Regulation of MDM4 (MDMX) function by p76MDM2: a new facet in the control of p53 activity

Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length p90MDM2, for a short protein, p76MDM2 that lacks the p53- binding domain. Despite this property and at variance with p90MDM2, this protein acts positively toward p53, although the molecular mechanism remains elusive. Here, we report that p76MDM2 antagonizes MDM4 inhibitory function. We show that p76MDM2 possesses intrinsic ubiquitinating and degrading activity, and through these activities controls MDM4 levels. Furthermore, the presence of p76MDM2 decreases the association of MDM4 with p53 and p90MDM2, and antagonizes p53 degradation by the heterodimer MDM4/p90MDM2. The p76MDM2-mediated regulation of MDM4 occurs in the cytoplasm, under basal growth conditions. Conversely, upon DNA damage, phosphorylation of MDM4Ser403 dissociates p76MDM2 and prevents MDM4 degradation. The overall negative control of MDM4 by p76MDM2 reflects on p53 function as p76MDM2 impairs MDM4-mediated inhibition of p53 activity. In agreement with the positive role of p76MDM2 toward p53, the p76MDM2/ p90MDM2 ratio significantly decreases in a group of thyroid tumor samples compared with normal counterparts. Overall,these findings reveal a new mechanism in the control of p53 basal activity that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins. Moreover, these data suggest an oncosuppressive function for a product of the Mdm2 gene.