MDM2 - master regulator of the p53 tumor suppressor protein

MDM2 is an oncogene that mainly functions to modulate p53 tumor suppressor activity. In normal cells the MDM2 protein binds to the p53 protein and mai ntains p53 at low levels by increasing its susceptibility to proteolysis by the 26S proteosome. Immediately after the application of cellular stress, the ability of MDM2 to bind to p53 is blocked or altered in a fashion that prevents MDM2-mediated degradation. As a result, p53 levels rise, causing c ell cycle arrest or apoptosis. In this review, we present evidence for the existence of three highly conserved regions (CRs) shared by MDM2 proteins a nd MDMX proteins of different species. These highly conserved regions encom pass residues 42-94 (CR1), 301-329 (CR2), and 444-483 (CR3) on human MDM2. These three domains are respectively important for binding p53, for binding the retinoblastoma protein, and for transferring ubiquitin to p53. This re view discusses the major milestones uncovered in MDM2 research during the p ast 12 years and potential uses of this knowledge in the fight against canc er. (C) 2000 Elsevier Science B.V. All rights reserved.