The C/EBP family of transcription factors consists of 6 members with similar DNA binding specificity, which can homo- and heterodimerize with each other, giving potential for 21 different transcriptional regulators. Many tissue culture model systems suggest a role for C/EBP proteins in the regulation of cell proliferation, growth arrest or programmed cell death. However, limitedinformation exists about their function in primary cells and in vivo. The long term goal of this project is to elucidate the specific developmental and molecular functions of individual C/EBP proteins in vivo. Specifically, we are using mouse models that lack either the C/EBPbeta or the C/EBPdelta gene in a number of approaches: 1) C/EBPbeta-deficient ovarian granulosa cells are unable to differentiate in response to luteinizing hormone. Thus, we are using hormone stimulated ovarian tissue as a tool to identify target genes of C/EBPbeta by Representational Difference Analysis and Microarray Hybridization Technology. 2) We found that under specific experimental conditions, C/EBPbeta-deficiency renders granulosa cells permissive to trans-differentiation into Sertoli-like cells, a cell type that gives rise to about 0.3% of human ovarian tumors. We are now addressing the molecular mechanism underlying this phenotype by testing the regulation of candidate genes, such as Inhibin, in mutant tissue. 3) C/EBPbeta null mice display multiple pathologies, including immune system dysfunctions,which preclude proper analysis of specific phenotypes. In order to have a better mouse model we are developing a mutation that allows for regulated conditional deletion of the C/EBPbeta gene in mice. 4) We found that C/EBPdelta-deficient mice develop mild mammary gland hyperplasia. We are now characterizing mammary epithelial cell growth regulation in these mice in more detail, with particular emphasis on programmed cell death during postlactational involution, since this is the stage at which C/EBPdelta is normally expressed. We are also using mouse embryo fibroblasts as an in vitro model to characterize the role of C/EBPdelta in cell growth control. 5) C/EBPdelta is expressed constitutively in the lung, and Knockout mice display slightly elevated occurrence of lung adenomas. Thus, we are addressing the role of this gene in cell growth control by in vitro and vivo analysis of mouse lung epithelial cells. In summary, these approaches shall contribute to our understanding of the role and mechanisms of C/EBP control and function in vivo. This knowledge should enable us to better understand growth regulation in different cell types and the pathological aberrations thereof.
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