Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

The p53 tumor suppressor is activated by various stress signals such as DNA damage, ribonucleotide depletion, oxidative stress, oncogene activation or incomplete mitotic stimuli.¹ Under these conditions, the p53 protein is stabilized and becomes transcriptionally active. p53 downstream responses include cell cycle arrest and apoptosis and are mainly mediated by its multiple target genes. Key mediators of p53 biological activities are the proapoptotic genes bax, PUMA and NOXA² and the cell cycle regulators p21³ and Ptprv.⁴

In the absence of stress signals, the p53 protein is kept in check to allow normal cell proliferation and/or maintenance of cell viability. Of critical importance for this process are the two structurally related proteins, Mdm2 and Mdm4 (also known as Mdmx). Germline inactivation of either mdm2 or mdm4 leads to embryonic lethal phenotypes that are completely overcome by concomitant inactivation of the p53 gene.^{5, 6, 7, 8, 9} Together, since physiological levels of each regulator cannot compensate for the loss of the other, both Mdm2 and Mdm4 are required, in a nonredundant manner, to restrain p53 function during embryonic development. Thus, clear genetic evidence highlights the importance of the p53/Mdm2 and p53/Mdm4 interactions. However, a clear understanding of the physiological contributions of Mdm2 and Mdm4 to the regulation of p53 stability and transcriptional activity is lacking.¹⁰ This is in part due to the technical difficulty to accurately reproduce the physiologic balance between p53, Mdm2 and Mdm4 in transfection studies. Furthermore, the possibility exists that these two p53 inhibitors function in a temporal and tissue-specific manner. Indeed, whereas mdm2-deficient mice die at the preimplantation stage, mdm4-null mice die much later, around mid-gestation. Moreover, increased p53 activity and frequency of spontaneous apoptosis was only observed in a subset of actively dividing cells such as lymphocytes and in the crypts of the small intestines of adult mice harboring a hypomorphic mdm2 allele.¹¹ Mdm2 function might therefore be dispensible in quiescent, terminally differentiated, cells in vivo.

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