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Vol. 11, Issue 10, 3509-3523, October 2000
-Catenin Induces Apoptosis Independent
of Its Transactivation Function with LEF-1 or the Involvement of Major
G1 Cell Cycle Regulators
Department of Cell Biology, Harvard Medical School, Boston,
Massachusetts 02115.
-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.
TOPFLASH/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.
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