Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation.
OBJECTIVE
Enterotoxigenic Bacteroides fragilis that secrete a zinc-dependent metalloprotease toxin termed the B. fragilis toxin (BFT) have been associated with acute diarrheal disease. BFT rapidly cleaves the extracellular domain of E-cadherin, leading to the complete degradation of the E-cadherin protein. E-cadherin is the primary intercellular adhesion protein of the zonula adherens, and its cytoplasmic domain associates with the nuclear signaling protein beta-catenin. The goal of this study was to examine if BFT triggers beta-catenin nuclear signaling in intestinal epithelial cells.


METHODS
Cell biologic and biochemical techniques were combined to address beta-catenin nuclear signaling stimulated by BFT.


RESULTS
Loss of membrane-associated E-cadherin after BFT treatment of human colonic epithelial cells (HT29/C1 clone) triggers beta-catenin nuclear localization within 3 hours. Subsequently, c-myc transcription and translation are induced and persistent cellular proliferation ensues, mediated in part by beta-catenin/T-cell factor-dependent transcriptional activation. Cellular proliferation is stimulated by as little as 5 x 10(-10) mol/L BFT.


CONCLUSIONS
To our knowledge, BFT is the first bacterial toxin reported to activate T-cell factor-dependent beta-catenin nuclear signaling in intestinal epithelial cells. These results suggest that genetic evolution of this common colonic commensal has rendered an organism with the potential to contribute to oncogenic transformation in the colon.
Wu
Shaoguang
S
Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Morin
Patrice J
PJ
Maouyo
Djik
D
Sears
Cynthia L
CL
D001427:Bacterial Toxins / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008666:Metalloendopeptidases / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors; D014018:Tissue Distribution / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D001427:Bacterial Toxins; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004768:Enterotoxins; D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; C405031:Bacteroides fragilis toxin; D008666:Metalloendopeptidases