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Function

Mdm2 is an E3 ubiquitin ligase that ubiquitylates and targets p53 for degradation. MDM2 and the closely related MDM4 are two of the main inhibitory proteins of the p53 pathway. The p53 pathway is activated when the cell is distressed and needs to be broken down. The p53 pathway leads to the ceasing of proliferation of the cell, or cell death. Too much MDM2 can turn off the p53 pathway, allowing the cell to grow uncontrollably, allowing for tumor growth. The association between p53 and the MDM proteins can be seen in . On the other hand, if MDM2 or MDM4 is under regulated, p53 will overwork, causing cell death more often and earlier on than necessary.^[1]

Relevance

Often, the p53 pathway is compromised due to the over expression of proteins such as MDM2 or MDM4. This over expression can lead to decreased activity of p53 which allows the cell to proliferate even when the body signals it to be destroyed. This is thought to be one of the lead causes of tumor progression^[1]. Data involving MDM2 and the SNP285 polymorphism within its promotor region have been researched, and this region has been shown to be significantly linked to a decreased cancer risk^[2]. It is believed that further MDM2 research and therapy could possibly lead to an anticancer strategy ^[3]. However, the cancer cells are very good at acquiring mutations to allow them to survive even in the presence of these drugs. Also, adverse side effects have been noted when trying to use these anti-cancer strategies^[1].

Structural highlights

Although there is a lot of research currently underway that involves the MDM2-p53 interactions, it is unsure exactly how these two molecules interact. This is in part because MDM2’s receptor structure contains highly flexible parts. There is evidence that has shown that as the binding with p53 occurs, the MDM2 structure changes conformation from “closed” to “open.” In the closed conformation, there is an N-terminus fragment (residues 25-109) that forms a lid that covers its hydrophobic binding site. This shows that there are many intermediate levels of binding for the MDM2 complex. During the interaction with p53, it is thought that the N-terminus fragment interacts with a short, helical region of p53 ^[4].