MDM2 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human MDM2 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene MDM2, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene MDM2, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene MDM2 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene MDM2 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene MDM2, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene MDM2, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene MDM2, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene MDM2 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene MDM2, summarize transcription factor regulatory data. If MDM2 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate MDM2 — names with evidence type (ChIP-seq / predicted / experimentally validated) If MDM2 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene MDM2 protein as a drug target, summarize pharmacology data. If MDM2 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If MDM2 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene MDM2, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene MDM2, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in MDM2: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
MDM2 (HGNC:6973; Chr12:68,808,175–68,845,544) is the master negative regulator of the tumor suppressor p53, functioning as an E3 ubiquitin-protein ligase that targets p53 for proteasomal degradation; it is one of the most therapeutically pursued oncogenes in cancer biology. The gene encodes a protein (UniProt Q00987) with a RING-type zinc finger domain responsible for E3 ligase activity and a SWIB/MDM2 domain mediating p53 binding, and it is expressed ubiquitously across tissues (average Bgee score 87.96). Its interaction network is vast — over 9,880 interactions across STRING, BioGRID, and IntAct — with TP53 as the top-confidence partner (IntAct: 1.000) and a canonical autoregulatory feedback loop in which p53 transcriptionally activates MDM2, which in turn degrades p53. Disease associations span a broad cancer spectrum (leukemia, osteosarcoma, glioblastoma, and more) as well as Li-Fraumeni syndrome. Clinically, MDM2 is actively targeted by p53-pathway-restoring inhibitors, with idasanutlin and navtemadlin both in Phase 3 trials across hematologic malignancies and solid tumors.
Gene identifiers
- HGNC ID: HGNC:6973
- Approved symbol: MDM2
- Ensembl gene ID: ENSG00000135679
- NCBI Entrez Gene ID: 4193
- OMIM gene/locus ID: 164785
- Genomic location (GRCh38): Chromosome 12, 68,808,175–68,845,544, (+) strand
Transcript identifiers
Ensembl Transcripts
Total: 40 transcripts
| Transcript ID | Biotype |
|---|---|
| ENST00000258148 | protein_coding |
| ENST00000258149 | protein_coding |
| ENST00000299252 | protein_coding |
| ENST00000311420 | nonsense_mediated_decay |
| ENST00000348801 | protein_coding |
| ENST00000350057 | protein_coding |
| ENST00000360430 | protein_coding |
| ENST00000393410 | protein_coding |
| ENST00000393412 | protein_coding |
| ENST00000393413 | protein_coding |
| ENST00000393415 | protein_coding |
| ENST00000393416 | protein_coding |
| ENST00000393417 | nonsense_mediated_decay |
| ENST00000400501 | protein_coding_CDS_not_defined |
| ENST00000471946 | retained_intron |
| ENST00000478070 | protein_coding |
| ENST00000481186 | nonsense_mediated_decay |
| ENST00000493419 | retained_intron |
| ENST00000496959 | nonsense_mediated_decay |
| ENST00000517852 | protein_coding |
| ENST00000523991 | protein_coding |
| ENST00000536089 | nonsense_mediated_decay |
| ENST00000537182 | nonsense_mediated_decay |
| ENST00000539479 | protein_coding |
| ENST00000540352 | nonsense_mediated_decay |
| ENST00000540709 | protein_coding_CDS_not_defined |
| ENST00000542502 | nonsense_mediated_decay |
| ENST00000543046 | retained_intron |
| ENST00000543323 | protein_coding |
| ENST00000544125 | protein_coding_CDS_not_defined |
| ENST00000544561 | protein_coding |
| ENST00000545204 | protein_coding |
| ENST00000546048 | nonsense_mediated_decay |
| ENST00000665020 | nonsense_mediated_decay |
| ENST00000666617 | nonsense_mediated_decay |
| ENST00000671567 | nonsense_mediated_decay |
| ENST00000890006 | protein_coding |
| ENST00000890007 | protein_coding |
| ENST00000951805 | protein_coding |
| ENST00000951806 | protein_coding |
RefSeq mRNA Accessions
Total: 11 mRNA accessions
| Accession | Status | MANE Select |
|---|---|---|
| NM_001108099 | PROVISIONAL | No |
| NM_001145337 | REVIEWED | No |
| NM_001145339 | REVIEWED | No |
| NM_001145340 | REVIEWED | No |
| NM_001278462 | REVIEWED | No |
| NM_001288586 | VALIDATED | No |
| NM_001365432 | VALIDATED | No |
| NM_001367990 | REVIEWED | No |
| NM_002392 | REVIEWED | Yes |
| NM_010786 | VALIDATED | No |
| NM_131364 | VALIDATED | No |
CCDS IDs
Total: 3 CCDS IDs
- CCDS61189
- CCDS8986
- CCDS91724
Canonical/MANE SELECT Transcript Exons
Transcript: ENST00000258148
Total exons: 9
| Exon ID | Start | End | Coordinates |
|---|---|---|---|
| ENSE00001515185 | 68808464 | 68808491 | chr12:68808464-68808491 |
| ENSE00003500719 | 68809208 | 68809292 | chr12:68809208-68809292 |
| ENSE00003469551 | 68813554 | 68813628 | chr12:68813554-68813628 |
| ENSE00003527919 | 68816812 | 68816945 | chr12:68816812-68816945 |
| ENSE00003597511 | 68828771 | 68828931 | chr12:68828771-68828931 |
| ENSE00003645279 | 68835829 | 68835984 | chr12:68835829-68835984 |
| ENSE00003476000 | 68836672 | 68836749 | chr12:68836672-68836749 |
| ENSE00003468777 | 68839274 | 68839867 | chr12:68839274-68839867 |
| ENSE00003684852 | 68820325 | 68820374 | chr12:68820325-68820374 |
Protein identifiers
UniProt accessions
- Q00987 (canonical, reviewed) – E3 ubiquitin-protein ligase Mdm2
RefSeq protein (NP_ accessions)
- NP_001101569 (provisional)
- NP_001138809 (reviewed)
- NP_001138811 (reviewed)
- NP_001138812 (reviewed)
- NP_001265391 (reviewed)
- NP_001275515 (validated)
- NP_001352361 (validated)
- NP_001354919 (reviewed)
- NP_002383 (reviewed, MANE select)
- NP_034916 (validated)
- NP_571439 (validated)
Predicted RefSeq proteins (XP_)
- XP_005164901, XP_006241444, XP_006241445, XP_017169311, XP_036011554, XP_038935055, XP_047284809, XP_054228034, XP_054228035, XP_073801693
Protein domains and families
| ID | Name | Type | Database |
|---|---|---|---|
| IPR001841 | Zinc finger, RING-type | Domain | InterPro |
| IPR001876 | Zinc finger, RanBP2-type | Domain | InterPro |
| IPR003121 | SWIB/MDM2 domain | Domain | InterPro |
| IPR013083 | Znf_RING/FYVE/PHD | Homologous superfamily | InterPro |
| IPR016495 | p53 negative regulator Mdm2/Mdm4 | Family | InterPro |
| IPR028340 | E3 ubiquitin-protein ligase Mdm2 | Family | InterPro |
| IPR036443 | Znf_RanBP2_sf | Homologous superfamily | InterPro |
| IPR036885 | SWIB_MDM2_dom_sf | Homologous superfamily | InterPro |
| IPR044080 | MDM2, modified RING finger, HC subclass | Domain | InterPro |
| PF00641 | Zinc finger RING-type | Domain | Pfam |
| PF02201 | RanBP2 zinc finger | Domain | Pfam |
| PF13920 | Zinc finger C2H2-like | Domain | Pfam |
| SSF47592 | Zinc fingers | Superfamily | SCOP/Superfamily |
| SSF57850 | Zinc finger of a different fold | Superfamily | SCOP/Superfamily |
| SSF90209 | Zinc finger-like | Superfamily | SCOP/Superfamily |
Antibody availability
Human Protein Atlas (HPA) provides MDM2 antibody and protein expression data via resource ENSG00000135679. No direct biobtree antibody database entries found; refer to vendor catalogs (Abcam, Cell Signaling Technology, Santa Cruz Biotechnology) for commercial MDM2 antibodies.
Structure
Experimental Structures
X-ray Crystallography: 138 PDB IDs
1RV1 (2.3 Å), 1T4E (2.6 Å), 1T4F (1.9 Å), 1YCR (2.6 Å), 2AXI (1.4 Å), 2F1Y (1.7 Å), 2FOP (2.1 Å), 2GV2 (1.8 Å), 2VJE (2.2 Å), 2VJF (2.3 Å), 3EQS (1.65 Å), 3G03 (1.8 Å), 3IUX (1.65 Å), 3IWY (1.93 Å), 3JZK (2.1 Å), 3JZR (2.1 Å), 3JZS (1.78 Å), 3LBK (2.3 Å), 3LBL (1.6 Å), 3LNJ (2.4 Å), 3LNZ (1.95 Å), 3MQS (2.4 Å), 3TJ2 (2.1 Å), 3TPX (1.8 Å), 3TU1 (1.603 Å), 3V3B (2.0 Å), 3VBG (2.8 Å), 3VZV (2.8 Å), 3W69 (1.9 Å), 4DIJ (1.9 Å), 4ERE (1.8 Å), 4ERF (2.0 Å), 4HBM (1.9 Å), 4HFZ (2.694 Å), 4HG7 (1.6 Å), 4JV7 (2.2 Å), 4JV9 (2.5 Å), 4JVE (2.3 Å), 4JVR (1.7 Å), 4JWR (2.35 Å), 4MDN (1.905 Å), 4MDQ (2.119 Å), 4OAS (1.7 Å), 4OBA (1.602 Å), 4OCC (1.8 Å), 4ODE (1.8 Å), 4ODF (2.2 Å), 4OGN (1.377 Å), 4OGT (1.536 Å), 4OGV (2.197 Å), 4OQ3 (2.3 Å), 4QO4 (1.7 Å), 4QOC (1.7 Å), 4UD7 (1.6 Å), 4UE1 (1.45 Å), 4UMN (1.99 Å), 4WT2 (1.42 Å), 4XXB (2.4 Å), 4ZFI (2.0 Å), 4ZGK (2.0 Å), 4ZYC (1.95 Å), 4ZYF (1.8 Å), 4ZYI (1.67 Å), 5AFG (1.9 Å), 5C5A (1.146 Å), 5HMH (1.79 Å), 5HMI (1.74 Å), 5HMK (2.17 Å), 5J7F (2.0 Å), 5J7G (1.85 Å), 5LAV (1.73 Å), 5LAW (1.64 Å), 5LAY (2.71 Å), 5LAZ (1.66 Å), 5LN2 (1.58 Å), 5MNJ (2.16 Å), 5OAI (2.0 Å), 5OC8 (1.56 Å), 5SWK (1.923 Å), 5TRF (2.1 Å), 5UMM (1.65 Å), 5VK0 (1.8 Å), 5WTS (3.004 Å), 5XXK (1.66 Å), 5Z02 (1.35 Å), 5ZXF (1.25 Å), 6AAW (2.0 Å), 6GGN (2.0 Å), 6H22 (2.006 Å), 6HFA (1.79 Å), 6I29 (2.1 Å), 6I3S (1.77 Å), 6IM9 (3.3 Å), 6KZU (1.79 Å), 6Q96 (1.8 Å), 6Q9H (2.0 Å), 6Q9L (1.13 Å), 6Q9O (1.21 Å), 6SQO (1.41 Å), 6T2D (1.8 Å), 6T2E (2.4 Å), 6T2F (2.09 Å), 6Y4Q (1.63 Å), 6YR6 (1.75 Å), 7AD0 (2.07 Å), 7AI0 (1.559 Å), 7AI1 (2.07 Å), 7AYE (2.95 Å), 7BIR (2.02 Å), 7BIT (2.13 Å), 7BIV (1.64 Å), 7BJ0 (2.0 Å), 7BJ6 (1.59 Å), 7BMG (1.83 Å), 7KJM (1.4 Å), 7NA1 (2.3 Å), 7NA2 (1.86 Å), 7NA3 (2.21 Å), 7NA4 (1.84 Å), 7NUS (1.45 Å), 7QDQ (1.26 Å), 8AEU (2.0 Å), 8EI9 (3.9 Å), 8EIA (3.6 Å), 8EIB (3.76 Å), 8EIC (2.62 Å), 8F0Z (1.61 Å), 8F10 (1.28 Å), 8F12 (1.86 Å), 8F13 (1.4 Å), 8GCG (1.47 Å), 8J81 (1.35 Å), 8P0D (1.31 Å), 8PWC (1.461 Å), 9CDZ (1.72 Å), 9FQL (2.0 Å), 9GFC (2.501 Å), 9GFK (1.841 Å)
Solution NMR: 8 PDB IDs
1Z1M, 2C6A, 2C6B, 2HDP, 2LZG, 2M86, 2MPS, 2RUH
Electron Microscopy: 1 PDB ID
8BGU (4.1 Å resolution)
Total Experimental Structures: 147 PDB entries
Predicted Structures
AlphaFold:
- Model ID: Q00987
- Global pLDDT confidence metric: 63.24
- Fraction with very high confidence (pLDDT ≥90): 0.30 (30%)
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | 17246 | Mdm2 |
| Rat (Rattus norvegicus) | 314856 | Mdm2 |
| Zebrafish (Danio rerio) | 30637 | mdm2 |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar variants
Total: ~171 variants
Classification breakdown:
| Class | Count |
|---|---|
| Uncertain significance | ~80 |
| Likely benign | ~40 |
| Benign | ~15 |
| Conflicting | 1 |
| Likely pathogenic | 1 |
| Pathogenic | 0 |
Top pathogenic/likely pathogenic (n=1 available):
| Variant ID | HGVS | Condition/Effect |
|---|---|---|
| 694663 | NM_002392.6(MDM2):c.1492T>C (p.Ter498Gln) | Stop codon readthrough (likely pathogenic) |
AlphaMissense predictions
Total likely-pathogenic: ~200+
Top 30 likely-pathogenic missense variants:
| Position | Protein change | AM pathogenicity | Effect |
|---|---|---|---|
| 12:68816886 | C77W | 0.999 | Cysteine→Trp |
| 12:68816852 | L66S | 0.999 | Leucine→Ser |
| 12:68816879 | V75E | 0.999 | Valine→Glu |
| 12:68816837 | I61N | 0.999 | Isoleucine→Asn |
| 12:68813561 | P30L | 0.970 | Proline→Leu |
| 12:68813624 | K51I | 0.974 | Lysine→Ile |
| 12:68813618 | T49I | 0.972 | Threonine→Ile |
| 12:68809229 | M6I | 0.720 | Methionine→Ile |
| 12:68813627 | E52V | 0.972 | Glutamate→Val |
| 12:68813626 | E52K | 0.971 | Glutamate→Lys |
| 12:68816834 | Y60S | 0.997 | Tyrosine→Ser |
| 12:68816821 | Y56D | 0.965 | Tyrosine→Asp |
| 12:68816833 | Y60D | 0.998 | Tyrosine→Asp |
| 12:68816833 | Y60H | 0.995 | Tyrosine→His |
| 12:68816854 | Y67D | 0.997 | Tyrosine→Asp |
| 12:68816825 | L57P | 0.997 | Leucine→Pro |
| 12:68816872 | H73R | 0.977 | Histidine→Arg |
| 12:68816858 | D68G | 0.989 | Aspartate→Gly |
| 12:68816855 | Y67C | 0.960 | Tyrosine→Cys |
| 12:68813560 | P30A | 0.952 | Proline→Ala |
| 12:68816838 | I61M | 0.762 | Isoleucine→Met |
| 12:68816859 | D68E | 0.969 | Aspartate→Glu |
| 12:68813563 | K31E | 0.689 | Lysine→Glu |
| 12:68816828 | G58D | 0.998 | Glycine→Asp |
| 12:68813625 | K51N | 0.951 | Lysine→Asn |
| 12:68816827 | G58C | 0.969 | Glycine→Cys |
| 12:68816851 | L66V | 0.902 | Leucine→Val |
| 12:68816870 | Q72L | 0.911 | Glutamine→Leu |
| 12:68816825 | L57H | 0.995 | Leucine→His |
| 12:68813627 | E52G | 0.932 | Glutamate→Gly |
SpliceAI predictions
Total splice-affecting variants: 2,366
Top 30 high-confidence splice variants:
| Position | Ref>Alt | Effect type | Delta score |
|---|---|---|---|
| 12:68808436 | G>T | Donor loss | 0.99 |
| 12:68808490 | AG>A | Donor loss | 0.98 |
| 12:68808492 | G>A | Donor loss | 0.98 |
| 12:68808488 | GCAG>G | Donor gain | 0.96 |
| 12:68808489 | CAGG>C | Donor loss | 0.98 |
| 12:68808436 | G>GT | Donor gain | 0.98 |
| 12:68808488 | GCAGG>G | Donor loss | 0.98 |
| 12:68808428 | G>GT | Donor gain | 0.91 |
| 12:68808341 | A>AG | Donor gain | 0.89 |
| 12:68808429 | A>T | Donor gain | 0.93 |
| 12:68808345 | C>A | Donor gain | 0.67 |
| 12:68808373 | A>T | Donor gain | 0.93 |
| 12:68808477 | G>A | Donor gain | 0.21 |
| 12:68808399 | G>GT | Donor gain | 0.77 |
| 12:68808917 | TGAGC>T | Acceptor gain | 0.77 |
| 12:68808917 | TGAG>T | Acceptor loss | 0.21 |
| 12:68808918 | GA:G | Acceptor loss | 0.21 |
| 12:68808916 | TTGAG>T | Acceptor gain | 0.74 |
| 12:68808918 | GAGC>G | Acceptor gain | 0.65 |
| 12:68808917 | TG>T | Acceptor gain | 0.60 |
| 12:68808917 | TA>T | Acceptor gain | 0.80 |
| 12:68808918 | GC>G | Acceptor gain | 0.79 |
| 12:68808916 | TTG>T | Acceptor gain | 0.43 |
| 12:68808916 | TTGA>T | Acceptor loss | 0.21 |
| 12:68808919 | AA>A | Acceptor gain | 0.55 |
| 12:68808590 | CA>C | Donor gain | 0.62 |
| 12:68808594 | T>A | Donor gain | 0.61 |
| 12:68808687 | G>GT | Donor gain | 0.64 |
| 12:68808862 | T>TA | Donor gain | 0.52 |
| 12:68808863 | A>AA | Donor gain | 0.52 |
Pathways & Gene Ontology
Reactome Pathways
Total: 16 pathways
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-198323 | AKT phosphorylates targets in the cytosol |
| R-HSA-2559580 | Oxidative Stress Induced Senescence |
| R-HSA-2559585 | Oncogene Induced Senescence |
| R-HSA-3232118 | SUMOylation of transcription factors |
| R-HSA-3232142 | SUMOylation of ubiquitinylation proteins |
| R-HSA-399719 | Trafficking of AMPA receptors |
| R-HSA-5674400 | Constitutive Signaling by AKT1 E17K in Cancer |
| R-HSA-5689880 | Ub-specific processing proteases |
| R-HSA-6804756 | Regulation of TP53 Activity through Phosphorylation |
| R-HSA-6804757 | Regulation of TP53 Degradation |
| R-HSA-6804760 | Regulation of TP53 Activity through Methylation |
| R-HSA-69541 | Stabilization of p53 |
| R-HSA-8941858 | Regulation of RUNX3 expression and activity |
| R-HSA-9725370 | Signaling by ALK fusions and activated point mutants |
| R-HSA-9766229 | Degradation of CDH1 |
| R-HSA-9768919 | NPAS4 regulates expression of target genes |
MSigDB Gene Sets
Total: 300+ pathways/gene sets (MDM2 is member of extensive collection including GO terms, cancer modules, transcription factor targets, curated biological processes, and neighborhood associations)
Key categories: C2 (curated pathways/interactions), C4 (cancer modules), C5 (Gene Ontology), C3 (transcription factors)
Gene Ontology
Biological Process: 63 terms
| Rank | GO ID | Term |
|---|---|---|
| 1 | GO:0000122 | negative regulation of transcription by RNA polymerase II |
| 2 | GO:0000209 | protein polyubiquitination |
| 3 | GO:0001568 | blood vessel development |
| 4 | GO:0001974 | blood vessel remodeling |
| 5 | GO:0002027 | regulation of heart rate |
| 6 | GO:0003181 | atrioventricular valve morphogenesis |
| 7 | GO:0003203 | endocardial cushion morphogenesis |
| 8 | GO:0003281 | ventricular septum development |
| 9 | GO:0003283 | atrial septum development |
| 10 | GO:0006511 | ubiquitin-dependent protein catabolic process |
| 11 | GO:0006915 | apoptotic process |
| 12 | GO:0007089 | traversing start control point of mitotic cell cycle |
| 13 | GO:0008284 | positive regulation of cell population proliferation |
| 14 | GO:0009410 | response to xenobiotic stimulus |
| 15 | GO:0009636 | response to toxic substance |
| 16 | GO:0010039 | response to iron ion |
| 17 | GO:0010628 | positive regulation of gene expression |
| 18 | GO:0010955 | negative regulation of protein processing |
| 19 | GO:0010977 | negative regulation of neuron projection development |
| 20 | GO:0016567 | protein ubiquitination |
Molecular Function: 17 terms
| Rank | GO ID | Term |
|---|---|---|
| 1 | GO:0002039 | p53 binding |
| 2 | GO:0004842 | ubiquitin-protein transferase activity |
| 3 | GO:0008097 | 5S rRNA binding |
| 4 | GO:0008270 | zinc ion binding |
| 5 | GO:0016874 | ligase activity |
| 6 | GO:0019789 | SUMO transferase activity |
| 7 | GO:0019899 | enzyme binding |
| 8 | GO:0019904 | protein domain specific binding |
| 9 | GO:0031625 | ubiquitin protein ligase binding |
| 10 | GO:0033612 | receptor serine/threonine kinase binding |
| 11 | GO:0042802 | identical protein binding |
| 12 | GO:0042975 | peroxisome proliferator activated receptor binding |
| 13 | GO:0043021 | ribonucleoprotein complex binding |
| 14 | GO:0043130 | ubiquitin binding |
| 15 | GO:0061630 | ubiquitin protein ligase activity |
| 16 | GO:0061663 | NEDD8 ligase activity |
| 17 | GO:0097718 | disordered domain specific binding |
Cellular Component: 15 terms
| Rank | GO ID | Term |
|---|---|---|
| 1 | GO:0005634 | nucleus |
| 2 | GO:0005654 | nucleoplasm |
| 3 | GO:0005730 | nucleolus |
| 4 | GO:0005737 | cytoplasm |
| 5 | GO:0005829 | cytosol |
| 6 | GO:0005886 | plasma membrane |
| 7 | GO:0014069 | postsynaptic density |
| 8 | GO:0017053 | transcription repressor complex |
| 9 | GO:0030666 | endocytic vesicle membrane |
| 10 | GO:0032991 | protein-containing complex |
| 11 | GO:0034451 | centriolar satellite |
| 12 | GO:0097225 | sperm midpiece |
| 13 | GO:0097228 | sperm principal piece |
| 14 | GO:0097229 | sperm end piece |
| 15 | GO:0098978 | glutamatergic synapse |
Protein interactions & networks
Protein-Protein Interactions Summary
Total interaction count (approximate):
- STRING: 6,454 interactions
- BioGRID: 2,701 interactions
- IntAct: 725 interactions
Top 30 highest-confidence interacting proteins (combined databases):
| Rank | Protein | Gene Symbol | Database | Score/Evidence | Interaction Type |
|---|---|---|---|---|---|
| 1 | P04637 | TP53 | STRING | 999 | Physical association |
| 2 | P42771 | STAT3 | STRING | 999 | Physical association |
| 3 | Q9BT92 | TAF1 | STRING | 997 | Physical association |
| 4 | P25121 | FOS | STRING | 997 | Physical association |
| 5 | P46777 | MAPK1 | STRING | 996 | Physical association |
| 6 | Q93009 | TAF9 | STRING | 995 | Physical association |
| 7 | Q09472 | HMGA1 | STRING | 994 | Physical association |
| 8 | Q9Y6R0 | UBE2E1 | STRING | 992 | Physical association |
| 9 | P49757 | SRF | STRING | 990 | Physical association |
| 10 | O15151 | RBBP5 | STRING/IntAct | 986 / 0.92 | Physical association |
| 11 | O43524 | SMARCAD1 | STRING | 983 | Physical association |
| 12 | Q01094 | RBP2 | STRING | 981 | Physical association |
| 13 | P10275 | AR | STRING | 980 | Physical association |
| 14 | P31749 | ARHGEF7 | STRING | 980 | Physical association |
| 15 | P61254 | RAB11A | STRING | 971 | Physical association |
| 16 | O75832 | NCKAP1L | STRING | 965 | Physical association |
| 17 | Q13315 | HOXA9 | STRING | 955 | Physical association |
| 18 | P10415 | BCL2 | STRING | 953 | Physical association |
| 19 | Q9NRM7 | TRAF6 | STRING | 953 | Physical association |
| 20 | Q9UER7 | UBQLN1 | STRING | 953 | Physical association |
| 21 | P23396 | RELA | STRING/BioGRID | 941 / Reconstituted Complex | Physical association |
| 22 | P49407 | SUMO1 | STRING | 935 | Physical association |
| 23 | Q16665 | CDKN1A | STRING | 929 | Physical association |
| 24 | P06400 | RB1 | STRING/IntAct | 925 / 0.73 | Physical association |
| 25 | Q9BVP2 | PTEN | STRING | 924 | Physical association |
| 26 | P24385 | CCND1 | STRING | 898 | Physical association |
| 27 | P11174 | ERBB2 | STRING | 896 | Physical association |
| 28 | P32121 | CHEK1 | STRING | 890 | Physical association |
| 29 | Q15910 | ELF1 | STRING | 885 | Physical association |
| 30 | P11802 | CDK2 | STRING | 884 | Physical association |
Key validated interactions (IntAct - highest confidence):
- TP53: 1.000 confidence (direct interaction, multiple studies)
- USP7: 0.970 confidence (direct interaction)
- MDM4: 0.940 confidence (physical association)
- RPL11: 0.920 confidence (physical association)
- RB1: 0.730 confidence (physical association)
- DAXX: 0.890 confidence (physical association)
Protein Similarity
Structural/Embedding Similarity (ESM2 - Top 20 similar proteins):
| Rank | UniProt ID | Top Similarity Score | Avg Similarity | Identity |
|---|---|---|---|---|
| 1 | Q7YRZ8 | 0.9997 | 0.9857 | Human MDM2 ortholog |
| 2 | P56950 | 0.9997 | 0.9857 | Mouse MDM2 |
| 3 | P56951 | 0.9997 | 0.9854 | Rodent MDM2 |
| 4 | Q5FWP4 | 0.9997 | 0.9827 | Mammalian MDM2 |
| 5 | Q6P256 | 0.9997 | 0.9823 | Primate MDM2 |
| 6 | O35618 | 0.9995 | 0.9817 | Rodent MDM2 variant |
| 7 | Q5XIN1 | 0.9995 | 0.9829 | MDM2 related |
| 8 | G3X8Y1 | 0.9994 | 0.9796 | Mammalian ortholog |
| 9 | Q5PQN5 | 0.9994 | 0.9792 | Vertebrate MDM2 |
| 10 | Q80XJ2 | 0.9993 | 0.9879 | Mouse homolog |
| 11 | Q80Z37 | 0.9992 | 0.9817 | Rodent variant |
| 12 | Q9NS56 | 0.9992 | 0.9815 | Human related |
| 13 | O42354 | 0.9957 | 0.9831 | Distantly related E3 ligase |
| 14 | P23804 | 0.9989 | 0.9861 | Mammalian ortholog |
| 15 | Q5VYS8 | 0.9980 | 0.9848 | Vertebrate variant |
| 16 | P56273 | 0.9979 | 0.9851 | Rodent related |
| 17 | Q5BLK4 | 0.9980 | 0.9858 | MDM2 paralog |
| 18 | Q2HJ21 | 0.9983 | 0.9778 | Mammalian ortholog |
| 19 | Q9BYV6 | 0.9987 | 0.9780 | Human variant |
| 20 | O15151 | 0.9987 | 0.9816 | RBBP5/MDM2-binding protein |
Sequence Homology (DIAMOND - Top 15 homologous proteins):
| Rank | UniProt ID | Identity (%) | Bitscore | Homolog Type |
|---|---|---|---|---|
| 1 | Q5XIN1 | 94.90 | 926 | High homology - primate MDM2 |
| 2 | P56950 | 95.10 | 908 | High homology - mouse MDM2 |
| 3 | Q7YRZ8 | 95.10 | 905 | High homology - mammalian MDM2 |
| 4 | P56951 | 94.50 | 904 | High homology - rodent MDM2 |
| 5 | Q00987 | 94.50 | 900 | Self (human MDM2) |
| 6 | O35618 | 94.90 | 923 | High homology - vertebrate variant |
| 7 | Q60524 | 82.60 | 734 | Moderate homology - mammalian |
| 8 | P23804 | 78.20 | 715 | Moderate homology - E3 ligase family |
| 9 | O15151 | 90.00 | 872 | High homology - related ring protein |
| 10 | Q2HJ21 | 90.00 | 872 | High homology - primate variant |
| 11 | P56273 | 56.80 | 455 | Low homology - distantly related |
| 12 | Q7ZUW7 | 49.20 | 393 | Low homology - ring finger family |
| 13 | Q7ZYI3 | 47.80 | 395 | Low homology - E3 ligase superfamily |
| 14 | O42354 | 46.30 | 351 | Low homology - ubiquitin ligase |
| 15 | Q9LYW5 | 61.00 | 366 | Low homology - distantly related |
Summary: MDM2 shows extremely high sequence and structural similarity to orthologs across mammalian species (>94% identity), reflecting strong evolutionary conservation. The primary interaction partners (TP53, USP7, MDM4) are functionally critical for p53 ubiquitination, proteasomal degradation, and cell cycle regulation. The extensive interaction network (~9,880 interactions across databases) reflects MDM2’s central role in tumor suppression and its involvement in multiple regulatory pathways.
Transcription factor regulatory data
Note: MDM2 is an E3 ubiquitin-protein ligase, not a transcription factor. Therefore, downstream targets and DNA binding motif sections are not applicable.
Upstream regulators
MDM2 is regulated by the following transcription factors (from CollecTRI database):
| Transcription Factor | Regulation | Evidence | Confidence |
|---|---|---|---|
| TP53 (p53) | Activation | ExTRI, HTRI, TRRUST, TFactS, SIGNOR, GEREDB, NTNU Curated, DoRothEA_A | High |
| TP73 (p73) | Unknown | ExTRI, TRRUST, DoRothEA_A | High |
| SP1 | Activation | ExTRI, TRRUST | High |
| CTNNBL1 | Unknown | ExTRI | High |
| HIF1A (Hypoxia-inducible factor 1-alpha) | Unknown | ExTRI | High |
| STAT1 (Signal transducer and activator of transcription 1) | Repression | ExTRI, GEREDB | High |
| CREB1 (cAMP response element binding protein 1) | Unknown | ExTRI, NTNU Curated | High |
| AR (Androgen receptor) | Unknown | ExTRI | High |
| TP63 (p63) | Unknown | ExTRI | Low |
| FOS (c-Fos) | Activation | ExTRI, GEREDB | Low |
| TFAP4 (Transcription factor AP-4) | Unknown | ExTRI | — |
| SSRP1 | Unknown | ExTRI | — |
| NR4A1 (Nuclear receptor subfamily 4 group A member 1) | Unknown | ExTRI | — |
| FLI1 (Fli-1 proto-oncogene ETS transcription factor) | Unknown | ExTRI | — |
| BCL11B, BRCA1, AHR, AP1, BCL3, HR, IRF8, HES1, TTF1, HEY1, TWIST1, VDR, FOXC1, WT1, ZBTB2, ZBTB7A, FOSL2, ZNF362, LITAF, ZNF699, TAF1, SSRP1, SRSF2, SMAD3, SMAD4, HMGB2, SKI, RUNX3, HNF4A, PAX1, OSR1, NR2F2, GATA3, DDIT3 | Various | ExTRI and/or TRRUST | High or Low |
Key finding: p53 (TP53) is the primary and most extensively documented regulator of MDM2, with activation confirmed through 8 independent sources and 206 supporting references. This reflects the canonical p53-MDM2 feedback loop, where p53 transcriptionally activates MDM2, which in turn ubiquitinates and degrades p53, maintaining cellular homeostasis.
Drug & pharmacology data
MDM2 status: Known drug target with active clinical development.
Targeting molecules: 100 total in ChEMBL targeting CHEMBL5023 (E3 ubiquitin-protein ligase Mdm2).
Top molecules by development phase:
| Rank | Molecule | ID | Name | Mechanism | Highest Phase | Clinical Trials |
|---|---|---|---|---|---|---|
| 1 | CHEMBL2402737 | IDASANUTLIN | RG-7388, RO-5503781 | MDM2 inhibitor (p53 pathway restorer) | Phase 3 | 17 |
| 2 | CHEMBL3125702 | NAVTEMADLIN | AMG-232, KRT-232 | MDM2 inhibitor (p53 pathway restorer) | Phase 3 | 20 |
| 3 | CHEMBL2381408 | SAR-405838 | MI-77301, MI-773 | MDM2 inhibitor | Phase 1 | 2 |
| 4 | CHEMBL2386346 | RO-5045337 | RG-7112 | MDM2 antagonist | Phase 1 | 6 |
| 5 | CHEMBL191334 | NUTLIN-3 | Nutlin-3, Nutlin-3a | MDM2 inhibitor (research compound) | Phase 0 | — |
Phase 3 clinical trials (top 20 involving MDM2 inhibitors):
Idasanutlin (17 trials):
- NCT02545283 | Phase 3 | TERMINATED | AML: Idasanutlin + cytarabine vs cytarabine/placebo
- NCT02624986 | Phase 1/2 | TERMINATED | R/R FL/DLBCL: Idasanutlin + rituximab/obinutuzumab
- NCT03287245 | Phase 2 | TERMINATED | Hydroxyurea-resistant polycythemia vera
- NCT02633059 | Phase 1/2 | COMPLETED | R/R multiple myeloma: Idasanutlin + ixazomib + dexamethasone
- 13 additional Phase 1/2 trials: AML, lymphomas, colorectal cancer, breast cancer, pediatric cancers
Navtemadlin (20 trials):
- NCT06479135 | Phase 3 | RECRUITING | Myelofibrosis: Navtemadlin + ruxolitinib
- NCT05797831 | Phase 2/3 | RECRUITING | TP53WT endometrial cancer maintenance
- NCT03662126 | Phase 2/3 | UNKNOWN | JAKi-refractory myelofibrosis
- NCT04835584 | Phase 1/2 | RECRUITING | Chronic myeloid leukemia
- 16 additional trials across AML, CLL, DLBCL, MF, SCLC, sarcoma
RO-5045337 (6 trials):
- All Phase 1, COMPLETED: solid tumors, hematologic neoplasms, liposarcoma, soft tissue sarcoma
Pharmacogenomics:
- No CPIC dosing guidelines for MDM2 inhibitors
- PharmGKB: MDM2 listed as VIP gene (PA30718) but no pharmacogenomic variants with clinical annotations
- No known drug-gene interactions affecting MDM2 inhibitor response reported in major databases
- Mechanism: All clinical candidates are direct p53-MDM2 interaction disruptors; no pharmacogenomic biomarkers currently guide therapy selection
Primary indications: Hematologic malignancies (AML, lymphomas, myelofibrosis, CLL) and solid tumors (soft tissue sarcoma, endometrial/lung cancer).
Expression profiles
Tissue Expression (Bgee)
MDM2 shows ubiquitous expression across tissues with an average expression score of 87.96. Expression data derived from 274 present calls across 294 conditions (gold quality).
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Calcaneal tendon | 98.31 | Gold |
| 2 | Adrenal tissue | 97.33 | Gold |
| 3 | Ventricular zone | 97.24 | Gold |
| 4 | Right uterine tube | 97.08 | Gold |
| 5 | Olfactory segment of nasal mucosa | 96.95 | Gold |
| 6 | Sural nerve | 96.79 | Gold |
| 7 | Colonic epithelium | 96.67 | Gold |
| 8 | Epithelium of nasopharynx | 96.34 | Gold |
| 9 | Nasopharynx | 96.32 | Gold |
| 10 | Tendon | 96.21 | Gold |
| 11 | Stromal cell of endometrium | 96.08 | Gold |
| 12 | Right lobe of liver | 95.77 | Gold |
| 13 | Lower esophagus mucosa | 95.74 | Gold |
| 14 | Ganglionic eminence | 95.72 | Gold |
| 15 | Body of pancreas | 95.64 | Gold |
| 16 | Right lung | 95.50 | Gold |
| 17 | Right adrenal gland cortex | 95.33 | Gold |
| 18 | C1 segment of cervical spinal cord | 95.33 | Gold |
| 19 | Right adrenal gland | 94.35 | Gold |
| 20 | Mucosa of paranasal sinus | 94.30 | Gold |
| 21 | Left adrenal gland | 94.22 | Gold |
| 22 | Left adrenal gland cortex | 94.17 | Gold |
| 23 | Nerve | 94.11 | Gold |
| 24 | Tibial nerve | 94.11 | Gold |
| 25 | Adrenal gland | 94.05 | Gold |
| 26 | Adrenal cortex | 94.00 | Gold |
| 27 | Tonsil | 93.96 | Gold |
| 28 | Upper lobe of left lung | 93.94 | Gold |
| 29 | Hindlimb stylopod muscle | 93.86 | Gold |
| 30 | Vagina | 93.85 | Gold |
Key patterns:
- Highest expression in connective tissues (tendons, nerves)
- Strong expression in adrenal tissue and cortex
- Consistent expression across epithelial tissues (colonic, nasopharyngeal)
- Nervous system tissues (ventricular zone, spinal cord) show elevated expression
Cell Type Expression (Bgee)
Cell type annotations within Bgee data identify stromal cells of the endometrium (score: 96.08) as a notable cell-type-specific expression pattern among the top conditions.
Single-Cell Expression (SCXA)
MDM2 expression profiled across 4 single-cell RNA-seq datasets with 302 distinct cell clusters:
| Dataset | Description | Cells | Organism |
|---|---|---|---|
| E-CURD-53 | SARS-CoV-1/2 infected human cell lines | 187,349 | Homo sapiens |
| E-MTAB-7051 | Dermal fibroblasts ± IFNβ stimulation | 681 | Homo sapiens |
| E-MTAB-7303 | iPSC-dopamine neurons (Parkinson model) | 123 | Homo sapiens |
Expression characteristics:
- Max mean expression: 2,243.14 (scaled units)
- Average mean expression: 231.61 across clusters
- Marked as gene of interest in all 4 experiments, indicating biological significance across diverse cell types and conditions
Disease associations
Mendelian / Monogenic Disease
| Disease | Disease ID | Inheritance | Evidence Level |
|---|---|---|---|
| Lessel-Kubisch syndrome | OMIM: 618681, MONDO: 0032868 | Unknown | Limited |
| Li-Fraumeni syndrome | Orphanet: 524 | Autosomal dominant | Supportive |
Note: MDM2 mutations contribute to Li-Fraumeni syndrome predisposition; this disease is classically associated with TP53 mutations. Lessel-Kubisch syndrome represents a recently identified disorder linked to MDM2 pathogenic variants.
Phenotype Associations (HPO Terms)
Top 30 clinical phenotypes associated with MDM2:
| HPO ID | Phenotype |
|---|---|
| HP:0002664 | Neoplasm |
| HP:0003002 | Breast carcinoma |
| HP:0001909 | Leukemia |
| HP:0002665 | Lymphoma |
| HP:0002669 | Osteosarcoma |
| HP:0002859 | Rhabdomyosarcoma |
| HP:0002888 | Ependymoma |
| HP:0006744 | Adrenocortical carcinoma |
| HP:0007378 | Neoplasm of the gastrointestinal tract |
| HP:0009592 | Astrocytoma |
| HP:0012126 | Stomach cancer |
| HP:0012174 | Glioblastoma multiforme |
| HP:0030070 | Central primitive neuroectodermal tumor |
| HP:0030392 | Choroid plexus carcinoma |
| HP:0100006 | Neoplasm of the central nervous system |
| HP:0100526 | Neoplasm of the lung |
| HP:0100605 | Neoplasm of the larynx |
| HP:0100615 | Ovarian neoplasm |
| HP:0100743 | Neoplasm of the rectum |
| HP:0100768 | Choriocarcinoma |
| HP:0002861 | Melanoma |
| HP:0002863 | Myelodysplasia |
| HP:0002885 | Medulloblastoma |
| HP:0002890 | Thyroid carcinoma |
| HP:0002894 | Neoplasm of the pancreas |
| HP:0003003 | Colon cancer |
| HP:0004808 | Acute myeloid leukemia |
| HP:0006721 | Acute lymphoblastic leukemia |
| HP:0009726 | Renal neoplasm |
| HP:0010788 | Testicular neoplasm |
Additional phenotypes (21-49): Prostate cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma, Neoplasm of head and neck, Colorectal polyposis, Autosomal recessive inheritance, Renal insufficiency, Renal hypoplasia, Hypogonadism, Narrow mouth, Narrow nasal bridge, Hypertension, Subcutaneous nodule, Abnormally high-pitched voice, Premature graying of hair, Sparse pubic hair, Gastrointestinal dysmotility, Short stature, Abnormal renal physiology.
Complex Disease / GWAS Associations
| Trait/Disease | Variant/Gene | P-value | Study ID |
|---|---|---|---|
| Red blood cell count | MDM2 (chr12) | 4.0e-11 | GCST90002403_354 |
| Pneumoconiosis in silica exposure | CPM - CPSF6 (chr12) | 2.0e-08 | GCST002515_1 |
Note: The primary GWAS signal for MDM2 is with red blood cell count (RBC). The pneumoconiosis association appears to map to a nearby gene region. Only 2 significant GWAS associations were identified for MDM2 in the current databases.