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Details on Person UniProt:Q00987 MDM2
| Class:Id | ReferenceGeneProduct:95018 |
|---|---|
| _chainChangeLog | chain:1-491 added on Sat February 7 2015 |
| _displayName | UniProt:Q00987 MDM2 |
| _timestamp | 2026-02-20 23:07:36 |
| chain | chain:1-491 |
| checksum | F37CE163876BC983 |
| comment | FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome (PubMed:29681526). Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis (PubMed:30879903).CATALYTIC ACTIVITY S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.SUBUNIT Component of a ternary complex composed of FAM193A, MDM4 and MDM2; interaction of FAM193A with MDM4 is mediated by the MDM4 RING-type zinc finger and results in MDM4 destabilization, leading to enhanced p53/TP53 transcriptional activity (PubMed:36897777). Although FAM193A interacts with MDM4 and MDM2, it does not affect formation of the p53-MDM2-MDM4 transcriptional repressor complex (PubMed:36897777). Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also a component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts (via its RanBP2-type zinc finger domain) with RPL11 in the 5S RNP complex composed of 5S RNA, RPL5 and RPL11; this interaction occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:15195100, PubMed:24120868, PubMed:37291423). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (PubMed:26203195). Interacts with NDUFS1 (PubMed:30879903). Interacts with MORN3; the interaction enhances the ubiquitination of p53/TP53 (PubMed:29681526). Interacts with RAD54B; RAD54B enhances the ubiquitin ligase activity of MDM2 on TP53 by promoting MDM2-MDM4 heterodimerization (PubMed:25384516).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein v-IRF4.SUBUNIT (Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.INTERACTION Expressed predominantly in the nucleoplasm. Interaction with ARF(P14) results in the localization of both proteins to the nucleolus. The nucleolar localization signals in both ARF(P14) and MDM2 may be necessary to allow efficient nucleolar localization of both proteins. Colocalizes with RASSF1 isoform A in the nucleus.ALTERNATIVE PRODUCTS Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.INDUCTION By DNA damage.DOMAIN Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.PTM Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53 (PubMed:19756449). Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this promotes its ubiquitination and degradation, preventing p53/TP53 degradation (PubMed:10611322, PubMed:12167711, PubMed:18382127, PubMed:19816404, PubMed:26124108).PTM Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN (PubMed:18382127, PubMed:30879903). Also ubiquitinated by TRIM13 (PubMed:21333377). ATM-phosphorylated MDM2 is ubiquitinated by the SCF(FBXO31) complex in response to genotoxic stress, promoting its degradation and p53/TP53-mediated DNA damage response (PubMed:26124108). Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53 (PubMed:17290220). Deubiquitinated by USP7 leading to its stabilization (PubMed:15053880).POLYMORPHISM A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.DISEASE Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.DISEASE The disease may be caused by variants affecting the gene represented in this entry.MISCELLANEOUS MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.MISCELLANEOUS Does not interact with p53/TP53.SIMILARITY Belongs to the MDM2/MDM4 family.CAUTION A report observed N-glycosylation at Asn-349 (PubMed:19139490). However, as the protein is not extracellular, additional evidence is required to confirm this result.ONLINE INFORMATION Mdm2 entry |
| description | recommendedName: E3 ubiquitin-protein ligase Mdm2 ecNumber evidence="15"2.3.2.27 alternativeName: Double minute 2 protein shortName: Hdm2 alternativeName: Oncoprotein Mdm2 alternativeName: fullName evidence="68"RING-type E3 ubiquitin transferase Mdm2 alternativeName: p53-binding protein Mdm2 |
| geneName | MDM2 |
| identifier | Q00987 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Alternative splicing Apoptosis Cytoplasm Host-virus interaction Metal-binding Nucleus Phosphoprotein Proteomics identification Proto-oncogene Reference proteome Transferase Ubl conjugation Ubl conjugation pathway Zinc Zinc-finger |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | MDM2 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:3700994] ENSEMBL:ENSG00000135679 MDM2 [Homo sapiens] |
| secondaryIdentifier | MDM2_HUMAN A6NL51 A8K2S6 Q13226 Q13297 Q13298 Q13299 Q13300 Q13301 Q53XW0 Q71TW9 Q8WYJ1 Q8WYJ2 Q9UGI3 Q9UMT8 |
| sequenceLength | 491 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:150181] UniProt:Q00987-2 MDM2 [Homo sapiens] [ReferenceIsoform:150182] UniProt:Q00987-3 MDM2 [Homo sapiens] [ReferenceIsoform:150183] UniProt:Q00987-4 MDM2 [Homo sapiens] [ReferenceIsoform:150184] UniProt:Q00987-5 MDM2 [Homo sapiens] [ReferenceIsoform:150185] UniProt:Q00987-6 MDM2 [Homo sapiens] [ReferenceIsoform:150186] UniProt:Q00987-7 MDM2 [Homo sapiens] [ReferenceIsoform:150187] UniProt:Q00987-8 MDM2 [Homo sapiens] [ReferenceIsoform:236942] UniProt:Q00987-9 MDM2 [Homo sapiens] [ReferenceIsoform:236943] UniProt:Q00987-10 MDM2 [Homo sapiens] [ReferenceIsoform:405010] UniProt:Q00987-1 MDM2 [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:69486] MDM2 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:69490] p-MDM2 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:198638] p-S166,S188-MDM2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:198644] MDM2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:416342] p-MDM2 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:416843] MDM2 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:416849] MDM2 [endocytic vesicle membrane] [Homo sapiens] [EntityWithAccessionedSequence:3000408] monoSUMO1-K182-MDM2 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:6782472] PolyUb-MDM2 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:6792862] p-S166,S188,T218-MDM2 [nucleoplasm] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:69440] phosphorylated residue at unknown position [ModifiedResidue:2399935] O-phospho-L-serine at 188 [ModifiedResidue:2399939] O-phospho-L-serine at 166 [GroupModifiedResidue:3000395] sumoylated lysine (monoSUMO1 [nucleoplasm]) at 182 [GroupModifiedResidue:6782511] ubiquitinylated lysine (PolyUb [nucleoplasm]) at unknown position [ModifiedResidue:6792877] O-phospho-L-threonine at 218 [ModifiedResidue:6804952] O-phospho-L-serine at 407 [ModifiedResidue:6804953] O-phospho-L-threonine at 419 [ModifiedResidue:6804958] O-phospho-L-serine at 386 [ModifiedResidue:6804959] O-phospho-L-serine at 395 |
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No pathways have been reviewed or authored by UniProt:Q00987 MDM2 (95018)
