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. Analysis if the embryos indicate that they are dying by apoptosis. Analysis of mice null for p53 and the presence or absence of the mdm2 gene indicate a longer tumor latency in p53--mdm2- mice. In addition, these mice exhibit an increase in sarcomas with a concomitant decrease in lymphomas. 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 suggesting novel functions for MDM2. Th mammary epithelial cells are overexpressing cyclin A, but not cyclin B suggesting that the cells never exit S-phase. The S-phase transcription factor that binds MDM2, E2F1, appears to have no role in this defect.