MDM-2, p53

MDM-2, p53

Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. MDM2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and an inhibitor of p53 transcriptional activation.

An overview of MDM2

Murine double minute 2 (MDM2) was initially discovered in BALB/3T3 cells with spontaneous transformation by Cahily-Snyder in 1987, and its amplified expression is related to the occurrence of tumor cells. The protein p53, one of the most important human tumor suppressors, is activated by carcinogens, DNA damage, heat shock and other stimulations, regulating DNA repair, apoptosis, aging, autophagy, etc. MDM2 in human and its homologous protein are the main negative regulatory proteins of p53. MDM2 can regulate the function of p53 through mediating the degradation of p53 proteins and inhibiting the transcriptional activity of p53.

Inhibition of MDM2

Studies on mice models show that the loss of p53 function can induce tumors, and the reactivation of p53 gene can effectively prevent tumors from developing in vivo. The negative feedback regulatory ring between MDM2-p53 provides an efficient therapeutic target for the treatment of malignant tumors. There are three major therapeutic methods: (1) down-regulating the expression of MDM2; (2) inhibiting the activity of MDM2 ubiquitin-ligase; (3) blocking p53-MDM2 binding. The effective drugs that have been reported can be divided into three categories including peptides and their analogues, modified p53 proteins and non-peptide small molecular compounds targeting the interaction of MDM2-p53. Currently, Nutlins and NJ-26854165 have aroused wide interest as MDM2 inhibitors. Nutlins interferes with the interaction between MDM2-p53, thereby blocking cell cycle progression and promoting cell apoptosis. NJ-26854165 affects the interaction of MDM2-p53 by binding to MDM2, activating the p53 pathway and mediating cell cycle arrest and apoptosis.

MDM2 and diseases

Accumulating evidence indicates that the overexpression or amplification of MDM2 gene exist in some tumors. It is believed that MDM2 plays an essential role in various tumors, such as cancers in lung, breast, stomach, esophagus and more on. Although scientists have confirmed MDM2 is associated with tumors, the function of MDM2 in tumors remains controversial and more researches on MDM2 gene are needed.

ReferenceS:

1. Chunhong, L. I., Hongjin, D. U., Wen, X. & Sun, H. Advances in inhibitors of MDM2 and MDM4. Journal of China Pharmaceutical University 46, 1-15 (2015).

2. Haupt et al. The role of MDM2 and MDM4 in breast cancer development and prevention. Journal of Molecular Cell Biology 9, 53-61 (2017).

3. Mendoza, M., Mandani, G. & Momand, J. The MDM2 gene family. Biomolecular Concepts 5, 9-19 (2014).

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