The MDM2-p53 Interaction

• Published in: Molecular cancer research Vol. 1; no. 14; pp. 1001 - 1008
• Main Authors: Moll, Ute M, Petrenko, Oleksi
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-12-2003
• Subjects: Animals; Binding Sites; Cysteine Endopeptidases - metabolism; Humans; Multienzyme Complexes - metabolism; Nuclear Proteins - metabolism; Proteasome Endopeptidase Complex; Protein Binding; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p14ARF - metabolism; Tumor Suppressor Protein p53 - metabolism; Ubiquitin - metabolism
• ISSN: 1541-7786; 1557-3125

Activation of the p53 protein protects the organism against the propagation of cells that carry damaged DNA with potentially
oncogenic mutations. MDM2, a p53-specific E3 ubiquitin ligase, is the principal cellular antagonist of p53, acting to limit
the p53 growth-suppressive function in unstressed cells. In unstressed cells, MDM2 constantly monoubiquitinates p53 and thus
is the critical step in mediating its degradation by nuclear and cytoplasmic proteasomes. The interaction between p53 and
MDM2 is conformation-based and is tightly regulated on multiple levels. Disruption of the p53-MDM2 complex by multiple routes
is the pivotal event for p53 activation, leading to p53 induction and its biological response. Because the p53-MDM2 interaction
is structurally and biologically well understood, the design of small lipophilic molecules that disrupt or prevent it has
become an important target for cancer therapy.