The NF-kappaB (NF-?B) family of dimeric transcription factors regulates diverse physiological processes including immune and inflammatory responses, cell proliferation and survival. The combinatorial NF-?B dimers are formed from five family members;p50, p52, RelA (p65), cRel and RelB. These dimers regulate transcription by binding to specific DNA sequences of target genes known as ?B sites. The long term goals of our laboratories are to understand how NF-?B dimers function specifically in gene regulation. To achieve that goal, we have pursued a variety of approaches ranging from the biophysical to the genetic. Recent studies have emphasized the role of post-translational modifications of NF-?B dimers and the role of dimer-specific co-activators in regulating specific target genes. The focus of this proposal is to examine transcriptional regulation by phosphorylation and coactivator recognition events. We employ genetic, genomic, biochemical and biophysical approaches to investigate the two NF-?B family members that play the most prominent roles in human disease: RelA and p52.
In aim 1 experiments are designed to investigate the mechanisms of transcriptional control by the RelA:CBP/p300 complex. Several reports have demonstrated the importance of RelA phosphorylation, and CBP/p300 binding in target gene regulation. Other studies have revealed that the effect of this modification/interaction is not global. Each modification/interaction affects the expression of only a subset of genes in stimulus and cell type specific manner. In this study we will investigate the role of RelA phosphorylation and CBP/p300 interaction mechanism and its impact on gene regulation.
In aim 2 Biophysical and in vivo experiments are designed to study the transcriptional control by the cancer-associated p52:Bcl3 complex. As homodimers, NF-?B p52 and p50 have been reported to associate with Bcl3 to activate transcription, and as such they play critical roles in immune organogenesis and tolerance. The goal of this aim is to investigate the molecular basis of how p52 homodimer associates with Bcl3 and the specificity of the interaction, and if these complexes target a subset of ?B sequences. Public Health Relevance: The NF-?B family of dimeric transcription activators, which regulates a large number of genes, is critical for maintaining normal cell physiology. The focus of this proposal is to understand the regulation of promoter and transcriptional coactivator recognition by the NF-?B dimers.

Public Health Relevance

The NF-?B family of dimeric transcription activators, which regulates a large number of genes, is critical for maintaining normal cell physiology. The focus of this proposal is to understand the regulation of promoter and transcriptional coactivator recognition by the NF-?B dimers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085490-04
Application #
8260199
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Marino, Pamela
Project Start
2009-07-01
Project End
2013-10-30
Budget Start
2012-05-01
Budget End
2013-10-30
Support Year
4
Fiscal Year
2012
Total Cost
$296,533
Indirect Cost
$95,612
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Vu, Don; Huang, De-Bin; Vemu, Annapurna et al. (2013) A structural basis for selective dimerization by NF-?B RelB. J Mol Biol 425:1934-45
Ghosh, Gourisankar; Wang, Vivien Ya-Fan; Huang, De-Bin et al. (2012) NF-?B regulation: lessons from structures. Immunol Rev 246:36-58
Cheng, Christine S; Feldman, Kristyn E; Lee, James et al. (2011) The specificity of innate immune responses is enforced by repression of interferon response elements by NF-ýýB p50. Sci Signal 4:ra11
Ho, Jessica Q; Asagiri, Masataka; Hoffmann, Alexander et al. (2011) NF-?B potentiates caspase independent hydrogen peroxide induced cell death. PLoS One 6:e16815
Huxford, Tom; Ghosh, Gourisankar (2009) A structural guide to proteins of the NF-kappaB signaling module. Cold Spring Harb Perspect Biol 1:a000075