Cell Growth Control In Vivo by C/EBPbeta and C/EBPdelta

Basic Sciences

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Abstract

The C/EBP family of transcription factors consists of six members with similar DNA binding specificity, which can homo- and heterodimerize with each other. The long term goal of this project is to elucidate the developmental and molecular functions of individual C/EBP proteins in normal cell growth control and during tumorigenesis . Specifically, we are using mouse models that lack either the C/EBPbeta (Cebpb) or the C/EBPdelta (Cebpd) gene in research on four organ sites. 1) Ovary: Cebpb-deficient ovarian granulosa cells are unable to differentiate in response to luteinizing hormone (LH) and therefore cause infertility. Thus, we are using hormone stimulated ovarian tissue as a tool to identify target genes of Cebpb by microarray hybridization technology. Furthermore, we found that Cebpd is a target of LH specifically in Theca cells, and that it is overexpressed in these cells from women with polycystic ovarian syndrome. 2) Skin: Cebpb-deficient mice are completely refractory to skin carcinogenesis. We are using a mouse model with a conditional null allele of Cebpb in combination with various transgenic mice to further characterize the role of Cebpb in keratinocyte specific tumor development. 3) Lung: Cebpd is expressed constitutively in the lung, and knockout mice display elevated occurrence of lung adenomas. Using mouse lung epithelial cells in vitro and in vivo we obtained evidence that Cebpd is a candidate tumor suppressor gene. Using mouse embryo fibroblasts as a model we discovered a role of Cebpd in maintenance of genome stability as a potential pathway for its tumor suppressor function. 4) Mammary: Cebpb-deficient mice display impaired mammary gland development. We are using a mouse model with a conditional null allele of Cebpb in combination with various transgenic models to further characterize the role of Cebpb in mammary epithelial cell growth, differentiation and tumorigenesis. In the mammary gland, Cebpd is expressed specifically at the onset of involution. We found that the involution process is delayed in Cebpd-deficient mice with specific alterations in expression of apoptosis regulators. Based on this phenotype, we are studying the potential of Cebpd to induce cell death in human breast tumor cell lines, and we are testing the effect of Cebpd mutation on mouse mammary tumor models. In summary, these approaches shall contribute to our understanding of the role and mechanisms of C/EBPs in cell growth, survival and death in vivo. This knowledge should enable us to better understand growth regulation in different normal and malignant cell types and possibly lead to the discovery of pathways amenable for diagnostics or therapeutic intervention.