[1]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MDM2).
TISSUE=Colon;
DOI=10.1038/358080a0; PubMed=1614537 [NCBI, ExPASy, EBI, Israel, Japan]
Oliner J.D.,
Kinzler K.W.,
Meltzer P.S.,
George D.L.,
Vogelstein B.;
"Amplification of a gene encoding a p53-associated protein in human sarcomas.";
Nature 358:80-83(1992).
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[2]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2-A; -B; -C; -D AND -E).
TISSUE=Ovarian carcinoma;
DOI=10.1038/nm0896-912; PubMed=8705862 [NCBI, ExPASy, EBI, Israel, Japan]
Sigalas I.,
Calvert A.H.,
Anderson J.J.,
Neal D.E.,
Lunec J.;
"Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer.";
Nat. Med. 2:912-917(1996).
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[3]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MDM2-ALPHA).
DOI=10.1038/sj.onc.1203182; PubMed=10597303 [NCBI, ExPASy, EBI, Israel, Japan]
Veldhoen N.,
Metcalfe S.,
Milner J.;
"A novel exon within the mdm2 gene modulates translation initiation in vitro and disrupts the p53-binding domain of mdm2 protein.";
Oncogene 18:7026-7033(1999).
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[4]
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NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2-F AND -G), AND INTERACTION WITH TP53.
DOI=10.1002/ijc.1271; PubMed=11351297 [NCBI, ExPASy, EBI, Israel, Japan]
Tamborini E.,
Della Torre G.,
Lavarino C.,
Azzarelli A.,
Carpinelli P.,
Pierotti M.A.,
Pilotti S.;
"Analysis of the molecular species generated by MDM2 gene amplification in liposarcomas.";
Int. J. Cancer 92:790-796(2001).
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[5]
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NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM MDM2).
Kalnine N.,
Chen X.,
Rolfs A.,
Halleck A.,
Hines L.,
Eisenstein S.,
Koundinya M.,
Raphael J.,
Moreira D.,
Kelley T.,
LaBaer J.,
Lin Y.,
Phelan M.,
Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
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[6]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Rieder M.J.,
Livingston R.J.,
Braun A.C.,
Montoya M.A.,
Chung M.-W.,
Miyamoto K.E.,
Nguyen C.P.,
Nguyen D.A.,
Poel C.L.,
Robertson P.D.,
Schackwitz W.S.,
Sherwood J.K.,
Witrak L.A.,
Nickerson D.A.;
"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
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[7]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-24.
DOI=10.1093/nar/23.14.2584; PubMed=7651818 [NCBI, ExPASy, EBI, Israel, Japan]
Zauberman A.,
Flusberg D.,
Haupt Y.,
Barak Y.,
Oren M.;
"A functional p53-responsive intronic promoter is contained within the human mdm2 gene.";
Nucleic Acids Res. 23:2584-2592(1995).
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[8]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-9.
PubMed=9270029 [NCBI, ExPASy, EBI, Israel, Japan]
Landers J.E.,
Cassel S.L.,
George D.L.;
"Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein.";
Cancer Res. 57:3562-3568(1997).
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[9]
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NUCLEOTIDE SEQUENCE [MRNA] OF 6-491 (ISOFORM MDM2-A1).
DOI=10.1016/j.gene.2004.05.015; PubMed=15315825 [NCBI, ExPASy, EBI, Israel, Japan]
Liang H.,
Atkins H.,
Abdel-Fattah R.,
Jones S.N.,
Lunec J.;
"Genomic organisation of the human MDM2 oncogene and relationship to its alternatively spliced mRNAs.";
Gene 338:217-223(2004).
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[10]
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NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 301-481.
DOI=10.1016/S0027-5107(00)00112-3; PubMed=11087894 [NCBI, ExPASy, EBI, Israel, Japan]
Taubert H.,
Kappler M.,
Meye A.,
Bartel F.,
Schlott T.,
Lautenschlaeger C.,
Bache M.,
Schmidt H.,
Wuerl P.;
"A MboII polymorphism in exon 11 of the human MDM2 gene occuring in normal blood donors and in soft tissue sarcoma patients: an indication for an increased cancer susceptibility?";
Mutat. Res. 456:39-44(2000).
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[11]
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SUBCELLULAR LOCATION, AND INTERACTION WITH TP53.
PubMed=7689721 [NCBI, ExPASy, EBI, Israel, Japan]
Olson D.C.,
Marechal V.,
Momand J.,
Chen J.,
Romocki C.,
Levine A.J.;
"Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes.";
Oncogene 8:2353-2360(1993).
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[12]
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MUTAGENESIS OF CYS-464.
DOI=10.1016/S0014-5793(97)01480-4; PubMed=9450543 [NCBI, ExPASy, EBI, Israel, Japan]
Honda R.,
Tanaka H.,
Yasuda H.;
"Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.";
FEBS Lett. 420:25-27(1997).
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[13]
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MUTAGENESIS OF CYS-441 AND CYS-478.
DOI=10.1074/jbc.274.53.38189; PubMed=10608892 [NCBI, ExPASy, EBI, Israel, Japan]
Sharp D.A.,
Kratowicz S.A.,
Sank M.J.,
George D.L.;
"Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein.";
J. Biol. Chem. 274:38189-38196(1999).
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[14]
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PHOSPHORYLATION BY ATM.
DOI=10.1073/pnas.96.26.14973; PubMed=10611322 [NCBI, ExPASy, EBI, Israel, Japan]
Khosravi R.,
Maya R.,
Gottlieb T.,
Oren M.,
Shiloh Y.,
Shkedy D.;
"Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage.";
Proc. Natl. Acad. Sci. U.S.A. 96:14973-14977(1999).
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[15]
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MUTAGENESIS.
DOI=10.1074/jbc.275.12.8945; PubMed=10722742 [NCBI, ExPASy, EBI, Israel, Japan]
Fang S.,
Jensen J.P.,
Ludwig R.L.,
Vousden K.H.,
Weissman A.M.;
"Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.";
J. Biol. Chem. 275:8945-8951(2000).
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[16]
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NUCLEOLAR LOCALIZATION SIGNAL.
DOI=10.1038/35004057; PubMed=10707090 [NCBI, ExPASy, EBI, Israel, Japan]
Lohrum M.A.E.,
Ashcroft M.,
Kubbutat M.H.G.,
Vousden K.H.;
"Identification of a cryptic nucleolar-localization signal in MDM2.";
Nat. Cell Biol. 2:179-181(2000).
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[17]
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MUTAGENESIS OF CYS-449.
DOI=10.1038/sj.onc.1203464; PubMed=10723139 [NCBI, ExPASy, EBI, Israel, Japan]
Honda R.,
Yasuda H.;
"Activity of MDM2, a ubiquitin ligase, toward p53 or itself is dependent on the RING finger domain of the ligase.";
Oncogene 19:1473-1476(2000).
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[18]
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INTERACTION WITH HIV-1 TAT.
DOI=10.1038/ncb1023; PubMed=12883554 [NCBI, ExPASy, EBI, Israel, Japan]
Bres V.,
Kiernan R.E.,
Linares L.K.,
Chable-Bessia C.,
Plechakova O.,
Treand C.,
Emiliani S.,
Peloponese J.-M.,
Jeang K.-T.,
Coux O.,
Scheffner M.,
Benkirane M.;
"A non-proteolytic role for ubiquitin in Tat-mediated transactivation of the HIV-1 promoter.";
Nat. Cell Biol. 5:754-761(2003).
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[19]
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INTERACTION WITH WWOX AND TP53.
DOI=10.1074/jbc.M505590200; PubMed=16219768 [NCBI, ExPASy, EBI, Israel, Japan]
Chang N.-S.,
Doherty J.,
Ensign A.,
Schultz L.,
Hsu L.-J.,
Hong Q.;
"WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53.";
J. Biol. Chem. 280:43100-43108(2005).
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[20]
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FUNCTION, INTERACTION WITH MTBP, AND MUTAGENESIS OF CYS-464.
DOI=10.1128/MCB.25.2.545-553.2005; PubMed=15632057 [NCBI, ExPASy, EBI, Israel, Japan]
Brady M.,
Vlatkovic N.,
Boyd M.T.;
"Regulation of p53 and MDM2 activity by MTBP.";
Mol. Cell. Biol. 25:545-553(2005).
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[21]
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UBIQUITINATION, INTERACTION WITH PYHIN1, AND MUTAGENESIS OF CYS-464.
DOI=10.1128/MCB.26.5.1979-1996.2006; PubMed=16479015 [NCBI, ExPASy, EBI, Israel, Japan]
Ding Y.,
Lee J.-F.,
Lu H.,
Lee M.-H.,
Yan D.-H.;
"Interferon-inducible protein IFIXalpha1 functions as a negative regulator of HDM2.";
Mol. Cell. Biol. 26:1979-1996(2006).
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[22]
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INTERACTION WITH CDKN2AIP.
DOI=10.1196/annals.1395.033; PubMed=17460193 [NCBI, ExPASy, EBI, Israel, Japan]
Kamrul H.M.,
Wadhwa R.,
Kaul S.C.;
"CARF binds to three members (ARF, p53, and HDM2) of the p53 tumor-suppressor pathway.";
Ann. N. Y. Acad. Sci. 1100:312-315(2007).
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[23]
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INTERACTION WITH TBRG1.
DOI=10.1074/jbc.M609612200; PubMed=17110379 [NCBI, ExPASy, EBI, Israel, Japan]
Tompkins V.S.,
Hagen J.,
Frazier A.A.,
Lushnikova T.,
Fitzgerald M.P.,
di Tommaso A.D.,
Ladeveze V.,
Domann F.E.,
Eischen C.M.,
Quelle D.E.;
"A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability.";
J. Biol. Chem. 282:1322-1333(2007).
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[24]
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X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 25-109 IN COMPLEX WITH P53.
DOI=10.1126/science.274.5289.948; PubMed=8875929 [NCBI, ExPASy, EBI, Israel, Japan]
Kussie P.H.,
Gorina S.,
Marechal V.,
Elenbaas B.,
Moreau J.,
Levine A.J.,
Pavletich N.P.;
"Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.";
Science 274:948-953(1996).
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[25]
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X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 224-232 IN COMPLEX WITH USP7, AND INTERACTION WITH USP7.
DOI=10.1371/journal.pbio.0040027; PubMed=16402859 [NCBI, ExPASy, EBI, Israel, Japan]
Hu M.,
Gu L.,
Li M.,
Jeffrey P.D.,
Gu W.,
Shi Y.;
"Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.";
PLoS Biol. 4:228-239(2006).
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[26]
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X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 145-150 IN COMPLEX WITH USP7, AND INTERACTION WITH USP7.
DOI=10.1038/nsmb1067; PubMed=16474402 [NCBI, ExPASy, EBI, Israel, Japan]
Sheng Y.,
Saridakis V.,
Sarkari F.,
Duan S.,
Wu T.,
Arrowsmith C.H.,
Frappier L.;
"Molecular recognition of p53 and MDM2 by USP7/HAUSP.";
Nat. Struct. Mol. Biol. 13:285-291(2006).
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- FUNCTION: Inhibits TP53/p53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Functions as a ubiquitin ligase E3, in the presence of E1 and E2, toward p53 and itself. Permits the nuclear export of p53 and targets it for proteasome-mediated proteolysis.
- SUBUNIT: Binds p53, p73, ARF(P14), ribosomal protein L5 and specifically to RNA. Can interact also with retinoblastoma protein (RB), E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with TP53/p53 and WWOX. Interacts with CDKN2AIP, MTBP, TRBG1 and USP7. Isoform Mdm2-F does not interact with TP53/p53. Interacts with PYHIN1. Interacts with, and ubiquitinates HIV-1 Tat.
- INTERACTION:
Self; NbExp=1; IntAct=EBI-389668, EBI-389668;
P60709:ACTB; NbExp=1; IntAct=EBI-389668, EBI-353944;
P10275:AR; NbExp=1; IntAct=EBI-389668, EBI-608057;
Q8N726:CDKN2A; NbExp=2; IntAct=EBI-389668, EBI-625922;
Q9UER7:DAXX; NbExp=3; IntAct=EBI-389668, EBI-77321;
P81605:DCD; NbExp=1; IntAct=EBI-389668, EBI-395625;
P68104:EEF1A1; NbExp=4; IntAct=EBI-389668, EBI-352162;
P03372:ESR1; NbExp=1; IntAct=EBI-389668, EBI-78473;
P04406:GAPDH; NbExp=1; IntAct=EBI-389668, EBI-354056;
P06396-2:GSN; NbExp=1; IntAct=EBI-389668, EBI-1018556;
Q8N9B5:JMY; NbExp=1; IntAct=EBI-389668, EBI-866435;
Q5BL16:Jmy (xeno); NbExp=1; IntAct=EBI-389668, EBI-866001;
P04264:KRT1; NbExp=1; IntAct=EBI-389668, EBI-298429;
P13645:KRT10; NbExp=1; IntAct=EBI-389668, EBI-465144;
P02533:KRT14; NbExp=1; IntAct=EBI-389668, EBI-702178;
P35908:KRT2; NbExp=1; IntAct=EBI-389668, EBI-1247312;
P05787:KRT8; NbExp=1; IntAct=EBI-389668, EBI-297852;
P35527:KRT9; NbExp=1; IntAct=EBI-389668, EBI-356382;
O15151:MDM4; NbExp=2; IntAct=EBI-389668, EBI-398437;
P06748:NPM1; NbExp=3; IntAct=EBI-389668, EBI-78579;
Q61937:Npm1 (xeno); NbExp=2; IntAct=EBI-389668, EBI-626362;
P29590:PML; NbExp=2; IntAct=EBI-389668, EBI-295890;
P29590-5:PML; NbExp=1; IntAct=EBI-389668, EBI-304008;
Q15959:PML; NbExp=1; IntAct=EBI-389668, EBI-779712;
O15297:PPM1D; NbExp=2; IntAct=EBI-389668, EBI-1551512;
P62913:RPL11; NbExp=1; IntAct=EBI-389668, EBI-354380;
P46777:RPL5; NbExp=1; IntAct=EBI-389668, EBI-358018;
P60866:RPS20; NbExp=1; IntAct=EBI-389668, EBI-353105;
P62988:RPS27A; NbExp=1; IntAct=EBI-389668, EBI-413034;
P62081:RPS7; NbExp=5; IntAct=EBI-389668, EBI-354360;
P20226:TBP; NbExp=1; IntAct=EBI-389668, EBI-355371;
P04637:TP53; NbExp=5; IntAct=EBI-389668, EBI-366083;
Q9BQE3:TUBA1C; NbExp=1; IntAct=EBI-389668, EBI-1103245;
Q13885:TUBB2A; NbExp=1; IntAct=EBI-389668, EBI-711595;
Q93009:USP7; NbExp=4; IntAct=EBI-389668, EBI-302474;
P08670:VIM; NbExp=1; IntAct=EBI-389668, EBI-353844;
- 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.
- ALTERNATIVE PRODUCTS:
10 named isoforms [FASTA] produced by alternative splicing.
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| Name | Mdm2-A |
| Isoform ID | Q00987-2 |
| Features which should be applied to build the isoform sequence: VSP_003208. |
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| Name | Mdm2-B |
| Isoform ID | Q00987-4 |
| Features which should be applied to build the isoform sequence: VSP_003209. |
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| Name | Mdm2-C |
| Isoform ID | Q00987-5 |
| Features which should be applied to build the isoform sequence: VSP_003211. |
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| Name | Mdm2-D |
| Isoform ID | Q00987-6 |
| Features which should be applied to build the isoform sequence: VSP_003210. |
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| |
| Name | Mdm2-alpha |
| Isoform ID | Q00987-8 |
| Features which should be applied to build the isoform sequence: VSP_003207. |
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| Name | Mdm2-F |
| Isoform ID | Q00987-9 |
| Features which should be applied to build the isoform sequence: VSP_022578. |
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| Name | Mdm2-G |
| Isoform ID | Q00987-10 |
| Features which should be applied to build the isoform sequence: VSP_022579. |
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- 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.
- PTM: Auto-ubiquitinated; which leads to proteasomal degradation.
- 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.
- 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=Wikipedia; Note=Mdm2 entry; URL="http://en.wikipedia.org/wiki/Mdm2";.
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