Cooperation between MDM2 and MDMX in the regulation of p53

Murine double minute-2 (MDM2) was first described as a p53-associated protein and potential oncogene in the early 1990s. Its paralogue MDMX was subsequently identified in a screen for p53-binding proteins. Extensive evidence now confirms both proteins to be oncogenic in both mice and humans, largely through their ability to negatively regulate the tumour-suppressor activities of p53. It is now clear that the two proteins form heterodimers, and act in concert to regulate p53 activity in proliferating and stressed cells. In this chapter I firstly review the several mechanisms whereby MDM2 and MDMX are potentially able to regulate p53 function independently of each other. I then examine how heterodimerisation between the two molecules influences how they regulate the abundance and activity of both p53, and each other. I conclude by examining current models of how the dynamic equilibrium between p53 and its two negative regulators is maintained in proliferating cells, and is targeted by multiple signalling pathways to control the magnitude and duration of the p53-dependent transcriptional response to genotoxic stress