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J. Biol. Chem., Vol. 283, Issue 43, 29485-29494, October 24, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/43/29485    most recent M801269200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Edelblum, K. L. Articles by Polk, D. B. Search for Related Content PubMed PubMed Citation Articles by Edelblum, K. L. Articles by Polk, D. B. Social Bookmarking                      What's this?

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

Karen L. Edelblum, Jeremy A. Goettel, Tatsuki Koyama, Steven J. McElroy^¶, Fang Yan^||, and D. Brent Polk¹

From the Department of Cell and Developmental Biology, Department of Biostatistics, and ^¶Department of Pediatrics, Division of Neonatology, and the ^||Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696

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-B 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-B 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.

Received for publication, February 15, 2008 , and in revised form, August 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK56008 and DK66176 (to D. B. P.), T32GM008554 (CBMS training grant) (to K. L. E.), and DK58404 (through Vanderbilt University Digestive Disease Research Center). This work was also supported by Frank Revetta and the Vanderbilt Ingram Cancer Center (for ARIOL image analysis). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: 2215 Garland Ave, 1025 MRB IV, Nashville, TN 37232-0696. Tel.: 615-322-7449; Fax: 615-343-5323; E-mail: d-brent.polk{at}vanderbilt.edu.

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