Mouse Double Minute 2 Actively Suppresses p53 Activity in Oocytes during Mouse Folliculogenesis

The p53 signaling network is indispensible in cellular stress responses and tumor suppression. Negative regulations of p53 by mouse double minute 2 (MDM2) and its homolog MDM4 are an integrated component of the network and have been implicated in regulating the stress responses and the maintenance of normal development and homeostasis of multiple somatic cell lineages. However, the regulatory role of MDM2 on p53 and stress responses in female germ cells remains undetermined. Here, we used the Cre-loxP system to delete Mdm2 in oocytes at different stages of folliculogenesis in mice. Mdm2 deletion resulted in a clear p53 nuclear accumulation in the oocytes and impeded fertilities with early follicular loss in mice, resembling human premature ovarian failure phenotypes. These phenotypes were fully rescued by concurrent deletion of p53 in mice. In addition, Nutlin-3, a small molecule compound that inhibited the binding of MDM2 to p53, also promoted p53-dependent oocyte death. Although cancer therapeutic agents 5-fluorouracil and doxorubicin could not induce a robust p53 activation in the wild-type oocytes, they induced p53 nuclear accumulation in the Mdm2 and Mdm4 double heterozygous oocytes. These results demonstrated a critical prosurvival role for MDM2 in the oocytes. Moreover, they suggested a more tightened and rigorous regulatory mode for the MDM2/MDM4-p53 network in female germ cells under stress situations.