The transcription factor NF-kappaB plays a critical role in immune and inflammatory responses by augmenting the expression of many inducible, immediate response genes, including cytokines such as IL-1 and TNFa, pro-inflammatory mediators such as COX-2, adhesion molecules such as E-selectin, co-stimulatory molecules such as B7, and chemokines such as MCP-1. NF-kappaB acts as a critical co-ordinating element in the body's response to infection and injury, and thus is an important mediator of immune responses. The activation of NF-?B involves the signal-induced degradation of the lkappaB protein in cytosolic NF-kappaB:lkappaB complexes leading to the subsequent nuclear translocation of the released NF-kappaB. It has been assumed that nuclear translocation of NF-?B would be sufficient for activation of NF-kappaB-dependent genes. However, studies carried out in our laboratory have demonstrated that the p65 subunit of NF-kappaB has to be phosphorylated to become competent for transcription. In particular we discovered that the catalytic subunit of cyclic-AMP-dependent protein kinase was present in cytosolic NF-kappaB:lkappaB complexes and that degradation of lkappaB in response to inducers such as LPS led to phosphorylation of p65 at serine 276, a canonical site for PKA-phosphorylation. Recent reports from other laboratories have implicated other protein kinases and different phosphorylation sites on p65 in the regulation of NF-kappaB transcriptional activity. Recent studies have also implicated acetylation and deacetylation of both p65 and histones as crucial regulatory steps. To resolve the outstanding questions concerning the exact role of phosphorylation of NF-kappaB in regulating its activity we are proposing to undertake a systematic genetic and biochemical approach. We believe that the proposed studies will help clarify the underlying mechanism by which the activity of nuclear NF-kappaB is regulated and will open up the possibility of developing specific inhibitors targeting these nuclear events.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B (CMI)
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Mallia, Conrad M
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Yale University
Schools of Medicine
New Haven
United States
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Hayden, Matthew S; Ghosh, Sankar (2014) Regulation of NF-?B by TNF family cytokines. Semin Immunol 26:253-66
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