ID:MDM2_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase Mdm2; EC=6.3.2.-; AltName: Full=Double minute 2 protein; Short=Hdm2; AltName: Full=Oncoprotein Mdm2; AltName: Full=p53-binding protein Mdm2; FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an 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 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 promotes it to proteasomal degradation. SUBUNIT: Binds p53/TP53, TP73/p73, ARF/P14, PML, RBL5 and RP11, and 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, MTBP, RFWD3, TBRG1, USP7, PYHIN1, UBXN6, and RBBP6. Isoform Mdm2-F does not interact with p53/TP53. Interacts with and ubiquitinates HIV-1 Tat. Interacts with ARRB1 and ARRB2. Interacts (isoform 2) with PSMA3. Found in a trimeric complex with MDM2, MDM4 and UPB2. 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 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. INTERACTION: Self; NbExp=2; IntAct=EBI-389668, EBI-389668; P10275:AR; NbExp=2; IntAct=EBI-389668, EBI-608057; Q9Y297:BTRC; NbExp=9; IntAct=EBI-389668, EBI-307461; Q8N726:CDKN2A; NbExp=3; IntAct=EBI-389668, EBI-625922; P48729:CSNK1A1; NbExp=3; IntAct=EBI-389668, EBI-1383726; P48729-2:CSNK1A1; NbExp=3; IntAct=EBI-389668, EBI-2040168; P48730:CSNK1D; NbExp=6; IntAct=EBI-389668, EBI-751621; Q06486:Csnk1d (xeno); NbExp=2; IntAct=EBI-389668, EBI-2910316; P49674:CSNK1E; NbExp=3; IntAct=EBI-389668, EBI-749343; Q13616:CUL1; NbExp=3; IntAct=EBI-389668, EBI-359390; Q9UER7:DAXX; NbExp=14; IntAct=EBI-389668, EBI-77321; P68104:EEF1A1; NbExp=6; IntAct=EBI-389668, EBI-352162; P03372:ESR1; NbExp=2; IntAct=EBI-389668, EBI-78473; P15311:EZR; NbExp=3; IntAct=EBI-389668, EBI-1056902; Q9UKB1:FBXW11; NbExp=4; IntAct=EBI-389668, EBI-355189; Q9BVP2:GNL3; NbExp=3; IntAct=EBI-389668, EBI-641642; Q9NVN8:GNL3L; NbExp=8; IntAct=EBI-389668, EBI-746682; Q8N9B5:JMY; NbExp=2; IntAct=EBI-389668, EBI-866435; P05412:JUN; NbExp=3; IntAct=EBI-389668, EBI-852823; P17535:JUND; NbExp=3; IntAct=EBI-389668, EBI-2682803; O15151:MDM4; NbExp=6; IntAct=EBI-389668, EBI-398437; P19338:NCL; NbExp=2; IntAct=EBI-389668, EBI-346967; P06748:NPM1; NbExp=3; IntAct=EBI-389668, EBI-78579; Q61937:Npm1 (xeno); NbExp=2; IntAct=EBI-389668, EBI-626362; P29590:PML; NbExp=6; IntAct=EBI-389668, EBI-295890; P29590-5:PML; NbExp=6; IntAct=EBI-389668, EBI-304008; O15297:PPM1D; NbExp=4; IntAct=EBI-389668, EBI-1551512; P06400:RB1; NbExp=3; IntAct=EBI-389668, EBI-491274; P62913:RPL11; NbExp=6; IntAct=EBI-389668, EBI-354380; P42677:RPS27; NbExp=5; IntAct=EBI-389668, EBI-356336; Q71UM5:RPS27L; NbExp=6; IntAct=EBI-389668, EBI-355126; P62081:RPS7; NbExp=15; IntAct=EBI-389668, EBI-354360; Q92736:RYR2; NbExp=2; IntAct=EBI-389668, EBI-1170425; Q01105:SET; NbExp=2; IntAct=EBI-389668, EBI-1053182; P04637:TP53; NbExp=27; IntAct=EBI-389668, EBI-366083; Q93009:USP7; NbExp=13; IntAct=EBI-389668, EBI-302474; SUBCELLULAR LOCATION: Nucleus, nucleoplasm. Cytoplasm. Nucleus, nucleolus. Note=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. TISSUE SPECIFICITY: 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: Phosphorylated in response to ionizing radiation in an ATM- dependent manner. Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. PTM: Auto-ubiquitinated; which leads to proteasomal degradation. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization. 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: Note=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. MISCELLANEOUS: MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells. SIMILARITY: Belongs to the MDM2/MDM4 family. SIMILARITY: Contains 1 RanBP2-type zinc finger. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 1 SWIB domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MDM2ID115ch12q15.html"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/mdm2/"; WEB RESOURCE: Name=Wikipedia; Note=Mdm2 entry; URL="http://en.wikipedia.org/wiki/Mdm2";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q00987
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0001568 blood vessel development GO:0001974 blood vessel remodeling GO:0002027 regulation of heart rate GO:0003170 heart valve development GO:0003181 atrioventricular valve morphogenesis GO:0003203 endocardial cushion morphogenesis GO:0003281 ventricular septum development GO:0003283 atrial septum development GO:0006511 ubiquitin-dependent protein catabolic process GO:0006977 DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest GO:0007089 traversing start control point of mitotic cell cycle GO:0007507 heart development GO:0008284 positive regulation of cell proliferation GO:0009636 response to toxic substance GO:0010039 response to iron ion GO:0010468 regulation of gene expression GO:0010628 positive regulation of gene expression GO:0010629 negative regulation of gene expression GO:0010955 negative regulation of protein processing GO:0010977 negative regulation of neuron projection development GO:0016032 viral process GO:0016567 protein ubiquitination GO:0016579 protein deubiquitination GO:0016925 protein sumoylation GO:0018205 peptidyl-lysine modification GO:0031648 protein destabilization GO:0032026 response to magnesium ion GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process GO:0034504 protein localization to nucleus GO:0036369 transcription factor catabolic process GO:0042176 regulation of protein catabolic process GO:0042220 response to cocaine GO:0042493 response to drug GO:0043066 negative regulation of apoptotic process GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043278 response to morphine GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator GO:0045184 establishment of protein localization GO:0045472 response to ether GO:0045787 positive regulation of cell cycle GO:0045892 negative regulation of transcription, DNA-templated GO:0045931 positive regulation of mitotic cell cycle GO:0046677 response to antibiotic GO:0046827 positive regulation of protein export from nucleus GO:0048545 response to steroid hormone GO:0051603 proteolysis involved in cellular protein catabolic process GO:0051865 protein autoubiquitination GO:0060411 cardiac septum morphogenesis GO:0065003 macromolecular complex assembly GO:0070301 cellular response to hydrogen peroxide GO:0071157 negative regulation of cell cycle arrest GO:0071236 cellular response to antibiotic GO:0071301 cellular response to vitamin B1 GO:0071310 cellular response to organic substance GO:0071312 cellular response to alkaloid GO:0071363 cellular response to growth factor stimulus GO:0071375 cellular response to peptide hormone stimulus GO:0071391 cellular response to estrogen stimulus GO:0071407 cellular response to organic cyclic compound GO:0071456 cellular response to hypoxia GO:0071480 cellular response to gamma radiation GO:0071494 cellular response to UV-C GO:0072717 cellular response to actinomycin D GO:1901796 regulation of signal transduction by p53 class mediator GO:1901797 negative regulation of signal transduction by p53 class mediator GO:1902254 negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator GO:1904404 response to formaldehyde GO:1904707 positive regulation of vascular smooth muscle cell proliferation GO:1904754 positive regulation of vascular associated smooth muscle cell migration GO:1990000 amyloid fibril formation GO:1990785 response to water-immersion restraint stress
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
