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Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).
While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005).
The nuclear localization of MDM2 is positively regulated by AKT- or SGK1- mediated phosphorylation (Mayo and Donner 2001, Zhou et al. 2001, Amato et al. 2009, Lyo et al. 2010). Phosphorylation of MDM2 by CDK1 or CDK2 decreases affinity of MDM2 for TP53 (Zhang and Prives 2001). ATM and CHEK2 kinases, activated by double strand DNA breaks, phosphorylate TP53, reducing its affinity for MDM2 (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998, Chehab et al. 1999, Chehab et al. 2000). At the same time, ATM phosphorylates MDM2, preventing MDM2 dimerization (Cheng et al. 2009, Cheng et al. 2011). Both ATM and CHEK2 phosphorylate MDM4, triggering MDM2-mediated ubiquitination of MDM4 (Chen et al. 2005, Pereg et al. 2005). 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 (Okamoto et al. 2002).
In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007).
In addition to ubiquitinating MDM4 (Pereg et al. 2005), MDM2 can also undergo auto-ubiquitination (Fang et al. 2000). MDM2 and MDM4 can be deubiquitinated by the ubiquitin protease USP2 (Stevenson et al. 2007, Allende-Vega et al. 2010). The ubiquitin protease USP7 can deubiquitinate TP53, but in the presence of DAXX deubiquitinates MDM2 (Li et al. 2002, Sheng et al. 2006, Tang et al. 2006).
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 (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005).
For review of this topic, please refer to Kruse and Gu 2009.