Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adenomatous Polyposis Coli Protein
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Animals
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Base Sequence
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CDC2-CDC28 Kinases*
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Cell Cycle / physiology*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism
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Cyclins / genetics
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Cyclins / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / physiology*
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Down-Regulation
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G1 Phase / physiology
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Genes, Tumor Suppressor*
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Humans
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Mice
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Molecular Sequence Data
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Mutation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins*
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Resting Phase, Cell Cycle / physiology
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S Phase / physiology
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Time Factors
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Tumor Cells, Cultured
Substances
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Adenomatous Polyposis Coli Protein
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Cyclins
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Cytoskeletal Proteins
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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CDK4 protein, human
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Cdk2 protein, mouse
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases