Li Laiji, Chapman Kimberly, Hu Xiuying, Wong Annissa, Pasdar Manijeh
Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Mol Carcinog. 2007 Oct;46(10):824-38. doi: 10.1002/mc.20310.
Plakoglobin (Pg) and beta-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, beta-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 beta-catenin levels (Pg-NES) or a decrease in the level of total and nuclear beta-catenin associated with N-cadherin and alpha-catenin (Pg-WT and -NLS) cells. Bcl-2 expression also was induced in SCC9 cells overexpressing beta-catenin. In contrast, SCC9 cells expressing mutant Pg proteins, unable to interact with N-cadherin and alpha-catenin, had noticeably lower Bcl-2 levels. Our data suggest that Bcl-2 expression is induced by beta-catenin and modulated by Pg. We show that the inhibition of beta-catenin-dependent TCF transactivation had no effect on Bcl-2 levels, suggesting that induction of Bcl-2 expression by beta-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 beta-catenin.
桥粒芯蛋白（Pg）和β-连环蛋白是在细胞间黏附和信号传导中发挥作用的同源蛋白。这些蛋白与钙黏蛋白相关的形式介导黏附，而胞质/核形式则具有信号传导作用。尽管它们与共同的细胞伴侣相互作用，但β-连环蛋白具有充分记录的致癌潜力，而Pg的肿瘤抑制活性特征较少。我们之前表明，在缺乏Pg的SCC9细胞（SCC9-Pg-WT）中过表达Pg可诱导Bcl-2表达并抑制细胞凋亡。为了评估Pg在Bcl-2表达中的确切作用，我们构建并鉴定了表达具有受限细胞质（Pg-NES）或核（Pg-NLS）分布的Pg的SCC9转染子。我们发现，无论Pg的定位如何，Bcl-2均有表达，尽管其水平在SCC9-Pg-NLS细胞中显著较低。Bcl-2表达与核β-连环蛋白水平升高（Pg-NES）或与N-钙黏蛋白和α-连环蛋白相关的总β-连环蛋白和核β-连环蛋白水平降低（Pg-WT和-NLS）细胞一致。在过表达β-连环蛋白的SCC9细胞中也诱导了Bcl-2表达。相反，表达无法与N-钙黏蛋白和α-连环蛋白相互作用的突变Pg蛋白的SCC9细胞，其Bcl-2水平明显较低。我们的数据表明，Bcl-2表达由β-连环蛋白诱导并受Pg调节。我们发现抑制β-连环蛋白依赖性TCF反式激活对Bcl-2水平没有影响，这表明β-连环蛋白诱导Bcl-2表达及其受Pg调节可能涉及除TCF之外或之外还包括的其他因素。这些结果通过Pg作为致癌性β-连环蛋白的调节剂的作用，为Pg的肿瘤抑制活性提供了一种可能的机制。
