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. In recently published reports, this group participated in research that identified the transcription factor C/EBPdelta as critical for expression of two solute carrier proteins. One of these, slc5a8, was characterized as a transporter for pyruvate. Furthermore, we found that pyruvate, a cell intrinsic metabolic product - and additive in cell culture media, is an inhibitor of histone deacetylases. Since histone deacetylase inhibitors initiate cell death in many tumor cells - for largely unknown reasons, pyruvate can induce cell death in tumor cell lines, which express scl5a8. Pyruvate is a common metabolic product and can be converted to lactate. Conversion of pyruvate to lactate is particularly efficient in tumor cells due to expression of specific lactate dehydrogenase enzyme isoforms. We suggest that this is in part for the purpose of removing pyruvate. These results have provided new insight into the metabolic pathways specific to tumor cells. We hypothesize that therapeutic manipulation of metabolic pathways leading to the accumulation of pyruvate may restrict tumor cell growth or survival.
| 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 |
