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Antianoikis effect of nuclear factor-κb through up-regulated expression of osteoprotegerin, bcl-2, and iap-1

Toruner, Murat
; 
Fernandez-Zapico, Martin
; 
Sha, Jing Jing
; 
Pham, Linh
; 
Urrutia, Raul
; 
Egan, Laurence J.
Repository DOI
Publication Date
2006-01-05
Keywords
focal adhesion kinase, intestinal epithelial-cells, apoptosis-inducing ligand, ikk-beta, phosphatidylinositol 3-kinase, signaling pathway, cancer-cells, tnf-alpha, activation, survival
Type
Article
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Citation
Toruner, Murat; Fernandez-Zapico, Martin; Sha, Jing Jing; Pham, Linh; Urrutia, Raul; Egan, Laurence J. (2006). Antianoikis effect of nuclear factor-κb through up-regulated expression of osteoprotegerin, bcl-2, and iap-1. Journal of Biological Chemistry 281 (13), 8686-8696
Abstract
Epithelial cells undergo a form of apoptosis termed anoikis when they lose extracellular attachments. We evaluated the role of transcription factor NF-kappa B in the regulation of anoikis susceptibility of intestinal epithelial cells. Culture of rat intestinal epithelial cells in suspension induced NF-kappa B activation, which blocked the anoikis of those cells, as assessed by internucleosomal DNA fragmentation and caspase-3 cleavage. Activation of NF-kappa 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-kappa B polypeptide. NF-kappa 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-kappa 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-kappa B-inactive intestinal epithelial cells. Together, these findings have identified the molecular components of a previously unrecognized antianoikis pathway in intestinal epithelial cells.
Funder
Publisher
American Society for Biochemistry & Molecular Biology (ASBMB)
Publisher DOI
10.1074/jbc.m512178200
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (1)