The APC-hDLG Complex Negatively Regulates Cell Cycle Progression From the G0/G1 to S Phase

Oncogene. 2000 Jan 20;19(3):365-72. doi: 10.1038/sj.onc.1203309.

Abstract

The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in many sporadic colorectal tumors. The carboxyl-terminal S/TXV motif of the APC gene product interacts with the PDZ domain of hDLG, the human homolog of the Drosophila lethal (1) discs larige-1 (dlg) tumor suppressor. In the present study, we found that overexpression of hDLG suppresses cell proliferation by blocking cell cycle progression from the G0/G1 to S phase. This inhibition of cell cycle progression was abolished when the PDZ, SH3 or guanylate kinase-like domain of hDLG was mutated. Moreover, overexpression of these mutant hDLGs partially interfered with the cell cycle blocking activity of APC. Consistent with this result, mutant APC lacking the S/TXV motif exhibited weaker cell cycle blocking activity than the intact APC. These results suggest that APC-hDLG complex formation plays an important role in transducing the APC cell cycle blocking signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • COS Cells
  • Cell Cycle*
  • Drosophila Proteins*
  • G1 Phase
  • Genes, APC / physiology*
  • Genes, Tumor Suppressor*
  • Guanylate Kinases
  • Humans
  • Insect Proteins / physiology*
  • Mice
  • Nucleoside-Phosphate Kinase / chemistry
  • Nucleoside-Phosphate Kinase / physiology*
  • Resting Phase, Cell Cycle
  • S Phase
  • Tumor Suppressor Proteins*
  • src Homology Domains

Substances

  • Drosophila Proteins
  • Insect Proteins
  • Tumor Suppressor Proteins
  • dlg1 protein, Drosophila
  • Nucleoside-Phosphate Kinase
  • Guanylate Kinases