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1 Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY
Requests for reprints: Ute M. Moll, Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY 11794-8691. Phone: (631) 444-2459; Fax: (631) 444-3424. E-mail: umoll{at}notes.cc.sunysb.edu
Abstract
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.
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