Stockinger A, Eger A, Wolf J, Beug H, Foisner R
Department of Biochemistry and Molecular Cell Biology, Vienna Biocenter, University of Vienna, A-1030 Vienna, Austria.
J Cell Biol. 2001 Sep 17;154(6):1185-96. doi: 10.1083/jcb.200104036.
beta-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells, but it also forms nuclear complexes with high mobility group transcription factors. Using a mouse mammary epithelial cell system, we have shown previously that conversion of epithelial cells to a fibroblastoid phenotype (epithelial-mesenchymal transition) involves downregulation of E-cadherin and upregulation of beta-catenin transcriptional activity. Here, we demonstrate that transient expression of exogenous E-cadherin in both epithelial and fibroblastoid cells arrested cell growth or caused apoptosis, depending on the cellular E-cadherin levels. By expressing E-cadherin subdomains, we show that the growth-suppressive effect of E-cadherin required the presence of its cytoplasmic beta-catenin interaction domain and/or correlated strictly with the ability to negatively interfere with beta-catenin transcriptional activity. Furthermore, coexpression of beta-catenin or lymphoid enhancer binding factor-1 or T cell factor 3 with E-cadherin rescued beta-catenin transcriptional activity and counteracted E-cadherin-mediated cell cycle arrest. Stable expression of E-cadherin in fibroblastoid cells decreased beta-catenin activity and reduced cell growth. Since proliferating cells had a higher beta-catenin activity than G1 phase-arrested or contact-inhibited cells, we conclude that beta-catenin transcriptional activity is essential for cell proliferation and can be controlled by E-cadherin in a cell adhesion-independent manner.
β-连环蛋白对于上皮细胞中E-钙黏蛋白介导的细胞黏附至关重要，但它也与高迁移率族转录因子形成核复合物。我们先前利用小鼠乳腺上皮细胞系统表明，上皮细胞向成纤维样表型的转变（上皮-间质转化）涉及E-钙黏蛋白的下调和β-连环蛋白转录活性的上调。在此，我们证明，在上皮细胞和成纤维样细胞中瞬时表达外源性E-钙黏蛋白会抑制细胞生长或导致细胞凋亡，这取决于细胞内E-钙黏蛋白的水平。通过表达E-钙黏蛋白的亚结构域，我们表明E-钙黏蛋白的生长抑制作用需要其细胞质β-连环蛋白相互作用结构域的存在，和/或与负向干扰β-连环蛋白转录活性的能力严格相关。此外，β-连环蛋白或淋巴样增强子结合因子-1或T细胞因子3与E-钙黏蛋白共表达可挽救β-连环蛋白的转录活性，并抵消E-钙黏蛋白介导的细胞周期停滞。在成纤维样细胞中稳定表达E-钙黏蛋白会降低β-连环蛋白活性并减少细胞生长。由于增殖细胞的β-连环蛋白活性高于G1期停滞或接触抑制的细胞，我们得出结论，β-连环蛋白转录活性对于细胞增殖至关重要，并且可以由E-钙黏蛋白以不依赖细胞黏附的方式进行调控。
