TNFR1 Promotes Tumor Necrosis Factor-mediated Mouse Colon Epithelial Cell Survival through RAF Activation of NF-κB

Karen L Edelblum; Jeremy A Goettel; Tatsuki Koyama; Steven J McElroy; Fang Yan; D. Brent Polk

doi:10.1074/jbc.M801269200

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TNFR1 Promotes Tumor Necrosis Factor-mediated Mouse Colon Epithelial Cell Survival through RAF Activation of NF-κB

Journal article

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TNFR1 Promotes Tumor Necrosis Factor-mediated Mouse Colon Epithelial Cell Survival through RAF Activation of NF-κB

Karen L Edelblum, Jeremy A Goettel, Tatsuki Koyama, Steven J McElroy, Fang Yan and D. Brent Polk

The Journal of biological chemistry, Vol.283(43), pp.29485-29494

10/24/2008

DOI: 10.1074/jbc.M801269200

PMCID: PMC2570867

PMID: 18713739

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Abstract

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-κB 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-κB 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.

Details

Title: Subtitle: TNFR1 Promotes Tumor Necrosis Factor-mediated Mouse Colon Epithelial Cell Survival through RAF Activation of NF-κB
Creators: Karen L Edelblum - Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696
Jeremy A Goettel - Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696
Tatsuki Koyama - Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696
Steven J McElroy - Department of Pediatrics, Division of Neonatology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696
Fang Yan - Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696
D. Brent Polk - Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.283(43), pp.29485-29494
DOI: 10.1074/jbc.M801269200
PMID: 18713739
PMCID: PMC2570867
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Grant note: DK66176; T32GM008554; DK58404 / Frank Revetta and the Vanderbilt Ingram Cancer Center DK56008 / National Institutes of Health
Language: English
Date published: 10/24/2008
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics
Record Identifier: 9984093235002771

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