p53-MDM2 autoregulatory circuit. (A) MDM2 and p53 mutually regulate their levels in unstressed proliferating cells. MDM2 expression is controlled by a p53-dependent promoter and increases when the level of p53 rises. In turn, MDM2 binds p53 and inhibits its transcriptional activity by blocking the transcriptional activation domain of the transcription factor. MDM2 also serves as the E3 ubiquitin ligase for p53 and facilitates its ubiquitin-dependent degradation in the proteasome. As a result, both p53 and MDM2 are kept at very low levels in proliferating cells. (B) Small-molecule antagonists of MDM2 that can bind to the p53 pocket on the surface of the molecule will inhibit the p53-MDM2 interaction and release p53 from negative control. p53 will stabilize, accumulate in cell nuclei, and activate the p53 pathway. Reproduced with permission from J Med Chem. 2005,48,4491-4499. Copyright 2005 Am. Chem. Soc.