EXPRESSION OF WILD-TYPE ALPHA-CATENIN PROTEIN IN CELLS WITH A MUTANT ALPHA-CATENIN GENE RESTORES BOTH GROWTH-REGULATION AND TUMOR-SUPPRESSOR ACTIVITIES

Recent studies indicate that disruption of the E-cadherin-mediated cel l-cell adhesion system is frequently associated with human cancers of epithelial origin. Reduced levels of both E-cadherin and the associate d protein, alpha-catenin, have been reported in human tumors. This rep ort describes the characterization of a human ovarian carcinoma-derive d cell line (Ov2008) which expresses a novel mutant form of the alpha- catenin protein lacking the extreme N terminus of the wild-type protei n. The altered form of alpha-catenin expressed in Ov2008 cells fails t o bind efficiently to beta-catenin and is localized in the cytoplasm. Deletion mapping has localized the beta-catenin binding site on alpha- catenin between amino acids 46 and 149, which encompasses the same reg ion of the protein that is deleted in the Ov2008 variant. Restoration of inducible expression of the wild-type alpha-catenin protein in thes e cells caused them to assume the morphology typical of an epithelial sheet and retarded their growth in vitro. Additionally, the induction of alpha-catenin expression in Ov2008 cells injected into nude mice at tenuated the ability of these cells to form tumors. These observations support the classification of alpha-catenin as a growth-regulatory an d candidate tumor suppressor gene.