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.
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