MDM2 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the MDM2 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | MDM2 |
|---|---|
| Full Name | MDM2 proto-oncogene |
| Gene Type | Protein coding |
| Chromosomal Location | 12q15 |
| NCBI Gene ID | 4193 ncbi.nlm.nih.gov/gene/4193 |
| Ensembl ID | ENSG00000135679 |
| UniProt ID | Q00987 |
| OMIM ID | 164785 |
| HGNC ID | 6973 |
| Aliases | HDM2, ACTFS |
Description
The MDM2 gene encodes a nuclear-localized E3 ubiquitin ligase that is a critical negative regulator of the p53 tumor suppressor. MDM2 binds to the N-terminal transactivation domain of p53, inhibiting its transcriptional activity and promoting its ubiquitin-dependent degradation. This interaction is essential for controlling p53 levels in normal cells. MDM2 is overexpressed in many human cancers, often through gene amplification or enhanced transcription, leading to inactivation of p53 and contributing to tumorigenesis. The gene also has p53-independent functions in various cellular processes including cell cycle regulation, apoptosis, and DNA damage response.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various types) | MDM2 amplification or overexpression leads to increased degradation of p53, impairing its tumor suppressor function. This promotes cell survival and proliferation. | Amplification of MDM2 is observed in sarcomas, gliomas, and breast cancer (COSMIC, TCGA). |
| Li-Fraumeni-like syndrome | Germline mutations in MDM2 (e.g., SNP309) may increase MDM2 expression, reducing p53 activity and predisposing to early-onset cancers. | Case reports and association studies (OMIM, ClinVar). |
| Atypical lipomatous tumor/Well-differentiated liposarcoma | MDM2 gene amplification is a hallmark of these tumors, used as a diagnostic marker. | FISH and CGH studies (COSMIC, literature). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 12.5 | Medium |
| Lymph node | 10.2 | Medium |
| Spleen | 9.8 | Medium |
| Bone marrow | 8.5 | Low |
| Brain | 7.0 | Low |
| Liver | 5.2 | Low |
| Kidney | 4.8 | Low |
| Heart | 3.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MCF7 (breast cancer) | 15.3 | High expression; p53 wild-type |
| A549 (lung cancer) | 12.1 | Moderate expression |
| HeLa (cervical cancer) | 10.5 | Moderate expression |
| HCT116 (colon cancer) | 9.2 | Moderate expression |
| K562 (leukemia) | 7.8 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| SNP309 (rs2279744) | SNV (T>G) | ~30% in general population | Increases MDM2 promoter activity, leading to higher MDM2 expression and attenuated p53 response. |
| Amplification | Copy number gain | Variable; common in sarcomas (up to 30%) | Overexpression of MDM2, leading to p53 inactivation. |
| Missense mutations (e.g., p.S22F) | Missense | Rare (<1%) | May alter MDM2-p53 interaction or stability. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in MDM2 are rare and typically not observed in cancers, as MDM2 is an oncogene. However, experimental mutations that disrupt its E3 ligase activity lead to p53 stabilization and growth suppression.
Gain of Function (GOF)
Gain-of-function mutations or amplifications increase MDM2 expression, enhancing p53 degradation and promoting tumorigenesis. SNP309 is a common gain-of-function variant.
Dominant Negative (DN)
Dominant-negative mutations have been described in experimental settings where mutant MDM2 can inhibit wild-type MDM2 function, leading to p53 activation. Such mutations are not commonly found in human cancers.
View complete mutation data：
Gene Ontology (GO)
| • ubiquitin protein ligase activity | • protein binding |
| • zinc ion binding | • p53 binding |
| • regulation of apoptotic process | • cell cycle arrest |
| • DNA damage response | • protein ubiquitination |
Pathways
• p53 signaling pathway
• Ubiquitin mediated proteolysis
• Cell cycle - G1/S checkpoint
• Apoptosis
Protein Summary
The MDM2 protein is a 491-amino acid E3 ubiquitin ligase that primarily regulates p53. It contains an N-terminal p53-binding domain, a central acidic domain, a zinc finger domain, and a C-terminal RING finger domain responsible for ubiquitin ligase activity. MDM2 ubiquitinates p53, targeting it for proteasomal degradation. It also auto-ubiquitinates itself, allowing for self-regulation. MDM2 is overexpressed in many cancers, often due to gene amplification, and is a major therapeutic target for reactivating p53 in tumors.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MDM2 Knockout HeLa Cell Line | EDC90538 | Human | 4193 | Details Get a Quote |
| MDM2 Knockout HEK293 Cell Line | EDC90667 | Human | 4193 | Details Get a Quote |
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