Figure 1.

MDM2 inhibitors activate p53 through MDM2 binding. MDM2 is the primary negative regulator of p53, whereas ARF binds and inhibits MDM2 regulation of p53. ARF also blocks MYCN function yet is paradoxically activated by MYCN. By specifically binding to the p53-binding pocket of MDM2, MDM2 inhibitors (Nutlin-3a, RG7112 and RG7388) disconnect the upstream regulation of p53 by MDM2, which leads to stabilization of the p53 protein and higher intranuclear concentrations of p53. In a p53-independent manner, MDM2 inhibitors suppress HIF-1α, which is the major regulator of VEGF, leading to inhibition of tumor angiogenesis. In malignancies such as neuroblastoma, increased p53 activity leads to activation of apoptotic pathways rather than cellular repair pathways, suggesting a promising therapeutic option for p53 wild-type tumors.