Bacterial activation of beta-catenin signaling in human epithelia.
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.
Sun
Jun
J
Dept. of Pathology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. jsun@bsd.uchicago.edu
Hobert
Michael E
ME
Rao
Anjali S
AS
Neish
Andrew S
AS
Madara
James L
JL
D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D001692:Biological Transport; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology*; D018014:Gene Transfer Techniques; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D051381:Rats; D012480:Salmonella Infections / Q000378:metabolism; D012486:Salmonella typhimurium / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051176:beta Catenin
C405989:AvrA protein, Salmonella dublin; C487891:AvrA protein, Salmonella typhimurium; D001426:Bacterial Proteins; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D014157:Transcription Factors; D025801:Ubiquitin; D051176:beta Catenin