The loss of mdm2 induces p53 mediated apoptosis

The p53 tumor suppressor gene product is negatively regulated by the produc t of its downstream target, mdm2. The deletion of mdm2 in the mouse results in embryonic lethality at 5.5 days post coitum (d.p.c.) which can be overc ome by simultaneous loss of the p53 tumor suppressor, substantiating the im portance of the negative regulatory function of MDM2 on p53 function ill rh o. Hence, the loss of MDM2 allowed the unregulated p53 protein to continuou sly exert its growth-suppressing activity, which either led to a complete G 1 arrest or induced the p53-dependent apoptotic pathway, resulting in the d eath of the mdm2-/- embryos. To determine which of these possibilities is o ccurring, mouse embryo fibroblasts (MEFs) from p53 null and p53/mdm2 double null embryos were transfected with a retroviral vector carrying a temperat ure-sensitive p53 (tsp53) cDNA. Shifting of single-cell clonal populations to the permissive temperature caused the p53-/-mdr2-/- fibroblasts expressi ng tsp53 to undergo apoptosis in a dose-dependent manner. This phenotype wa s not observed in the tsp53 expressing p53-/- clones nor the parental cell lines. Thus, our data indicate that the simple loss of mdm2 can induce the p53-dependent apoptotic pathway in vivo.