TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB.

Edelblum KL, Goettel JA, Koyama T, McElroy SJ, Yan F, Polk DB
J Biol Chem. 2008 283 (43): 29485-94

PMID: 18713739 · PMCID: PMC2570867 · DOI:10.1074/jbc.M801269200

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.

MeSH Terms (15)

Animals Apoptosis Cells, Cultured Cell Survival Colon Epithelial Cells Mice Mice, Inbred C57BL Mice, Knockout Models, Biological NF-kappa B Phosphorylation Proto-Oncogene Proteins c-raf Receptors, Tumor Necrosis Factor, Type I Signal Transduction

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