HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 13, 8686-8696, March 31, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/13/8686    most recent M512178200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Toruner, M. Articles by Egan, L. J. Search for Related Content PubMed PubMed Citation Articles by Toruner, M. Articles by Egan, L. J. Social Bookmarking                      What's this?

Antianoikis Effect of Nuclear Factor-B through Up-regulated Expression of Osteoprotegerin, BCL-2, and IAP-1^*

Murat Toruner, Martin Fernandez-Zapico, Jing Jing Sha, Linh Pham, Raul Urrutia, and Laurence J. Egan^¶1

From the Gastroenterology Research Unit and Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905 and the ^¶Department of Pharmacology and Therapeutics, National University of Ireland, Galway, Ireland

Epithelial cells undergo a form of apoptosis termed anoikis when they lose extracellular attachments. We evaluated the role of transcription factor NF-B in the regulation of anoikis susceptibility of intestinal epithelial cells. Culture of rat intestinal epithelial cells in suspension induced NF-B activation, which blocked the anoikis of those cells, as assessed by internucleosomal DNA fragmentation and caspase-3 cleavage. Activation of NF-B after the loss of extracellular attachments required focal adhesion kinase tyrosine 397 phosphorylation. This triggered a signaling cascade through phosphatidylinositol 3-kinase and AKT, to induce DNA binding of the RelA/p65 NF-B polypeptide. NF-B activated in this manner induced the up-regulated expression of a distinct program of genes that included osteoprotegerin, BCL-2, and IAP-1 (inhibitor of apoptosis protein-1). Chromatin immunoprecipitation experiments revealed that NF-B directly regulated the promoters of these 3 genes. Knock-down of the expression of osteoprotegerin, BCL-2, or inhibitor of apoptosis protein-1 by RNA interference showed that these factors inhibit anoikis, and genetic reconstitution of their expression alone or in combination restored normal levels of anoikis to NF-B-inactive intestinal epithelial cells. Together, these findings have identified the molecular components of a previously unrecognized antianoikis pathway in intestinal epithelial cells.

Received for publication, November 14, 2005 , and in revised form, January 4, 2006.

^* This work was supported by National Institutes of Health Grant DK60792 and a Crohn's and Colitis Foundation of America award (both to L. J. E.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Clinical Science Institute, University College Hospital, Galway, Ireland. Tel.: 353-91-495355; Fax: 353-91-495572.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. K. Decker, S. S. Abdelmoneim, U. Yaqoob, H. Hendrickson, J. Hormes, M. Bentley, H. Pitot, R. Urrutia, G. J. Gores, and V. H. Shah Nitric Oxide Regulates Tumor Cell Cross-Talk with Stromal Cells in the Tumor Microenvironment of the Liver Am. J. Pathol., October 1, 2008; 173(4): 1002 - 1012. [Abstract] [Full Text] [PDF]

				P. Secchiero, F. Corallini, E. Rimondi, C. Chiaruttini, M. G. di Iasio, A. Rustighi, G. Del Sal, and G. Zauli Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells Blood, February 1, 2008; 111(3): 1287 - 1294. [Abstract] [Full Text] [PDF]