The Roles of MDM2 and MDMX Phosphorylation in Stress Signaling to p53

Abstract

The p53 tumor suppressor is highly responsive to different physiological stresses such as abnormal cell proliferation, nutrient deprivation, and DNA damage. Distinct signaling mechanisms have evolved to activate p53, which in turn modulate numerous pathways to enhance fitness and survival of the organism. Elucidating the molecular mechanisms of these signaling events is critical for understanding tumor suppression by p53 and development of novel therapeutics. Studies in the past decade have established that MDM2 and MDMX are important targets of signaling input from different pathways. Here, we focus our discussion on MDM2 and MDMX phosphorylation, which is important for p53 activation by DNA damage. Investigations in this area have generated new insight into the inner workings of MDM2 and MDMX and underscore the importance of allosteric communication between different domains in achieving an efficient response to phosphorylation. It is likely that MDM2 and MDMX regulation by phosphorylation will share mechanistic similarities to other signaling hub molecules. Phosphorylation-independent p53 activators such as ARF and ribosomal proteins ultimately achieve the same outcome as phosphorylation, suggesting that they may induce similar changes in the structure and function of MDM2 and MDMX through protein-protein interactions.