Overexpression of β-Catenin Induces Apoptosis Independent of Its Transactivation Function with LEF-1 or the Involvement of Major G1 Cell Cycle Regulators

β-Catenin promotes epithelial architecture by forming cell surface complexes with E-cadherin and also interacts with TCF/LEF-1 in the nucleus to control gene expression. By DNA transfection, we overexpressed β-catenin and/or LEF-1 in NIH 3T3 fibroblasts, corneal fibroblasts, corneal epithelia, uveal melanoma cells, and several carcinoma cell lines. In all cases (with or without LEF-1), the abundant exogenous β-catenin localizes to the nucleus and forms distinct nuclear aggregates that are not associated with DNA. Surprisingly, we found that with time (5–8 d after transfection) cells overexpressing β-catenin all undergo apoptosis. LEF-1 does not need to be present. Moreover, LEF-1 overexpression in the absence of exogenous β-catenin does not induce apoptosis, even though some endogenous β-catenin moves with the exogenous LEF-1 into the nucleus. TOPFLASH/FOPFLASH reporter assays showed that full-length β-catenin is able to induce LEF-1–dependent transactivation, whereas Arm β-catenin totally abolishes the transactivating function. However, Arm β-catenin, containing deletions of known LEF-1–transactivating domains, has the same apoptotic effects as full-length β-catenin. Overexpressed β-catenin also induces apoptosis in cells transfected with nuclear localization signal–deleted LEF-1 that localizes only in the cytoplasm. Thus, the apoptotic effects of overexpressed exogenous β-catenin do not rely on its transactivating function with nuclear LEF-1. Overexpressed δ-catenin, containing 10 Arm repeats, induces only minor apoptosis, suggesting that the major apoptotic effect may be due to domains specific to β-catenin as well as to Arm repeats. The absence of p53, Rb, cyclin D1, or E2F1 does not affect the apoptotic effect of overexpressed β-catenin, but Bcl-x(L) reduces it. We hypothesize that in vivo apoptosis of cells overexpressing β-catenin might be a physiological mechanism to eliminate them from the population.