This project is focused on the identification of physiologically critical functions and mechanisms of action of NF-kB transcription factors and their regulators in health and disease. NF-kB is a family of related dimeric transcription factors that serve as primary intracellular mediators during innate and adaptive immune responses. In addition, and importantly, dysregulation of NF-kB plays a major role in inflammatory and autoimmune diseases as well as in numerous tumors. It is thus imperative to understand the functions and mechanisms of action of NF-kB factors, as this will be required to devise appropriate strategies for therapeutic interventions aimed at curtailing dysregulated NF-kB. To identify physiologic roles we make use of mouse models engineered to lack components of the NF-kB transcription factor family or their regulators as well as models in which the NF-kB factors can be selectively activated. Our work is focused on alternatively and classically activated NF-kB factors and especially on Bcl-3. The alternative NF-kB activation pathway is normally initiated by a subset of TNF receptors. Bcl-3 is an atypical IkB family member that functions as nuclear regulator of NF-kB activity. In FY 2012 we have succeeded to develop lines of mice with which we can ablate Bcl-3 in a cell-specific manner. These mice can now be evaluated as to effects on development of the immune system, responses to pathogenic challenge and pathogenesis in experimentally induced inflammation, contexts in which a role for Bcl-3 has been implicated, but in which Bcl-3s mechanisms of actions are not understood. In FY 2012 we have also succeeded in generating mice in which multiple NF-kB factors can be cell-specifically activated and preliminary analysis reveals an unexpected hyperproliferative phenotype of some epithelial cells, which is currently under investigation.

Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2012
Total Cost
$675,884
Indirect Cost
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State
Country
Zip Code
Tang, W; Wang, H; Ha, H L et al. (2016) The B-cell tumor promoter Bcl-3 suppresses inflammation-associated colon tumorigenesis in epithelial cells. Oncogene :
Kaileh, Mary; Vazquez, Estefania; MacFarlane 4th, Alexander W et al. (2016) mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes. PLoS One 11:e0146955
O'Reilly, L A; Hughes, P; Lin, A et al. (2015) Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation. Cell Death Differ 22:767-78
Tassi, Ilaria; Claudio, Estefania; Wang, Hongshan et al. (2015) Adaptive immune-mediated host resistance to Toxoplasma gondii is governed by the NF-κB regulator Bcl-3 in dendritic cells. Eur J Immunol 45:1972-9
Low, J T; Hughes, P; Lin, A et al. (2015) Impact of loss of NF-κB1, NF-κB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice. Immunol Cell Biol :
Tassi, Ilaria; Rikhi, Nimisha; Claudio, Estefania et al. (2015) The NF-κB regulator Bcl-3 modulates inflammation during contact hypersensitivity reactions in radioresistant cells. Eur J Immunol 45:1059-68
Kanno, Tomohiko; Kanno, Yuka; LeRoy, Gary et al. (2014) BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones. Nat Struct Mol Biol 21:1047-57
Liu, Sanhong; Sun, Xiaohua; Wang, Mingliang et al. (2014) A microRNA 221- and 222-mediated feedback loop maintains constitutive activation of NFκB and STAT3 in colorectal cancer cells. Gastroenterology 147:847-859.e11
Chen, Pengfei; Zhang, Jun; Zhan, Yu et al. (2013) Established thymic epithelial progenitor/stem cell-like cell lines differentiate into mature thymic epithelial cells and support T cell development. PLoS One 8:e75222
Liu, Zhanjie; Jiang, Yuhang; Hou, Yinyong et al. (2013) The IýýB family member Bcl-3 stabilizes c-Myc in colorectal cancer. J Mol Cell Biol 5:280-2

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