MDM4

Official Full Name

MDM4 regulator of p53

Organism

Homo sapiens

GeneID

4194

Background

This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]

Synonyms

HDMX; MDMX; MRP1; BMFS6;

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Detailed Information

MDM4 (routine double minute 4, MDMX, HDMX) is an important regulator of p53 upstream. Its structure is similar to that of MDM2, but its function is more complicated and controversial. On the one hand, it is similar to MDM2 and has oncogene activity. Its high expression leads to the inactivation of the tumor suppressor gene p53 and induces tumors. On the other hand, it activates p53 and promotes apoptosis. MDM4 has different regulatory pathways under different external stresses.

MDM4 Features

MDM4 is not a target gene for P53 and does not have ubiquitin protease activity. It mainly cooperates with MDM2 to exert its ubiquitin protease activity by regulating the activity of P53. MDM4 also increases and stabilizes P53 protein expression by dependent/independent MDM2, and these two completely opposite regulatory approaches may indicate that MDM4 is a multifunctional protein. Mice lacking the MDM4 gene had a higher incidence of tumors than wild-type mice. The study found that MDM4 located in the mitochondria positively regulates P53. Decreased MDM4 protein levels diminished P53 apoptosis induced by different genotoxicities (such as UV, anticancer drugs, etc.) and were independent of P53 transcriptional activity. Mitochondria MDM4 is approximately 1/10 of the cytoplasm and binds to Bcl-2, anchoring Bcl-2 to the mitochondrial outer membrane. Under the stimulation of apoptosis signal, mitochondrial MDM4 stably localizes in mitochondria, promotes P53 Ser46 phosphorylation, and binds with Bcl-2 to form a complex, which promotes the release of cytochrome c. However, studies have shown that MDM4 exerts an anti-apoptotic effect in differentiated mature neurons. This may be related to the fact that the P53 mitochondrial apoptotic pathway is not present in all cell types. At present, some scholars believe that MDM4 may play different roles under different cell states and damage factors.

Figure 1. Mechanism of p53 activation in response to DNA damage. (Meek, et al.2015)

P53-MDM2-MDM4 Regulation Network

In vitro experiments suggest that MDM2 and MDM4 are functionally related to each other, MDM4 can stabilize the expression of MDM2, and MDM2 is beneficial to the nuclear translocation of MDM4. However, in vivo experimental studies have found that MDM2 and MDM4 have different and complementary effects on the regulation of P53. The prerequisite for initiation of the P53 pathway after DNA damage is the degradation of MDM2 by itself and MDM4. Studies have proposed a dynamic model of P53 damage response. In normal cells, P53 is maintained at a low level due to the inhibition of MDM2 and MDM4. After cell damage, MDM2 degrades itself and MDM4, and P53 expression and activity begin to increase. P53 activation also increases MDM2 expression. Further degradation of MDM4, P53 is fully activated. After the elimination of the injury factors, the accumulated MDM2 again exerts its ubiquitin protease activity with P53 as the target, MDM4 expression also increases, and P53 activity decreases.

MDM4 and Tumor

Studies have shown that MDM4 expression is detected in a variety of tumor tissues. The results of MDM4 knockout mice confirmed the regulation of p53 by MDM4. Mitochondrial MDM4 regulates cisplatin reactivity in tumor therapy, and human ovarian tumors with high expression of MDM4 are more effective in treating cisplatin lower expression. MDM4 gene amplification was found in some tumors with wild-type P53 expression, such as breast cancer, glioblastoma, and retinoblastoma, but MDM4 was down-regulated in some tumors. Therefore, drugs developed for MDM4 may require tissue specificity. Moreover, although the structures of P53-MDM2 and P53-MDM4 interacted similarly, the compounds that inhibited P53-MDM2 had weak antagonism against P53-MDM4. Tumor cells that combined with Nutlin 3a and siRNA MDM4 showed greater P53 activity.

References:

Meek, & David?W. (2015). Regulation of the p53 response and its relationship to cancer. Biochemical Journal, 469(3), 325-346.
Boris, B. , & Franck, T. . (2017). Targeting mdm4 splicing in cancers. Genes, 8(2), 82-.
Haupt, S. , Vijayakumaran, R. , Panimaya, J. , Burgess, A. , Lim, E. , & Haupt, Y. . (2017). The role of mdm2 and mdm4 in breast cancer development and prevention. Journal of Molecular Cell Biology, mjx007.

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