TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB.
Tumor necrosis factor (TNF) is a therapeutic target in the treatment of inflammatory bowel disease; however, the exact role of TNF signaling in the colon epithelium remains unclear. We demonstrate that TNF activation of TNF receptor (R)1 stimulates both pro- and anti-apoptotic signaling pathways in the colon epithelium; however, TNFR1 protects against colon epithelial cell apoptosis following TNF exposure. To investigate anti-apoptotic signaling pathways downstream of TNFR1, we generated an intestinal epithelium-specific Raf knock-out mouse and identified Raf kinase as a key regulator of colon epithelial cell survival in response to TNF. Surprisingly, Raf promotes NF-kappaB p65 phosphorylation, independent of MEK signaling, to support cell survival. Taken together, these data demonstrate a novel pathway in which Raf promotes colon epithelial cell survival through NF-kappaB downstream of TNFR1 activation. Thus, further understanding of colon epithelial cell-specific TNFR signaling may result in the identification of new targets for inflammatory bowel disease treatment and define novel mediators of colitis-associated cancer.
Edelblum
Karen L
KL
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696, USA.
Goettel
Jeremy A
JA
Koyama
Tatsuki
T
McElroy
Steven J
SJ
Yan
Fang
F
Polk
D Brent
DB
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D019908:Proto-Oncogene Proteins c-raf