Mdm2 Function in Tumorigenesis

To examine mdm2 function in vivo, we have performed experiments in two mouse models. The mdm2 null mouse is an embryo lethal whose phenotype is completely rescued in the absence of p53. The lethal phenotype is not rescued by loss of p21 and is partially rescued by loss of bax, two transcriptional targets of p53 involved in growth arrest and apoptosis, respectively. Detailed analyses of mdm2-- embryos indicate that they are dying by apoptosis. A system has been established that reproduces the apoptosis defect upon loss of mdm2 in culture and will allow further biochemical characterization of the pathway of apoptosis. We have also analyzed transgenic mice that overexpress mdm2 in the breast epithelium and find that the mammary epithelial cells undergo multiple rounds of DNA synthesis without cell division. Importantly, this phenomenon is independent of p53 and another MDM2 interacting protein E2F1, suggesting novel functions for MDM2.