MDM2

Official Full Name

MDM2 proto-oncogene

Organism

Homo sapiens

GeneID

4193

Background

This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells. [provided by RefSeq, Jun 2013]

Synonyms

HDMX; LSKB; hdm2; ACTFS;

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Detailed Information

Murine double minute 2 (MDM2) is an important negative regulator of p53, regulating cell proliferation and apoptosis through p53 pathway and non-p53-dependent pathway. It plays an important role in the development of tumors. At present, MDM2 gene mutation, amplification and overexpression are confirmed in various human tumors, and the expression and dysfunction of this gene have different effects on the susceptibility, biological behavior, prognosis and treatment of malignant tumors.

Biological Function of MDM2

Numerous studies have shown that p53 protein is one of the most important molecules in human tumorigenesis. The tumor suppressor gene TP53 inhibits cell proliferation and promotes cell apoptosis by regulating cell cycle arrest during cell cycle arrest, apoptosis, and DNA repair. Its functional status affects tumorigenesis and development, so the prognosis and the relationship between this gene and tumor patients Chemotherapeutic drug sensitivity is related. Inactivation of p53 is implicated in most human tumors, including TP53 mutations, deletion of p53 positive regulators, inactivation, methylation of the p53 promoter, and overexpression of MDM2 and its family members.

Figure 1. Regulation of the Mdm2–p53 pathway by the ubiquitin E3 ligase MARCH7. (Zhao, et al. 2018)

As an important negative regulator of p53 function, MDM2 is an important component of p53 signaling pathway and plays an important role in the development of tumors. A variety of cellular stresses such as hypoxia, DNA damage, and oncogene activation simultaneously activate p53 and its downstream MDM2 gene. When TP53 gene activates cell cycle regulation, the level of p53 is down-regulated due to elevated MDM2 level, leading to the formation of a negative feedback regulatory loop, which precisely regulates intracellular p53 levels and regulates cell proliferation and apoptosis. MDM2 can regulate the function of p53 in several ways. MDM2 can directly bind to p53, block the interaction of p53 protein with related transcription factors, inhibit the transcription factor activity of p53, and thus inhibit the transcription of p53 downstream genes. MDM2 can also mediate the transfer of p53 protein binding from it to the cytoplasm. The E3 ubiquitinating enzyme activity of MDM2 enables ubiquitination of its associated p53 protein, which is then degraded by proteolytic enzymes.

MDM2 and Malignant Tumor

In recent years, in breast cancer, studies have shown that MDM2 SNP309 polymorphism is mostly related to race, especially in women in China, that is, women with SNP polymorphism have breast cancer than women without this polymorphism. The risk is great. In addition, immunohistochemistry was used to detect the expression of MDM2 in 90 invasive ductal tissues of breast and 30 normal tissues. The positive rate of expression in cancer tissues was 81. 1%, significantly higher than the positive rate of expression in normal tissues. 3%, its overexpression is associated with the presence or absence of axillary lymph node metastasis and pathological grade, indicating that this protein plays an important role in the occurrence, development and metastasis of invasive ductal carcinoma of the breast.

The expression of MDM2 in 70 cases of hepatocellular carcinoma and 40 cases of adjacent tissues was detected by immunohistochemical EliVision method. The results showed that the positive expression rate of MDM2 in hepatocellular carcinoma was significantly higher than that in adjacent tissues. The rate was statistically significant in the presence or absence of lymph node metastasis and tumor size. This suggests that abnormalities in the MDM2 gene may be a poor indicator of the prognosis of hepatocellular carcinoma. The expression level of MDM2 protein in laryngeal squamous cell carcinoma was detected by immunohistochemistry. The results showed that MDM2 was highly expressed in laryngeal carcinoma tissues, and the lower the degree of differentiation, the higher the positive expression rate.

References:

Zhao, K. , Yang, Y. , Zhang, G. , Wang, C. , Wang, D. , & Wu, M. , et al. (2018). Regulation of the mdm2–p53 pathway by the ubiquitin e3 ligase march7. EMBO reports, e44465.
Lu, J., Mceachern, D., Li, S., Ellis, M. J., & Wang, S. (2016). Reactivation of p53 by mdm2 inhibitor mi-77301 for the treatment of endocrine-resistant breast cancer. Molecular Cancer Therapeutics, 15(12), 2887.
Rubio-Patiño, Camila, Trotta, A. P. , & Chipuk, J. E. . (2018). Mdm2 and mitochondrial function: one complex intersection. Biochemical Pharmacology.

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