Activator Protein-1 (AP-1) consists of dimerizing basic leucine zipper transcription factors and plays an essential role in cell proliferation, cell survival and cell death. The most well characterized AP-1 family members, the Fos and Jun proteins, are nuclear targets of all major intracellular signaling pathways. As a result, in vivo approaches to control the activities of the Fos:Jun heterodimer would find clinical applications in disease states as diverse as cancer and neurodegenerative disorders. BATF and the highly related protein, JDP1, are unique among AP-1 family members in that they form high affinity dimers with Jun that show the same DNA binding preference as Fos:Jun dimers, yet display no ability to activate gene transcription. Thus, these proteins possess the properties of naturally occurring, negative regulators of AP-1 that could be exploited to control AP-1 activity in vivo. Transgenic mouse models of tissue-specific expression of wild type and variant BATF proteins will be employed to examine the biological consequences of BATF-mediated modulation of AP-1 activity in vivo. Target genes that are regulated by BATF containing AP-1 complexes will be identified using a novel approach combining chromatin immunoprecipitation with AP-1 promoter microarray screening. Mice in which BATF and JDP1 have been functionally inactivated will reveal the importance of these proteins to mammalian growth and development and will be used to profile gene expression changes associated with the absence of BATF-mediated AP-1 regulation in selected tissues. Lastly, as a first step toward identifying signaling pathways that could be exploited for strategies to manipulate the levels of BATF expression in vivo, the regulatory elements and associated transcription factors that control BATF gene expression will be characterized. Inducible BATF expression in cultured cells will be used to validate BATF target genes identified in mice and to explore the role (if unknown) of the proteins encoded by these genes in the cellular phenotypes associated with BATF expression. Our short-term goal is to fully characterize the impact of BATF on AP-1 activity in cells, with the long-term goal of using the properties of this unique AP-1 family member (or molecular strategies based on the properties of BATF) to control the aberrant activity of AP-1 that is frequently associated with human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078264-08
Application #
7104836
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Howcroft, Thomas K
Project Start
1998-02-20
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
8
Fiscal Year
2006
Total Cost
$292,920
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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