Sun Jun, Hobert Michael E, Rao Anjali S, Neish Andrew S, Madara James L
Dept. of Pathology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G220-7. doi: 10.1152/ajpgi.00498.2003. Epub 2004 Feb 5.
The mucosal lining of the human intestine is constantly bathed in a milieu of commensal gut flora, the vast majority of these being nonpathogenic microorganisms. Here, we demonstrate that microbial-epithelial cell interactions not only affect proinflammatory pathways but also influence beta-catenin signaling, a key component in regulating epithelial cell proliferation. The nonpathogenic Salmonella strain PhoP(c) activates the beta-catenin signaling pathway of human epithelia via a blockade of beta-catenin degradation. Normal beta-catenin ubiquitination necessary for constitutive beta-catenin degradation is abolished, allowing the accumulation and translocation of beta-catenin to the nucleus. Transcriptional activation mediated by the beta-catenin/T cell factor complex increases c-myc expression and enhances cell proliferation. We also show that the Salmonella effector protein AvrA is involved in modulating this beta-catenin activation. These data suggest that nonvirulent bacterial-epithelial interactions can influence beta-catenin signaling and cell growth control in a manner previously unsuspected.
人类肠道的黏膜层持续浸润在共生肠道菌群的环境中，其中绝大多数是无致病性的微生物。在此，我们证明微生物与上皮细胞的相互作用不仅影响促炎途径，还会影响β-连环蛋白信号传导，这是调节上皮细胞增殖的关键组成部分。无致病性的沙门氏菌菌株PhoP(c) 通过阻断β-连环蛋白降解来激活人类上皮细胞的β-连环蛋白信号通路。组成型β-连环蛋白降解所必需的正常β-连环蛋白泛素化被消除，使得β-连环蛋白得以积累并转运至细胞核。由β-连环蛋白/T细胞因子复合物介导的转录激活增加了c-myc的表达并增强了细胞增殖。我们还表明，沙门氏菌效应蛋白AvrA参与调节这种β-连环蛋白的激活。这些数据表明，无毒细菌与上皮细胞的相互作用能够以一种先前未被怀疑的方式影响β-连环蛋白信号传导和细胞生长控制。
