28 Kinases; Cell Cycle/physiology; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases/antagonists & inhibitors; Cyclin-Dependent Kinases/genetics; Cyclin-Dependent Kinases/metabolism; Cyclins/genetics; Cyclins/metabolism; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/physiology; Down-Regulation; G0 Phase/physiology; G1 Phase/physiology; Genes, Tumor Suppressor; Humans; Mice; Molecular Sequence Data; Mutation; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins; S Phase/physiology; Time Factors; Tumor Cells, Cultured