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Modulation of the oncogenic potential of β‐catenin by the subcellular distribution of plakoglobin
Author(s) -
Li Laiji,
Chapman Kimberly,
Hu Xiuying,
Wong Annissa,
Pasdar Manijeh
Publication year - 2007
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20310
Subject(s) - plakoglobin , biology , catenin , microbiology and biotechnology , transactivation , beta catenin , cadherin , nuclear localization sequence , cytoplasm , signal transduction , cell , wnt signaling pathway , gene expression , biochemistry , gene
Plakoglobin (Pg) and β‐catenin are homologous proteins that function in cell–cell adhesion and signaling. The cadherin‐associated form of these proteins mediates adhesion, whereas the cytosolic/nuclear form has a signaling role. Despite their interactions with common cellular partners, β‐catenin has a well‐documented oncogenic potential while Pg has a less characterized tumor suppressor activity. We showed previously that Pg overexpression in Pg‐deficient SCC9 cells (SCC9‐Pg‐WT) induced Bcl‐2 expression and inhibited apoptosis. To assess the exact role of Pg in Bcl‐2 expression, we generated and characterized SCC9 transfectants expressing Pg with a restricted cytoplasmic (Pg‐NES) or nuclear (Pg‐NLS) distribution. We show that Bcl‐2 was expressed regardless of Pg localization, although its level was substantially lower in SCC9‐Pg‐NLS cells. Bcl‐2 expression coincided with increased nuclear β‐catenin levels (Pg‐NES) or a decrease in the level of total and nuclear β‐catenin associated with N‐cadherin and α‐catenin (Pg‐WT and ‐NLS) cells. Bcl‐2 expression also was induced in SCC9 cells overexpressing β‐catenin. In contrast, SCC9 cells expressing mutant Pg proteins, unable to interact with N‐cadherin and α‐catenin, had noticeably lower Bcl‐2 levels. Our data suggest that Bcl‐2 expression is induced by β‐catenin and modulated by Pg. We show that the inhibition of β‐catenin‐dependent TCF transactivation had no effect on Bcl‐2 levels, suggesting that induction of Bcl‐2 expression by β‐catenin and its modulation by Pg may involve factors other than, or in addition, to, TCF. These results provide a possible mechanism for the tumor suppressor activity of Pg via its role as a regulator of the oncogenic potential β‐catenin. © 2007 Wiley‐Liss, Inc.