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

Abstract

␤-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 ␤-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 ␤-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 ␤-catenin all undergo apoptosis. LEF-1 does not need to be present. Moreover, LEF-1 overexpression in the absence of exogenous ␤-catenin does not induce apoptosis, even though some endogenous ␤-catenin moves with the exogenous LEF-1 into the nucleus. TOP-FLASH/FOPFLASH reporter assays showed that full-length ␤-catenin is able to induce LEF-1-dependent transactivation, whereas Arm ␤-catenin totally abolishes the transactivating function. However, Arm ␤-catenin, containing deletions of known LEF-1-transactivating domains, has the same apoptotic effects as full-length ␤-catenin. Overexpressed ␤-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 ␤-catenin do not rely on its transactivating function with nuclear LEF-1. Overexpressed ␦-catenin, containing 10 Arm repeats, induces only minor apoptosis, suggesting that the major apoptotic effect may be due to domains specific to ␤-catenin as well as to Arm repeats. The absence of p53, Rb, cyclin D1, or E2F1 does not affect the apoptotic effect of overexpressed ␤-catenin, but Bcl-x(L) reduces it. We hypothesize that in vivo apoptosis of cells overexpressing ␤-catenin might be a physiological mechanism to eliminate them from the population.

A Role for the β-Catenin/T-Cell Factor Signaling Cascade in Vascular Remodeling

“…26 The role of ␤-catenin in apoptotic regulation appears to be cell-type specific. [27][28][29] In line with our data, upregulation of the ␤-catenin/Tcf-4 signaling pathway has been demonstrated to inhibit apoptosis in fibroblasts. 27 However, recent work has reported that ␤-catenin promotes apoptosis in other cell types.…”

“…27 However, recent work has reported that ␤-catenin promotes apoptosis in other cell types. 28,29 The disparity concerning the pro-or antiapoptotic role of ␤-catenin in different cell types is not surprising to the field of vascular biology given that numerous factors, including nitric oxide, glucose, and TGF␤, have opposing effects on vascular endothelial cells compared with VSMCs. 2 Our work demonstrates that the ability of ␤-catenin to promote survival and activate cyclin D1 was mediated through Tcf-4.…”

A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

“…However, a proapoptotic role of HGF (Arakaki et al, 1998;Matteucci et al, 2003;Rasola et al, 2004) and b-catenin (Kim et al, 2000;van Gijn et al, 2001;Edlund et al, 2005) was also reported in several models. Here, we show that the HGFR transduction axis and the b-catenin/TCF pathway cooperate in underpinning survival signals, whose importance probably increases during carcinoma progression.…”

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

“…Kim et al reported that overexpression of ␤-catenin induced apoptosis independent of its transactivation function or the involvement of G1 cell cycle regulators. 29 They transfected NIH 3T3 cells as well as tumor cell lines (colon carcinomas, an ovarian tumor, and a uveal melanoma) with wild-type ␤-catenin DNA and observed the apoptosis in those cells overexpressing ␤-catenin. Collectively, in NSCLCs, accumulated ␤-catenin in the cytoplasm and/or nucleus with might act favorably to overcome the activation of proliferative signals and thus have no or little oncogenic effect via activation of the Wnt pathway, unlike in colon carcinomas or HCCs.…”