The fate of a cell, such as its specific responses to extracellular cues, its commitment to proliferate or which differentiation program to execute, are ultimately the result of specific transcriptional programs. We use the CCAAT/enhancer binding protein (C/EBP) transcription factors as molecular tools in mouse models and in vitro systems to gain insight into the molecular mechanisms that govern specific cellular decisions. The objective of this group is to use C/EBP-deficient mice to characterize basic mechanisms regulating cell growth and differentiation in normal cells within physiologically relevant systems. Next, we want to apply this knowledge to understand the emergence and biology of tumorigenic cells. Our ultimate aim is the identification of molecules and regulatory mechanisms that can be targeted for cancer diagnostics, prognostics or therapy.1) Ovary: We found that the C/EBPdelta gene is a target of luteinizing hormone receptor specifically in ovarian theca and interstitial cells, and that it is overexpressed in these cells from women with polycystic ovarian syndrome (Huang et al., submitted)2) Skin: C/EBPbeta-deficient mice are completely refractory to skin carcinogenesis. However, carcinogenesis is a complex process that requires the interplay of tumor cell and environment. We have generated a new mouse model with a conditional allele. This mouse in combination with a keratinocyte-specific cre recombinase transgenic, demonstrated a keratinocyte-intrinsic requirement of C/EBPbeta for mouse skin carcinogenesis (Sterneck et al., 2006). This model can now be used to test the hypothesis that C/EBPbeta is required for tumor cell survival.3) Mammary Gland: In the mammary gland, C/EBPdelta is expressed specifically at the onset of postlactiational involution when mammary epithelial cells (MEC) undergo cell death. We found that the involution process is delayed in C/EBPdelta-deficient mice with specific alterations in expression of apoptosis regulators. This study identified a pro-apoptotic role for C/EBPdelta in MEC (Thangaraju et al., 2005), which was further confirmed in human breast tumor cells (Thangaraju et al., in preparation).
| Smink, Jeske J; Begay, Valerie; Schoenmaker, Ton et al. (2009) Transcription factor C/EBPbeta isoform ratio regulates osteoclastogenesis through MafB. EMBO J 28:1769-81 |
| Sterneck, E; Zhu, S; Ramirez, A et al. (2006) Conditional ablation of C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis. Oncogene 25:1272-6 |
| Thangaraju, Muthusamy; Rudelius, Martina; Bierie, Brian et al. (2005) C/EBPdelta is a crucial regulator of pro-apoptotic gene expression during mammary gland involution. Development 132:4675-85 |
| Thangaraju, Muthusamy; Sharan, Shikha; Sterneck, Esta (2004) Comparison of mammary gland involution between 129S1 and C57BL/6 inbred mouse strains: differential regulation of Bcl2a1, Trp53, Cebpb, and Cebpd expression. Oncogene 23:2548-53 |
| Huang, A-Mei; Montagna, Cristina; Sharan, Shikha et al. (2004) Loss of CCAAT/enhancer binding protein delta promotes chromosomal instability. Oncogene 23:1549-57 |
