Antianoikis effect of nuclear factor-κB through up-regulated expression of osteoprotegerin, BCL-2, and IAP-1

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

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Epithelial cells undergo a form of apoptosis termed anoikis when they lose extracellular attachments. We evaluated the role of transcription factor NF-κB in the regulation of anoikis susceptibility of intestinal epithelial cells. Culture of rat intestinal epithelial cells in suspension induced NF-κB activation, which blocked the anoikis of those cells, as assessed by internucleosomal DNA fragmentation and caspase-3 cleavage. Activation of NF-κB 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-κB polypeptide. NF-κB 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-κB 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-κB-inactive intestinal epithelial cells. Together, these findings have identified the molecular components of a previously unrecognized antianoikis pathway in intestinal epithelial cells.

Original languageEnglish (US)
Pages (from-to)8686-8696
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number13
DOIs
StatePublished - Mar 31 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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