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MBC in Press, published online ahead of print January 3, 2007
Mol. Biol. Cell 10.1091/mbc.E06-03-0217

A more recent version of this article appeared on March 1, 2007
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Submitted on March 21, 2006
Revised on December 18, 2006
Accepted on December 22, 2006

Adipocyte Enhancer-binding Protein-1 Promotes Macrophage Inflammatory Responsiveness by Up-Regulating NF-{kappa}B via I{kappa}B{alpha} Negative Regulation

Amin Majdalawieh, Lei Zhang, and Hyo-Sung Ro

Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5

Monitoring Editor: William Tansey

NF-{kappa}B subunits comprise a family of eukaryotic transcription factors that are critically involved in cell proliferation, inflammation, and apoptosis. Under basal conditions, NF-{kappa}B subunits are kept under inhibitory regulation by physical interaction with NF-{kappa}B inhibitors (I{kappa}B subunits) in the cytosol. On stimulation, I{kappa}B subunits become phosphorylated, ubiquitinated, and subsequently degraded, allowing NF-{kappa}B subunits to translocate to the nucleus and bind as dimers to {kappa}B responsive elements of target genes. Previously, we have shown that AEBP1 enhances macrophage inflammatory responsiveness by inducing the expression of various proinflammatory mediators. Herein, we provide evidence suggesting that AEBP1 manifests its proinflammatory function by up-regulating NF-{kappa}B activity via hampering I{kappa}B{alpha}, but not I{kappa}B{beta}, inhibitory function through protein-protein interaction mediated by the discoidin-like domain (DLD) of AEBP1. Such interaction renders I{kappa}B{alpha} susceptible to enhanced phosphorylation and degradation, subsequently leading to augmented NF-{kappa}B activity. Collectively, we propose a novel molecular mechanism whereby NF-{kappa}B activity is modulated by means of protein-protein interaction involving AEBP1 and I{kappa}B{alpha}. Moreover, our study provides a plausible mechanism explaining the differential regulatory functions exhibited by I{kappa}B{alpha} and I{kappa}B{beta} in various cell types. We speculate that AEBP1 may serve as a potential therapeutic target for the treatment of various chronic inflammatory diseases and cancer.

Address correspondence to: Hyo-Sung Ro (hsro{at}dal.ca)






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