The p53 protein is notoriously unstable, which is due to changeable degradation process that occurs in ubiquitin-dependent and ubiquitin-independent systems of 20S and 26S proteasomes.
Mdm2 play a key role in regulation of p53 activity -
• Mdm2 is an important negative regulator of the p53 tumor suppressor.
• Mdm2 binds to p53,preventing its action and transport it from the nucleus to the cytosol.
• Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53.
• Mdm2 is a p53 responsive gene—that is, its transcription can be activated by p53. Thus when p53 is stabilized and activation of p53 increases the amount of mdm2.
So the interaction between p53 and mdm2 forms a negative feedback loop in which the two componenets limit each other’s activity.
• Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. Mdm2 is capable of auto-polyubiquitination, in complex with p300.
Fig: Regulation of Degradation of P53 Protein in Proteaosome
• Some other E3 ubiquitin ligases (Cop1, Pirh2, ARFBP/ MULE, CHIP) have been recently found to be connected to regulation of p53 levels.
• HAUSP can remove ubiquitin from p53 itself leading to its stabilization .By inducing opposite effects within the p53 degrading system.
• When p53 is phosphorylated,mdm2 is incapable to bind p53 and no p53 degradation.
• 20S proteasomes(Ubiquitin-independent )is regulated by the NAD(P)H-dependent quinine oxidoreductase NQO1. In the presence of NADH the NQO1 binds to such proteins and prevents their degradation in the 20S proteasome.
• An important regulator of the Mdm2-dependent degradation of p53 is p14ARF (or ARF),which mediates upregulation of p53 in response to oncogene activation.
• ARF has tumor suppressor activity, and its One of the binding partners of ARF is the Mdm2 protein. By binding to Mdm2, ARF inhibits its ubiquitin ligase activity, leading to p53 stabilization and the induction of apoptosis..
• ARF can also block the other E3 ligase ARF-BP (or MULE), which also participates in degradation of p53..