The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase

EMBO J. 1995 Nov 15;14(22):5618-25.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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*
  • Resting Phase, Cell Cycle / physiology
  • S Phase / physiology
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Adenomatous Polyposis Coli Protein
  • Cyclins
  • Cytoskeletal Proteins
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • CDK4 protein, human
  • Cdk2 protein, mouse
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases