Xie Huimin, Huang Zhaofeng, Sadim Maureen S, Sun Zuoming
Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
J Immunol. 2005 Dec 15;175(12):7981-8. doi: 10.4049/jimmunol.175.12.7981.
CD4+CD8+ double-positive (DP) thymocytes, which are extremely sensitive to apoptosis, specifically up-regulate Bcl-xL to extend their lifespan. Deletion of the Bcl-xL gene leads to premature apoptosis of the thymocytes. In this study, we show that stabilization of beta-catenin, a critical coactivator for T cell factor (TCF), enhances DP thymocyte survival via up-regulating Bcl-xL. Spontaneous or glucocorticoid-induced thymocyte apoptosis was associated with reduced levels of beta-catenin and Bcl-xL. Transgenic expression of a stabilized beta-catenin protected DP thymocytes from both spontaneous and glucocorticoid-induced apoptosis, resulting in significantly increased thymic cellularity. Compared with the wild-type mice, both protein and transcript levels of Bcl-xL were significantly increased in thymocytes of beta-catenin transgenic mice. In addition, TCF-1 as well as beta-catenin were able to stimulate transcriptional activity of the reporter driven by a Bcl-xL promoter. beta-Catenin/TCF is thus able to act as a signal to up-regulate Bcl-xL levels in DP thymocytes, resulting in their enhanced survival.
对凋亡极为敏感的CD4⁺CD8⁺双阳性（DP）胸腺细胞会特异性地上调Bcl-xL以延长其寿命。Bcl-xL基因的缺失会导致胸腺细胞过早凋亡。在本研究中，我们发现β-连环蛋白（一种T细胞因子（TCF）的关键共激活因子）的稳定化通过上调Bcl-xL来增强DP胸腺细胞的存活。自发性或糖皮质激素诱导的胸腺细胞凋亡与β-连环蛋白和Bcl-xL水平降低有关。稳定化β-连环蛋白的转基因表达可保护DP胸腺细胞免受自发性和糖皮质激素诱导的凋亡，从而使胸腺细胞数量显著增加。与野生型小鼠相比，β-连环蛋白转基因小鼠胸腺细胞中Bcl-xL的蛋白质和转录水平均显著升高。此外，TCF-1以及β-连环蛋白能够刺激由Bcl-xL启动子驱动的报告基因的转录活性。因此，β-连环蛋白/TCF能够作为一种信号上调DP胸腺细胞中Bcl-xL的水平，从而提高其存活率。
