REGULATION OF INTRACELLULAR BETA-CATENIN LEVELS BY THE ADENOMATOUS POLYPOSIS-COLI (APC) TUMOR-SUPPRESSOR PROTEIN

The APC tumor-suppressor protein associates with beta-catenin, a cell adhesion protein that is upregulated by the WNT1 oncogene, We examined the effects of esogenous APC expression on the distribution and amoun t of beta-catenin in a colorectal cancer cell containing only mutant A PC. Expression of wild-type APC caused a pronounced reduction in total beta-catenin levels by eliminating an excessive supply of cytoplasmic beta-catenin indigenous to the SW480 colorectal cancer cell line. Thi s reduction was due to an enhanced rate of beta-catenin protein degrad ation. Truncated mutant APC proteins, characteristic of those associat ed with cancer, lacked this activity. Mutational analysis revealed tha t the central region of the APC protein, which is typically deleted or severely truncated in tumors, was responsible for the down-regulation of beta-catenin. These results suggest that the tumor-suppressor acti vity of mutant APC map be compromised due to a defect in its ability t o regulate beta-catenin.