The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase.
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.
Ishidate
T
T
Department of Oncogene Research, Institute for Microbial Diseases, Osaka University, Suita, Japan.
Matsumine
A
A
Toyoshima
K
K
Akiyama
T
T
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D029721:Drosophila Proteins; D016193:G1 Phase; D017491:Genes, APC / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D051528:Guanylate Kinases; D006801:Humans; D019476:Insect Proteins / Q000502:physiology*; D051379:Mice; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry / Q000502:physiology*; D016192:Resting Phase, Cell Cycle; D016196:S Phase; D025521:Tumor Suppressor Proteins; D018909:src Homology Domains
D029721:Drosophila Proteins; D019476:Insect Proteins; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases