The functional characterization of tissue-specific transcription factors that regulate hematopoietic cell growth and lineage development will provide molecular targets for the design of strategies to manipulate the leukemic phenotype. B-ATF is a new basic leucine zipper (bZIP) protein that is expressed in a tissue-specific manner and is induced rapidly in human B cells following infection with Epstein-Barr virus (EBV) and the expression of the EBV-encoded transactivator protein, EBNA-2. B-ATF is a nuclear protein that heterodimerizes with members of the Jun family of oncoproteins to bind to AP-1 target DNA sites. In cultured cells engineered to overexpress B-ATF, Jun, and Fos, transcription of an AP-1 responsive reporter gene is repressed. This suggests that B-ATF functions as a negative regulator of AP-1, a transcription complex that normally is associated with the induction of cellular growth. Based on these observations, it remains unclear why EBNA-2, a viral latency gene product required for B cell immortalization and transformation, triggers the expression of B-ATF. To explore further the relationship between EBV and B-ATF, the cis-trans regulatory mechanisms responsible for enhanced expression of the human B-ATF gene by EBNA-2 will be investigated. To establish a functional role for B-ATF in B cells, experiments will be performed to assess the impact of B-ATF on the biochemical and biological function of the AP-1 transcription factor complex and on the activities of an additional B-ATF-interacting protein (BIP-13) that is expressed preferentially in human B cells. The requirement for spatial and temporal control of B-ATF expression in vivo will be investigated using in situ hybridization to fully characterize the B-ATF gene expression pattern in embryonic and adult mice. Transgenic technology will be used to establish if perturbation of B-ATF expression adversely impacts the development of the whole animal. The PI anticipates that these studies will elucidate the role of B-ATF in B cell growth and development and provide the information needed to assess the feasibility of using this new bZIP protein as a target in the management of B cell malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078264-02
Application #
2872022
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Finerty, John F
Project Start
1998-02-20
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Purdue University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Liao, Juan; Humphrey, Sean E; Poston, Stacie et al. (2011) Batf promotes growth arrest and terminal differentiation of mouse myeloid leukemia cells. Mol Cancer Res 9:350-63
Zullo, Alfred J; Benlagha, Kamel; Bendelac, Albert et al. (2007) Sensitivity of NK1.1-negative NKT cells to transgenic BATF defines a role for activator protein-1 in the expansion and maturation of immature NKT cells in the thymus. J Immunol 178:58-66
Deppmann, Christopher D; Alvania, Rebecca S; Taparowsky, Elizabeth J (2006) Cross-species annotation of basic leucine zipper factor interactions: Insight into the evolution of closed interaction networks. Mol Biol Evol 23:1480-92
Zullo, Alfred J; Brutkiewicz, Randy R; Taparowsky, Elizabeth J (2006) Selective identification of Valpha14i T cells using slide-immobilized, CD1d-antigen complexes. J Immunoassay Immunochem 27:207-12
Vinson, Charles; Acharya, Asha; Taparowsky, Elizabeth J (2006) Deciphering B-ZIP transcription factor interactions in vitro and in vivo. Biochim Biophys Acta 1759:4-12
Thornton, Tina M; Zullo, Alfred J; Williams, Kristi L et al. (2006) Direct manipulation of activator protein-1 controls thymocyte proliferation in vitro. Eur J Immunol 36:160-9
Liu, Han; Deng, Xuehong; Shyu, Y John et al. (2006) Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. EMBO J 25:1058-69
Deppmann, Christopher D; Thornton, Tina M; Utama, Fransiscus E et al. (2003) Phosphorylation of BATF regulates DNA binding: a novel mechanism for AP-1 (activator protein-1) regulation. Biochem J 374:423-31
Johansen, Lisa M; Deppmann, Christopher D; Erickson, Kimberly D et al. (2003) EBNA2 and activated Notch induce expression of BATF. J Virol 77:6029-40
Deppmann, Christopher D; Taparowsky, Elizabeth J (2003) Reverse-polarity PAGE for examining DNA binding domain phosphorylation. Biotechniques 34:56-9

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