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 adenomatou s 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, t he human homolog of the Drosophila lethal (I) discs large-1 (dlg) tumor sup pressor. In the present study, we found that overexpression of hDLG suppres ses 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, ove rexpression of these mutant hDLGs partially interfered with the cell cycle blocking activity of APC. Consistent with this result, mutant APC lacking t he S/TXV motif exhibited weaker cell cycle blocking activity than the intac t APC, These results suggest that APC-hDLG complex formation plays an impor tant role in transducing the APC cell cycle blocking signal.