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lity t p lt ti n th do as a substrate of Mdm2/MdmX E3 complex. The insufficiency of Mdm2 for p53 polyubiquitination also demands other p53 E3 ligases or E4 factors be incorporated into the p53 degradation arena. Deubiquitinases nullify the effects of E3 actions and reverse the ubiquitination process, which per-sor p5 nt thro t, apo pressi and ag lethal to many cell types, but initiates a rapid p53 response when stress signals are sensed. The key molecule in the p53 regulatory network is Mdm2, an E3 ubiquitin ligase with potentially onco-genic activity. Dynamic fine-tuning of the Mdm2-centered net-work dictates the proper rapidity, intensity, and duration of a 2. Mdm2-dependent p53 inhibition: canceling transcription or degrading the protein Mdm2 was initially discovered as a p53 binding protein that possesses potent inhibitory effects on p53-mediated transcription [18]. The crystal structure of an Mdm2 N-terminal fragment bound with a p53 transactivation domain peptide demonstrated that the amino acids of p53 involved in binding to the Mdm2 cleft are ⇑ Corresponding author. FEBS Letters 586 (2012) 1390–1396 wwE-mail address