Regulation of TP53 Degradation

The nuclear localization of MDM2 is positively regulated by AKT- or SGK1- mediated phosphorylation. Phosphorylation of MDM2 by CDK1 or CDK2 decreases affinity of MDM2 for TP53. ATM and CHEK2 kinases, activated by double strand DNA breaks, phosphorylate TP53, reducing its affinity for MDM2. At the same time, ATM phosphorylates MDM2, preventing MDM2 dimerization. Both ATM and CHEK2 phosphorylate MDM4, triggering MDM2-mediated ubiquitination of MDM4. Cyclin G1 (CCNG1), transcriptionally induced by TP53, targets the PP2A phosphatase complex to MDM2, resulting in dephosphorylation of MDM2 at specific sites, which can have either a positive or a negative impact on MDM2 function.

In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53.

In addition to ubiquitinating MDM4, MDM2 can also undergo auto-ubiquitination. MDM2 and MDM4 can be deubiquitinated by the ubiquitin protease USP2. The ubiquitin protease USP7 can deubiquitinate TP53, but in the presence of DAXX deubiquitinates MDM2.

The tumor suppressor p14-ARF, expressed from the CDKN2A gene in response to oncogenic or oxidative stress, forms a tripartite complex with MDM2 and TP53, sequesters MDM2 from TP53, and thus prevents TP53 degradation.

For review of this topic, please refer to Kruse and Gu 2009.