The long-term goal of this project is to understand how genetic alterations of the NF-(B2 gene may lead to tumorigenesis. The NF-kappaBeta2 gene encodes a protein of approximately 100-kDa (p100) that can promote apoptosis via its C-terminal death domain and/or lkappaB activity. In response to certain signals, p100 is processed to generate a 52-kDa transcriptional factor (p52) corresponding to the N-terminal half of p100. Aberrant activation of p52 has been observed in breast cancers. Also, C-terminal deletions and rearrangements of the NF-kappaB2 gene occur recurrently in a variety of B- and T-cell lymphomas. A fundamental feature of these genetic alterations is the generation of C-terminally truncated NF-kappaB2 mutants with oncogenic potential and the inactivation of p100 as an apoptotic protein. Our recent work suggests that p100 is a crucial regulator of TNF-alpha- and activation-induced apoptosis in thymocytes, and an inhibitor of the oncogenic activity of the tumor-derived NF-kappaB2 mutant p80HT in cells and in animals. These findings lead us to hypothesize that p100 is a tumor suppressor that promotes apoptosis and acts as a built-in defense against oncogenic mutations of NF-kappaB2 and aberrant activation of p52. We will test this hypothesis in both cell- and animal-based systems. In animal-based studies (Aim 1), we will establish p100 as a tumor suppressor against lymphomagenesis in transgenic mice with targeted expression of p80HT or p52 in lymphocytes; we will examine the possibility that the NF-kappaB2 p100 gene is haplo-insufficient for tumor suppression in these mouse models; the potential of p100 as a general tumor suppressor will be assessed in E/mu-myc transgenic mice. In cell-based studies (Aim 2), we will use bone marrow cell transformation as readout to define the biochemical activity of p100 essential for its anti-oncogenic function and the apoptotic pathway through which p100 suppresses oncogenic transformation; we will characterize apoptotic responses in lymphocytes and lymphoma cells from the animals with defined NF-kappaB2 mutations to identify at molecular levels the defects in apoptosis regulation that are linked to lymphomagenesis; we will use thymic activation-induced apoptosis as a model to delineate the molecular mechanism for p100 as an apoptotic protein. These studies may define a new class of tumor suppressors that act as a surveillance mechanism against oncogenic mutations of their own genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA106550-05
Application #
7626529
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Howcroft, Thomas K
Project Start
2005-07-11
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
5
Fiscal Year
2008
Total Cost
$220,224
Indirect Cost
Name
Georgia Regents University
Department
Pathology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Yang, Liqun; Cui, Hongjuan; Wang, Zhe et al. (2010) Loss of negative feedback control of nuclear factor-kappaB2 activity in lymphocytes leads to fatal lung inflammation. Am J Pathol 176:2646-57
Wang, Zhe; Zhang, Baochun; Yang, Liqun et al. (2008) Constitutive production of NF-kappaB2 p52 is not tumorigenic but predisposes mice to inflammatory autoimmune disease by repressing Bim expression. J Biol Chem 283:10698-706
Cui, Hongjuan; Hu, Bo; Li, Tai et al. (2007) Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 170:1370-8
Zhang, Baochun; Wang, Zhe; Li, Tai et al. (2007) NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis. Blood 110:743-51
Cui, Hongjuan; Ma, Jun; Ding, Jane et al. (2006) Bmi-1 regulates the differentiation and clonogenic self-renewal of I-type neuroblastoma cells in a concentration-dependent manner. J Biol Chem 281:34696-704
Zhang, Baochun; Wang, Zhe; Ding, Jane et al. (2006) NF-kappaB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells. J Biol Chem 281:38617-24