MDM2 Gene Editing    

In recent 30 years, murine double minute 2 (MDM2) has been widely investigated for its diverse biological activities in human development, tissue regeneration, and inflammation, although its oncogenic roles in human cancers have been considered to be the most important function. MDM2 has been confirmed to directly bind to the p53 tumor suppressor, restrain its transcriptional activity and protein stability, and inhibit p53-mediated cell cycle arrest and cell apoptosis. The p53 protein is widely expressed in human cells and tight control of p53 activation by MDM2, which is necessary for embryogenesis and development. The deregulation of the MDM2-p53 pathways contributes to cancer and noncancer diseases. These activities provide a reason for inhibiting MDM2 to treat and prevent human diseases.

MDM2-p53 Interaction

P53 is a tumor suppressor protein that blocks mitogenic signals in the nucleus. The p53 tumor suppressor protein induces apoptosis and cell cycle arrest in response to different types of cellular stress. Typically, p53 expression is strictly regulated in normal, unstressed cells; however, p53 levels rise rapidly in response to DNA damage and cellular stress, such as oxidative and deregulated oncogene expression. The MDM2 protein is an important regulator of p53 protein levels. MDM2 inhibits p53 by binding to residues 12-26 of the transactivating domain within the p53 N-terminus, which is necessary to increase RNA polymerase II-mediated transcription. This interferes with p53-mediated transactivation through forming a complex with p53.

Figure 1. Activation of p53 by MDM2 inhibition. (Konopleva M, et al., 2020)

The MDM2 gene contains two promoters: P1 and P2. P1 is constitutively active in many low-level cells. The p53-responsive P2 promoter contains two p53 binding sites and is stimulated in response to cellular stress in a p53-dependent manner. It is through interaction with these sites that p53 mediates transcription of the MDM2 gene, thus forming the p53 component of the p53-MDM2 negative-feedback loop. The autoregulatory circuit formed between p53 and MDM2 is critical for both keeping p53 in check in unstressed cells and recovering low levels of p53 after milder forms of stress. This relationship leads to oscillation of the cellular levels of the two proteins, which has been studied both in populations of cells and at the single-cell level.

MDM2 and Cancer Therapy

p53 gene is an attractive target for novel cancer therapy due to the high frequency of mutations in p53 resulting in cancerous growth. Therefore, activation of the p53 tumor suppressor gene and thereby activating its related pathway in malignant tumors may be considered an attractive method for cancer therapy. Because MDM2 functions as a primary inhibitor of the p53 tumor suppressor function, agents that target MDM2 can reactivate wild-type p53. MDM2 inhibits p53 through a variety of mechanisms that are dependent on its direct interaction with p53. Thus, peptides or nonpeptide small molecules designed to block the MDM2–p53 protein-protein interaction can result in an increase of p53 protein and transcriptional activation of p53. By utilizing the powerful tumor suppressor function of p53, such compounds may have therapeutic potential for the treatment of human cancer that retains wild-type p53.

Based on the strategy of blocking the protein-protein interaction between p53 and MDM2, some small molecules have been developed, with some currently being studied in clinical trials. In hematologic malignancies, such as acute myeloid leukemia (AML)—in which TP53 mutations are rare (5–8% in newly diagnosed AML cases)—targeting MDM2 is a particularly attractive therapeutic strategy. Of note, overexpression of MDM2 is associated with poor prognosis in AML. MDM2 inhibition is also being evaluated in the clinic in solid tumors.

MDM2 Gene Editing Services

CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively MDM2 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• MDM2 Gene Knockout: We offer MDM2 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service covers from sgRNA design and construction, pronuclear microinjection to Founders genotyping and breeding.
• MDM2 Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop MDM2 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of MDM2 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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