Intracellular signaling culminates in gene expression changes that are mediated by transcription factors such as activator protein-1 (AP-1). AP-1 is a widely expressed transcription complex consisting of dimerizing basic leucine zipper (bZIP) proteins. AP-1 functions in cell growth, differentiation, survival and apoptosis, and deregulated AP-1 activity figures prominently in human diseases from cancer to neurodegenerative disorders. Transcription factors are major targets for therapeutic intervention, and in vivo strategies designed to modulate AP-1 activity would be a significant advance in many clinical situations. BATF, and the highly related JDP1 protein, are unique AP-1 family members that dimerize with the central components of AP-1 - the Jun proteins - and inhibit AP-1 activity. The objective of this application is to define the roles of these AP-1 inhibitors in vivo and to test the hypothesis that these roles are linked to the regulation of specific AP-1 target genes.
In Aim 1, genetically engineered mouse models expressing epitope-tagged BATF and JDP1 at endogenous levels will be used for defining the precise expression patterns of these proteins and for identifying genes directly bound by BATF using chromatin immunoprecipitation (ChIP) coupled with the screening of novel AP-1 promoter microarrays. BATF null, JDP1 null and double null mice will be used to assess how the loss of AP-1 inhibition mediated by these proteins affects development and to profile the full spectrum of gene expresson changes that characterize the BATF null phenotype.
Aim 2 will use mass spectral analysis to identify and quantify discreet phosphorylation events that regulate the DNA binding and dimerization properties of BATF and influence its efficacy as an AP-1 inhibitor. Lastly, in Aim 3, the M1 cell system will be used to further investigate the function of BATF by following BATF-mediated regulation of target genes and by positioning BATF within the signaling network that controls the differentiation of these cells. These studies have the short-term goal of establishing the function of BATF and JDP1 in vivo and will generate the information necessary to address our long-term goals of using these AP-1 inhibitors for transcription-targeted therapies. Relevance: The aberrant cell growth that is a feature of many human diseases often is linked to deregulated gene expression mediated by proteins such as the AP-1 family of transcription factors. BATF and JDP1 have been identified as AP-1 family members that negatively regulate gene expression. The goal of this research is to fully characterize the biological activities of these proteins as a first step towards establishing their utility in AP-1 targeted therapies.
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