The WEHI231 and CH33 immature B-cell lines have served extensively as models for the study of B-cell tolerance through clonal deletion via apoptosis. The investigator has recently shown that treatment of these lines with antisera against surface IgM or TGF-beta-1 leads to a reduction in activity of NF-kappaB/Rel transcription factors, causing a drop in c-myc expression which induces apoptosis. Rescue from apoptosis by CD40 ligation leads to maintenance of NF-kappaB/Rel and c-Myc expression.
In Specific Aim 1, the regulation of expression and role in apoptosis of the NF-kappaB/Rel inhibitor I-kappaB-beta following anti-IgM and CD40 ligation will be assessed. Also the control of transcriptional induction of I-kappaB-alpha by TGF-beta-1 and of its sustained reduction by CD40 ligation will be characterized.
In Specific Aim 2, the functional role of the drop in c-Myc levels in the induction of apoptosis will be pursued. Myc has been shown to either induce transcription of E-box driven promoters via interaction with its partner MAX, or to repress transcription of genes driven by Inr elements. The investigator has identified an alternate transcript of Max that generates protein functioning as a dominant negative Max (dMax) in B-cells, which inhibits c-Myc transactivation. The investigator proposes that expression of dMax serves to reduce the level of positive transactivation by c-Myc in immature B-cells, such that a drop in c-Myc levels results in de-repression of gene transactivation. Therefore, dMax will be characterized: 1) in different functional B-cell stages; 2) as a negative regulator of c-Myc-promoted transactivation and apoptosis in myeloid cells; and 3) with respect to c-Myc de-repression of Inr-mediated transcription. Finally, since expression of Mad1, the Max binding partner, was induced following the drop in c-Myc expression and activated apoptosis in WEHI 231 cells following microinjection, the regulation of Mad1 expression and its role in apoptosis will be characterized. Together, these studies should provide important insights into the role of the c-Myc oncogene and NF-kappaB/Rel in the control of apoptosis of immature B-cells and the induction of tolerance via clonal deletion.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036355-15
Application #
2882315
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mufson, R Allan
Project Start
1984-01-01
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Wang, Xiaobo; Belguise, Karine; O'Neill, Christine F et al. (2009) RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1. Mol Cell Biol 29:3832-44
Chandramohan, Vidyalakshmi; Mineva, Nora D; Burke, Brian et al. (2008) c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor. J Cell Biochem 104:2091-106
Wang, Xiaobo; Belguise, Karine; Kersual, Nathalie et al. (2007) Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol 9:470-8
Mineva, Nora D; Rothstein, Thomas L; Meyers, John A et al. (2007) CD40 ligand-mediated activation of the de novo RelB NF-kappaB synthesis pathway in transformed B cells promotes rescue from apoptosis. J Biol Chem 282:17475-85
Chandramohan, Vidyalakshmi; Jeay, Sebastien; Pianetti, Stefania et al. (2004) Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. J Immunol 172:5522-7
Guo, Shangqin; Sonenshein, Gail E (2004) Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. Mol Cell Biol 24:8681-90
Arsura, Marcello; Panta, Ganesh R; Bilyeu, Jennifer D et al. (2003) Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22:412-25
Jiang, H Y; Petrovas, Constantinos; Sonenshein, Gail E (2002) RelB-p50 NF-kappa B complexes are selectively induced by cytomegalovirus immediate-early protein 1: differential regulation of Bcl-x(L) promoter activity by NF-kappa B family members. J Virol 76:5737-47
Yang, W; Shen, J; Wu, M et al. (2001) Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 20:1688-702
Jeay, S; Sonenshein, G E; Kelly, P A et al. (2001) Growth hormone exerts antiapoptotic and proliferative effects through two different pathways involving nuclear factor-kappaB and phosphatidylinositol 3-kinase. Endocrinology 142:147-56

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