MDMX under stress: the MDMX-MDM2 complex as stress signals hub.

The tumor suppressor p53 plays a central role in safeguarding cellular homeostasis. Upon various types of stress signals such as DNA damage or oncogenic stress, p53 is promptly activated to prevent and repair damages that can threaten the genome stability. The two major negative regulators of p53 are MDM2 and MDMX, two homolog proteins that control p53 activity and turnover, hence keeping it in check during normal cell cycling. In the event of cellular stress, they have to be inhibited in order to relieve p53 from their suppression and allow its activation. As the essential upstream modulator of p53, the MDMX-MDM2 complex integrates multiple signaling pathways regulating p53 response to perturbations of cellular homeostasis. Given its predominantly cytoplasmic localization in normal conditions, we hypothesize that MDMX, rather than MDM2, is the first recipient of signaling cues directed towards the MDMX-MDM2 complex and aimed at modulating p53. In this review we give a synthetic overview of the phosphorylation sites of MDMX that are known to affect its degradation, ubiquitination, intracellular localization and interaction with MDM2 and p53, ultimately modulating the stability and activity of p53. The role of MDMX in response to the main types of cellular stress is also briefly discussed, along with the potential of the MDMX-MDM2 complex as therapeutic target to restore p53 activity.