Puzzling over MDM4–p53 network

MDM4 (also called MDMX) has been initially identified as p53 inhibitor. Subsequent data have reinforced this role pointing to the requirement for MDM4 repressive activity on p53 for mouse embryo development. Molecular studies have shown that MDM4 exerts different activities by controlling both p53 transcriptional function and protein levels. On the basis of these data, therapeutic strategies aiming at releasing p53 from MDM4 inhibition are under development.However, recent studies suggest a more complex relationship between MDM4 and p53. These have evidenced heterogeneity of MDM4 function under different growth conditions and particularly positive activity exerted by MDM4 on stress-activated p53 levels and pro-apoptotic function.This review summarizes the different facets of MDM4-mediated regulation of p53 and the modifications able to modulate MDM4 localization and function.