The transcription factor NF-kappaB is critical in inflammatory gene expression, lymphocyte proliferation and cell death/survival decisions. Its activity is controlled by three inhibitory proteins, iKappaBalpha -beta -epsilon, whose synthesis and protein half-life is tightly regulated. Stimulus-induced degradation of IkappaB proteins associated with NFkappaB studied in great detail. The goals of the work proposed here are to characterize and contrast half-life regulation of NF-kappaB-bound and """"""""free"""""""" IkappaB proteins in resting cells and those responding to inflammatory stimuli and UV irradiation. The mechanisms and potential signaling pathways that determine these degradation rates will be characterized, and importantly, the role of the interaction with NF-kappaB in determining half-regulation will be examined. These results will serve to refine a computational model of NF-kappaB signaling significantly, that will allow us to examine the role of regulating these previously neglected degradation rates in NF-kapppaB signaling. First, we will focus on the equilibrium state in resting cells: Robustness of the signaling system vis-a-vis transient perturbations (""""""""noise"""""""") or long-term perturbations due to chronic changes in expression levels of the signaling components for example. Such perturbations may be caused by genetic changes that may be associated with inflammatory disease or tumorigenesis. Next, we will focus on the performance of the IkappaB/NF-kappaB signaling system during signal transduction, especially in response to weak or transient stimuli. Computational predictions will be examined experimentally using mutant cell lines generated from knockout mice and by lentivirus-mediated reconstitution of these with IkappaB mutant molecules. We will identify NF-kappaB target genes whose expression is sensitive to the regulation of IkappaB degradation rates and thereby demonstrate the specificity and physiological relevance of these mechanisms in human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071573-04
Application #
7413421
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Anderson, Richard A
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$232,296
Indirect Cost
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
Hoffmann, Alexander (2016) Immune Response Signaling: Combinatorial and Dynamic Control. Trends Immunol 37:570-572
Almaden, Jonathan V; Liu, Yi C; Yang, Edward et al. (2016) B-cell survival and development controlled by the coordination of NF-?B family members RelB and cRel. Blood 127:1276-86
Xu, Jinjin; Zhou, Lei; Ji, Lei et al. (2016) The REG?-proteasome forms a regulatory circuit with I?B? and NF?B in experimental colitis. Nat Commun 7:10761
Fortmann, Karen T; Lewis, Russell D; Ngo, Kim A et al. (2015) A Regulated, Ubiquitin-Independent Degron in I?B?. J Mol Biol 427:2748-56
Cheng, Zhang; Taylor, Brooks; Ourthiague, Diana R et al. (2015) Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation. Sci Signal 8:ra69
Ourthiague, Diana R; Birnbaum, Harry; Ortenlöf, Niklas et al. (2015) Limited specificity of IRF3 and ISGF3 in the transcriptional innate-immune response to double-stranded RNA. J Leukoc Biol 98:119-28
Shokhirev, Maxim N; Almaden, Jonathan; Davis-Turak, Jeremy et al. (2015) A multi-scale approach reveals that NF-?B cRel enforces a B-cell decision to divide. Mol Syst Biol 11:783
Fagerlund, Riku; Behar, Marcelo; Fortmann, Karen T et al. (2015) Anatomy of a negative feedback loop: the case of I?B?. J R Soc Interface 12:0262
Caldwell, Andrew B; Cheng, Zhang; Vargas, Jesse D et al. (2014) Network dynamics determine the autocrine and paracrine signaling functions of TNF. Genes Dev 28:2120-33
Alves, Bryce N; Tsui, Rachel; Almaden, Jonathan et al. (2014) I?B? is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol 192:3121-32

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