Regulation of the p53 Tumor Suppressor by MDM Proteins
The MDM2 and MDMX oncogenes are amplified and overexpressed in a wide variety of human cancers. Our previous research has demonstrated that the MDM oncoproteins complex with the p53 tumor suppressor protein and inhibit p53 functions during mouse embryogenesis. In addition to negatively regulating the p53 tumor suppressor, we have also identified p53-independent roles for Mdm2 and MdmX in governing cell proliferation and tumorigenesis. We have also explored the effects of post-translational modifications to p53 and MDM proteins to gain insight into the regulation of p53 stability and transcriptional activation. Collectively, our work has established that MDM proteins are the major regulators of the p53 tumor suppressor in normal cell growth and in development, and that alterations in MDM-p53 signaling is a common mechanistic feature in cancer. In addition, we have determined that dysregulation of p53 activity can lead to accelerated aging phenotypes in mice, linking Mdm2-p53 signaling in tumor suppression with the regulation of aging. Work to further dissect the roles of MDM proteins in regulating p53 activity in response to DNA damage and oncogene activation using knock-in mouse models is ongoing.