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E3 ubiquitin-protein ligase Mdm2 (EC 2.3.2.27) (Double minute 2 protein) (Hdm2) (Oncoprotein Mdm2) (RING-type E3 ubiquitin transferase Mdm2) (p53-binding protein Mdm2)

 MDM2_HUMAN              Reviewed;         491 AA.
Q00987; A6NL51; A8K2S6; Q13226; Q13297; Q13298; Q13299; Q13300;
Q13301; Q53XW0; Q71TW9; Q8WYJ1; Q8WYJ2; Q9UGI3; Q9UMT8;
01-APR-1993, integrated into UniProtKB/Swiss-Prot.
01-APR-1993, sequence version 1.
30-AUG-2017, entry version 225.
RecName: Full=E3 ubiquitin-protein ligase Mdm2;
EC=2.3.2.27;
AltName: Full=Double minute 2 protein;
Short=Hdm2;
AltName: Full=Oncoprotein Mdm2;
AltName: Full=RING-type E3 ubiquitin transferase Mdm2 {ECO:0000305};
AltName: Full=p53-binding protein Mdm2;
Name=MDM2;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MDM2).
TISSUE=Colon;
PubMed=1614537; DOI=10.1038/358080a0;
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).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2-A; MDM2-B; MDM2-C; MDM2-D
AND MDM2-E).
TISSUE=Ovarian carcinoma;
PubMed=8705862; DOI=10.1038/nm0896-912;
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).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MDM2-ALPHA).
PubMed=10597303; DOI=10.1038/sj.onc.1203182;
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).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2-F AND MDM2-G), AND
INTERACTION WITH TP53.
PubMed=11351297; DOI=10.1002/ijc.1271;
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).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM MDM2).
TISSUE=Tongue;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[6]
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.
[7]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
NIEHS SNPs program;
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16541075; DOI=10.1038/nature04569;
Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
Kucherlapati R., Weinstock G., Gibbs R.A.;
"The finished DNA sequence of human chromosome 12.";
Nature 440:346-351(2006).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 11).
TISSUE=Rhabdomyosarcoma;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[10]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-24.
PubMed=7651818; DOI=10.1093/nar/23.14.2584;
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).
[11]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-9.
PubMed=9270029;
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).
[12]
NUCLEOTIDE SEQUENCE [MRNA] OF 6-491 (ISOFORM MDM2-A1).
PubMed=15315825; DOI=10.1016/j.gene.2004.05.015;
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).
[13]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 301-481.
PubMed=11087894; DOI=10.1016/S0027-5107(00)00112-3;
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 occurring in
normal blood donors and in soft tissue sarcoma patients: an indication
for an increased cancer susceptibility?";
Mutat. Res. 456:39-44(2000).
[14]
SUBCELLULAR LOCATION, AND INTERACTION WITH TP53.
PubMed=7689721;
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).
[15]
MUTAGENESIS OF CYS-464.
PubMed=9450543; DOI=10.1016/S0014-5793(97)01480-4;
Honda R., Tanaka H., Yasuda H.;
"Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.";
FEBS Lett. 420:25-27(1997).
[16]
MUTAGENESIS OF CYS-441 AND CYS-478.
PubMed=10608892; DOI=10.1074/jbc.274.53.38189;
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).
[17]
PHOSPHORYLATION BY ATM.
PubMed=10611322; DOI=10.1073/pnas.96.26.14973;
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).
[18]
MUTAGENESIS.
PubMed=10722742; DOI=10.1074/jbc.275.12.8945;
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).
[19]
NUCLEOLAR LOCALIZATION SIGNAL.
PubMed=10707090; DOI=10.1038/35004057;
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).
[20]
MUTAGENESIS OF CYS-449.
PubMed=10723139; DOI=10.1038/sj.onc.1203464;
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).
[21]
PHOSPHORYLATION AT SER-240; SER-242; SER-246; SER-260 AND SER-262.
PubMed=12167711; DOI=10.1128/MCB.22.17.6170-6182.2002;
Blattner C., Hay T., Meek D.W., Lane D.P.;
"Hypophosphorylation of Mdm2 augments p53 stability.";
Mol. Cell. Biol. 22:6170-6182(2002).
[22]
INTERACTION WITH HIV-1 TAT (MICROBIAL INFECTION).
PubMed=12883554; DOI=10.1038/ncb1023;
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).
[23]
FUNCTION IN UBIQUITINATION OF IGF1R, AND INTERACTION WITH IGF1R.
PubMed=12821780; DOI=10.1073/pnas.1431613100;
Girnita L., Girnita A., Larsson O.;
"Mdm2-dependent ubiquitination and degradation of the insulin-like
growth factor 1 receptor.";
Proc. Natl. Acad. Sci. U.S.A. 100:8247-8252(2003).
[24]
INTERACTION WITH FHIT.
PubMed=15313915; DOI=10.1158/0008-5472.CAN-04-0195;
Nishizaki M., Sasaki J., Fang B., Atkinson E.N., Minna J.D.,
Roth J.A., Ji L.;
"Synergistic tumor suppression by coexpression of FHIT and p53
coincides with FHIT-mediated MDM2 inactivation and p53 stabilization
in human non-small cell lung cancer cells.";
Cancer Res. 64:5745-5752(2004).
[25]
INVOLVEMENT IN SUSCEPTIBILITY TO ACCELERATED TUMOR FORMATION.
PubMed=15550242; DOI=10.1016/j.cell.2004.11.022;
Bond G.L., Hu W., Bond E.E., Robins H., Lutzker S.G., Arva N.C.,
Bargonetti J., Bartel F., Taubert H., Wuerl P., Onel K., Yip L.,
Hwang S.J., Strong L.C., Lozano G., Levine A.J.;
"A single nucleotide polymorphism in the MDM2 promoter attenuates the
p53 tumor suppressor pathway and accelerates tumor formation in
humans.";
Cell 119:591-602(2004).
[26]
INTERACTION WITH DAXX.
PubMed=15364927; DOI=10.1074/jbc.M406743200;
Zhao L.Y., Liu J., Sidhu G.S., Niu Y., Liu Y., Wang R., Liao D.;
"Negative regulation of p53 functions by Daxx and the involvement of
MDM2.";
J. Biol. Chem. 279:50566-50579(2004).
[27]
FUNCTION, INTERACTION WITH USP7, AND DEUBIQUITINATION BY USP7.
PubMed=15053880; DOI=10.1016/S1097-2765(04)00157-1;
Li M., Brooks C.L., Kon N., Gu W.;
"A dynamic role of HAUSP in the p53-Mdm2 pathway.";
Mol. Cell 13:879-886(2004).
[28]
FUNCTION, INTERACTION WITH PML AND RPL11, AND SUBCELLULAR LOCATION.
PubMed=15195100; DOI=10.1038/ncb1147;
Bernardi R., Scaglioni P.P., Bergmann S., Horn H.F., Vousden K.H.,
Pandolfi P.P.;
"PML regulates p53 stability by sequestering Mdm2 to the nucleolus.";
Nat. Cell Biol. 6:665-672(2004).
[29]
INTERACTION WITH ARRB1 AND ARRB2.
PubMed=15878855; DOI=10.1074/jbc.M501129200;
Girnita L., Shenoy S.K., Sehat B., Vasilcanu R., Girnita A.,
Lefkowitz R.J., Larsson O.;
"{beta}-Arrestin is crucial for ubiquitination and down-regulation of
the insulin-like growth factor-1 receptor by acting as adaptor for the
MDM2 E3 ligase.";
J. Biol. Chem. 280:24412-24419(2005).
[30]
INTERACTION WITH WWOX AND TP53.
PubMed=16219768; DOI=10.1074/jbc.M505590200;
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).
[31]
FUNCTION, AND INTERACTION WITH PSMA3.
PubMed=16337594; DOI=10.1016/j.molcel.2005.10.017;
Sdek P., Ying H., Chang D.L., Qiu W., Zheng H., Touitou R.,
Allday M.J., Xiao Z.X.;
"MDM2 promotes proteasome-dependent ubiquitin-independent degradation
of retinoblastoma protein.";
Mol. Cell 20:699-708(2005).
[32]
FUNCTION, INTERACTION WITH MTBP, AND MUTAGENESIS OF CYS-464.
PubMed=15632057; DOI=10.1128/MCB.25.2.545-553.2005;
Brady M., Vlatkovic N., Boyd M.T.;
"Regulation of p53 and MDM2 activity by MTBP.";
Mol. Cell. Biol. 25:545-553(2005).
[33]
INTERACTION WITH CDK5RAP3 AND CDKN2A/ARF.
PubMed=16173922; DOI=10.1042/BJ20050960;
Wang J., He X., Luo Y., Yarbrough W.G.;
"A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2.";
Biochem. J. 393:489-501(2006).
[34]
UBIQUITINATION, INTERACTION WITH PYHIN1, AND MUTAGENESIS OF CYS-464.
PubMed=16479015; DOI=10.1128/MCB.26.5.1979-1996.2006;
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).
[35]
IDENTIFICATION IN A COMPLEX WITH DAXX AND USP7, INTERACTION WITH DAXX,
AND SUBCELLULAR LOCATION.
PubMed=16845383; DOI=10.1038/ncb1442;
Tang J., Qu L.K., Zhang J., Wang W., Michaelson J.S., Degenhardt Y.Y.,
El-Deiry W.S., Yang X.;
"Critical role for Daxx in regulating Mdm2.";
Nat. Cell Biol. 8:855-862(2006).
[36]
INTERACTION WITH CDKN2AIP.
PubMed=17460193; DOI=10.1196/annals.1395.033;
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).
[37]
FUNCTION, INTERACTION WITH USP2, UBIQUITINATION, AND DEUBIQUITINATION
BY USP2.
PubMed=17290220; DOI=10.1038/sj.emboj.7601567;
Stevenson L.F., Sparks A., Allende-Vega N., Xirodimas D.P., Lane D.P.,
Saville M.K.;
"The deubiquitinating enzyme USP2a regulates the p53 pathway by
targeting Mdm2.";
EMBO J. 26:976-986(2007).
[38]
INVOLVEMENT IN SUSCEPTIBILITY TO ACCELERATED TUMOR FORMATION AND
LI-FRAUMENI SYNDROME.
PubMed=17003841; DOI=10.1038/sj.ejhg.5201715;
Ruijs M.W., Schmidt M.K., Nevanlinna H., Tommiska J., Aittomaki K.,
Pruntel R., Verhoef S., Van't Veer L.J.;
"The single-nucleotide polymorphism 309 in the MDM2 gene contributes
to the Li-Fraumeni syndrome and related phenotypes.";
Eur. J. Hum. Genet. 15:110-114(2007).
[39]
INTERACTION WITH TBRG1.
PubMed=17110379; DOI=10.1074/jbc.M609612200;
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).
[40]
INTERACTION WITH RBBP6.
PubMed=17470788; DOI=10.1073/pnas.0701916104;
Li L., Deng B., Xing G., Teng Y., Tian C., Cheng X., Yin X., Yang J.,
Gao X., Zhu Y., Sun Q., Zhang L., Yang X., He F.;
"PACT is a negative regulator of p53 and essential for cell growth and
embryonic development.";
Proc. Natl. Acad. Sci. U.S.A. 104:7951-7956(2007).
[41]
INTERACTION WITH RFFL AND RNF34, AND AUTOUBIQUITINATION.
PubMed=18382127; DOI=10.4161/cc.7.5.5701;
Yang W., Dicker D.T., Chen J., El-Deiry W.S.;
"CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing
MDM2.";
Cell Cycle 7:670-682(2008).
[42]
IDENTIFICATION IN A COMPLEX WITH DAXX; RASSF1 AND USP7, INTERACTION
WITH RASSF1; USP7 AND DAXX, AND SUBCELLULAR LOCATION.
PubMed=18566590; DOI=10.1038/emboj.2008.115;
Song M.S., Song S.J., Kim S.Y., Oh H.J., Lim D.S.;
"The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by
disrupting the MDM2-DAXX-HAUSP complex.";
EMBO J. 27:1863-1874(2008).
[43]
RETRACTION, AND CAUTION.
PubMed=18768758; DOI=10.1091/mbc.E08-01-0067;
Zweitzig D.R., Shcherbik N., Haines D.S.;
"AAA ATPase p97 and adaptor UBXD1 suppress MDM2 ubiquitination and
degradation and promote constitutive p53 turnover.";
Mol. Biol. Cell 19:5029-5029(2008).
[44]
PHOSPHORYLATION AT SER-386; SER-395; SER-407; THR-419; SER-425 AND
SER-429.
PubMed=19816404; DOI=10.1038/emboj.2009.294;
Cheng Q., Chen L., Li Z., Lane W.S., Chen J.;
"ATM activates p53 by regulating MDM2 oligomerization and E3
processivity.";
EMBO J. 28:3857-3867(2009).
[45]
FUNCTION, INTERACTION WITH RYBP, AND IDENTIFICATION IN A COMPLEX WITH
RYBP AND TP53.
PubMed=19098711; DOI=10.1038/embor.2008.231;
Chen D., Zhang J., Li M., Rayburn E.R., Wang H., Zhang R.;
"RYBP stabilizes p53 by modulating MDM2.";
EMBO Rep. 10:166-172(2009).
[46]
FUNCTION, AND INTERACTION WITH MTA1.
PubMed=19837670; DOI=10.1074/jbc.M109.056499;
Li D.Q., Divijendra Natha Reddy S., Pakala S.B., Wu X., Zhang Y.,
Rayala S.K., Kumar R.;
"MTA1 coregulator regulates p53 stability and function.";
J. Biol. Chem. 284:34545-34552(2009).
[47]
PHOSPHORYLATION AT SER-166 BY SGK1.
PubMed=19756449; DOI=10.1007/s00109-009-0525-5;
Amato R., D'Antona L., Porciatti G., Agosti V., Menniti M.,
Rinaldo C., Costa N., Bellacchio E., Mattarocci S., Fuiano G.,
Soddu S., Paggi M.G., Lang F., Perrotti N.;
"Sgk1 activates MDM2-dependent p53 degradation and affects cell
proliferation, survival, and differentiation.";
J. Mol. Med. 87:1221-1239(2009).
[48]
INTERACTION WITH HHV-8 PROTEIN VIRF4 (MICROBIAL INFECTION).
PubMed=19369353; DOI=10.1128/JVI.02353-08;
Lee H.R., Toth Z., Shin Y.C., Lee J.S., Chang H., Gu W., Oh T.K.,
Kim M.H., Jung J.U.;
"Kaposi's sarcoma-associated herpesvirus viral interferon regulatory
factor 4 targets MDM2 to deregulate the p53 tumor suppressor
pathway.";
J. Virol. 83:6739-6747(2009).
[49]
FUNCTION, INTERACTION WITH APEX1, AND MUTAGENESIS OF CYS-464.
PubMed=19219073; DOI=10.1038/onc.2009.5;
Busso C.S., Iwakuma T., Izumi T.;
"Ubiquitination of mammalian AP endonuclease (APE1) regulated by the
p53-MDM2 signaling pathway.";
Oncogene 28:1616-1625(2009).
[50]
IDENTIFICATION.
PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
"A strategy for precise and large scale identification of core
fucosylated glycoproteins.";
Mol. Cell. Proteomics 8:913-923(2009).
[51]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-166, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[52]
FUNCTION, AND INTERACTION WITH SNAI1.
PubMed=20385133; DOI=10.1016/j.febslet.2010.04.006;
Lim S.O., Kim H., Jung G.;
"p53 inhibits tumor cell invasion via the degradation of snail protein
in hepatocellular carcinoma.";
FEBS Lett. 584:2231-2236(2010).
[53]
FUNCTION IN DYRK2 UBIQUITINATION, AND INTERACTION WITH DYRK2.
PubMed=19965871; DOI=10.1074/jbc.M109.042341;
Taira N., Yamamoto H., Yamaguchi T., Miki Y., Yoshida K.;
"ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the
apoptotic response to DNA damage.";
J. Biol. Chem. 285:4909-4919(2010).
[54]
INTERACTION WITH TRIM28 IN THE TRIM28/KAP1-ERBB4-MDM2 COMPLEX AND WITH
TP53 IN THE TRIM28/KAP1-MDM2-P53/TP53 COMPLEX, FUNCTION, AND
SUBCELLULAR LOCATION.
PubMed=20858735; DOI=10.1158/1541-7786.MCR-10-0042;
Gilmore-Hebert M., Ramabhadran R., Stern D.F.;
"Interactions of ErbB4 and Kap1 connect the growth factor and DNA
damage response pathways.";
Mol. Cancer Res. 8:1388-1398(2010).
[55]
FUNCTION, INTERACTION WITH TP53 AND RFWD3, AND MUTAGENESIS OF CYS-464.
PubMed=20173098; DOI=10.1073/pnas.0912094107;
Fu X., Yucer N., Liu S., Li M., Yi P., Mu J.J., Yang T., Chu J.,
Jung S.Y., O'Malley B.W., Gu W., Qin J., Wang Y.;
"RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53
stability in response to DNA damage.";
Proc. Natl. Acad. Sci. U.S.A. 107:4579-4584(2010).
[56]
INTERACTION WITH USP2 AND MDM4.
PubMed=19838211; DOI=10.1038/onc.2009.330;
Allende-Vega N., Sparks A., Lane D.P., Saville M.K.;
"MdmX is a substrate for the deubiquitinating enzyme USP2a.";
Oncogene 29:432-441(2010).
[57]
FUNCTION, AND INTERACTION WITH SNAI1 AND NOTCH1.
PubMed=22128911; DOI=10.1186/1741-7007-9-83;
Lim S.O., Kim H.S., Quan X., Ahn S.M., Kim H., Hsieh D., Seong J.K.,
Jung G.;
"Notch1 binds and induces degradation of Snail in hepatocellular
carcinoma.";
BMC Biol. 9:83-83(2011).
[58]
INTERACTION WITH TRIM13, AND UBIQUITINATION.
PubMed=21333377; DOI=10.1016/j.ejcb.2010.12.001;
Joo H.M., Kim J.Y., Jeong J.B., Seong K.M., Nam S.Y., Yang K.H.,
Kim C.S., Kim H.S., Jeong M., An S., Jin Y.W.;
"Ret finger protein 2 enhances ionizing radiation-induced apoptosis
via degradation of AKT and MDM2.";
Eur. J. Cell Biol. 90:420-431(2011).
[59]
SUBUNIT.
PubMed=24120868; DOI=10.1016/j.celrep.2013.08.049;
Sloan K.E., Bohnsack M.T., Watkins N.J.;
"The 5S RNP couples p53 homeostasis to ribosome biogenesis and
nucleolar stress.";
Cell Rep. 5:237-247(2013).
[60]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-166, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[61]
SUBCELLULAR LOCATION, AND INTERACTION WITH PML.
PubMed=22869143; DOI=10.1038/onc.2012.332;
Yang Q., Liao L., Deng X., Chen R., Gray N.S., Yates J.R. III,
Lee J.D.;
"BMK1 is involved in the regulation of p53 through disrupting the PML-
MDM2 interaction.";
Oncogene 32:3156-3164(2013).
[62]
X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 25-109 IN COMPLEX WITH P53.
PubMed=8875929; DOI=10.1126/science.274.5289.948;
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).
[63]
X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 224-232 IN COMPLEX WITH
USP7, AND INTERACTION WITH USP7.
PubMed=16402859; DOI=10.1371/journal.pbio.0040027;
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).
[64]
X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 145-150 IN COMPLEX WITH USP7,
AND INTERACTION WITH USP7.
PubMed=16474402; DOI=10.1038/nsmb1067;
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).
-!- 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 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 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).
{ECO:0000250|UniProtKB:P23804, ECO:0000269|PubMed:12821780,
ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100,
ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:16337594,
ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19098711,
ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670,
ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:20173098,
ECO:0000269|PubMed:20385133, ECO:0000269|PubMed:20858735,
ECO:0000269|PubMed:22128911}.
-!- 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: 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
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 with the 5S RNP which is composed
of the 5S RNA, RPL5 and RPL11; the interaction is direct, occurs
in the nucleoplasm and negatively regulates MDM2-mediated TP53
ubiquitination and degradation (PubMed:15195100, PubMed:24120868).
{ECO:0000269|PubMed:11351297, ECO:0000269|PubMed:12821780,
ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100,
ECO:0000269|PubMed:15313915, ECO:0000269|PubMed:15364927,
ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:15878855,
ECO:0000269|PubMed:16173922, ECO:0000269|PubMed:16219768,
ECO:0000269|PubMed:16337594, ECO:0000269|PubMed:16402859,
ECO:0000269|PubMed:16474402, ECO:0000269|PubMed:16479015,
ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:17110379,
ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:17460193,
ECO:0000269|PubMed:17470788, ECO:0000269|PubMed:18382127,
ECO:0000269|PubMed:18566590, ECO:0000269|PubMed:19098711,
ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670,
ECO:0000269|PubMed:19838211, ECO:0000269|PubMed:19965871,
ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:20385133,
ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:21333377,
ECO:0000269|PubMed:22128911, ECO:0000269|PubMed:22869143,
ECO:0000269|PubMed:24120868, ECO:0000269|PubMed:7689721,
ECO:0000269|PubMed:8875929}.
-!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8
protein v-IRF4 (PubMed:19369353). Interacts with and ubiquitinates
HIV-1 Tat (PubMed:12883554). {ECO:0000269|PubMed:12883554,
ECO:0000269|PubMed:19369353}.
-!- INTERACTION:
Self; NbExp=4; IntAct=EBI-389668, EBI-389668;
P31749:AKT1; NbExp=4; IntAct=EBI-389668, EBI-296087;
P10275:AR; NbExp=2; IntAct=EBI-389668, EBI-608057;
Q9Y297:BTRC; NbExp=9; IntAct=EBI-389668, EBI-307461;
P42574:CASP3; NbExp=2; IntAct=EBI-389668, EBI-524064;
Q8N726:CDKN2A; NbExp=5; 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=18; IntAct=EBI-389668, EBI-77321;
P78352:DLG4; NbExp=3; IntAct=EBI-389668, EBI-80389;
P68104:EEF1A1; NbExp=9; 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;
Q00688:FKBP3; NbExp=2; IntAct=EBI-389668, EBI-1044081;
Q62446:Fkbp3 (xeno); NbExp=4; IntAct=EBI-389668, EBI-8313562;
Q9BVP2:GNL3; NbExp=3; IntAct=EBI-389668, EBI-641642;
Q9NVN8:GNL3L; NbExp=8; IntAct=EBI-389668, EBI-746682;
Q5T7V8:GORAB; NbExp=6; IntAct=EBI-389668, EBI-3917143;
P25098:GRK2; NbExp=4; IntAct=EBI-389668, EBI-3904795;
P61978:HNRNPK; NbExp=2; IntAct=EBI-389668, EBI-304185;
P08069:IGF1R; NbExp=2; IntAct=EBI-389668, EBI-475981;
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=8; IntAct=EBI-389668, EBI-398437;
P19338:NCL; NbExp=8; IntAct=EBI-389668, EBI-346967;
P06748:NPM1; NbExp=5; IntAct=EBI-389668, EBI-78579;
Q61937:Npm1 (xeno); NbExp=2; IntAct=EBI-389668, EBI-626362;
Q15466:NR0B2; NbExp=4; IntAct=EBI-389668, EBI-3910729;
Q96FW1:OTUB1; NbExp=5; IntAct=EBI-389668, EBI-1058491;
P53350:PLK1; NbExp=7; IntAct=EBI-389668, EBI-476768;
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;
Q13362:PPP2R5C; NbExp=5; IntAct=EBI-389668, EBI-1266156;
P25788:PSMA3; NbExp=2; IntAct=EBI-389668, EBI-348380;
P61289:PSME3; NbExp=8; IntAct=EBI-389668, EBI-355546;
Q9NS23:RASSF1; NbExp=5; IntAct=EBI-389668, EBI-367363;
P06400:RB1; NbExp=4; IntAct=EBI-389668, EBI-491274;
P62913:RPL11; NbExp=11; IntAct=EBI-389668, EBI-354380;
P62829:RPL23; NbExp=3; IntAct=EBI-389668, EBI-353303;
P46777:RPL5; NbExp=5; IntAct=EBI-389668, EBI-358018;
P42677:RPS27; NbExp=5; IntAct=EBI-389668, EBI-356336;
Q71UM5:RPS27L; NbExp=6; IntAct=EBI-389668, EBI-355126;
P23396:RPS3; NbExp=8; IntAct=EBI-389668, EBI-351193;
P62081:RPS7; NbExp=15; IntAct=EBI-389668, EBI-354360;
Q8N488:RYBP; NbExp=11; IntAct=EBI-389668, EBI-752324;
Q92736:RYR2; NbExp=2; IntAct=EBI-389668, EBI-1170425;
P23297:S100A1; NbExp=2; IntAct=EBI-389668, EBI-743686;
P29034:S100A2; NbExp=2; IntAct=EBI-389668, EBI-752230;
P26447:S100A4; NbExp=3; IntAct=EBI-389668, EBI-717058;
P06703:S100A6; NbExp=2; IntAct=EBI-389668, EBI-352877;
P04271:S100B; NbExp=2; IntAct=EBI-389668, EBI-458391;
Q01105:SET; NbExp=2; IntAct=EBI-389668, EBI-1053182;
P04637:TP53; NbExp=65; IntAct=EBI-389668, EBI-366083;
P0CG48:UBC; NbExp=6; IntAct=EBI-389668, EBI-3390054;
O75604:USP2; NbExp=4; IntAct=EBI-389668, EBI-743272;
Q93009:USP7; NbExp=18; IntAct=EBI-389668, EBI-302474;
Q2HR73:vIRF-4 (xeno); NbExp=2; IntAct=EBI-389668, EBI-9001898;
-!- 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.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=11;
Name=Mdm2;
IsoId=Q00987-1; Sequence=Displayed;
Name=Mdm2-A;
IsoId=Q00987-2; Sequence=VSP_003208;
Name=Mdm2-A1;
IsoId=Q00987-3; Sequence=VSP_003208, VSP_003214;
Name=Mdm2-B;
IsoId=Q00987-4; Sequence=VSP_003209;
Name=Mdm2-C;
IsoId=Q00987-5; Sequence=VSP_003211;
Name=Mdm2-D;
IsoId=Q00987-6; Sequence=VSP_003210;
Name=Mdm2-E;
IsoId=Q00987-7; Sequence=VSP_003212, VSP_003213;
Name=Mdm2-alpha;
IsoId=Q00987-8; Sequence=VSP_003207;
Name=Mdm2-F;
IsoId=Q00987-9; Sequence=VSP_022578;
Note=Does not interact with p53/TP53.;
Name=Mdm2-G;
IsoId=Q00987-10; Sequence=VSP_022579;
Name=11;
IsoId=Q00987-11; Sequence=VSP_037997;
-!- 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: Phosphorylation on Ser-166 by SGK1 activates ubiquitination
of p53/TP53. Phosphorylated at multiple sites near the RING domain
by ATM upon DNA damage; this prevents oligomerization and E3
ligase processivity and impedes constitutive p53/TP53 degradation.
{ECO:0000269|PubMed:10611322, ECO:0000269|PubMed:12167711,
ECO:0000269|PubMed:18382127, ECO:0000269|PubMed:19756449,
ECO:0000269|PubMed:19816404}.
-!- PTM: Autoubiquitination leads to proteasomal degradation;
resulting in p53/TP53 activation it may be regulated by SFN. 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.
{ECO:0000269|PubMed:18382127}.
-!- 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. {ECO:0000305}.
-!- CAUTION: Was reported to interact with UBXN6 but the corresponding
article has been retracted (PubMed:18768758).
-!- CAUTION: A report observed N-glycosylation at Asn-349
(PubMed:19139490). However, as the protein is not extracellular,
additional evidences are required to confirm this result.
{ECO:0000305|PubMed:19139490}.
-!- 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="https://en.wikipedia.org/wiki/Mdm2";
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EMBL; M92424; AAA60568.1; -; mRNA.
EMBL; Z12020; CAA78055.1; -; mRNA.
EMBL; U33199; AAA75514.1; -; mRNA.
EMBL; U33200; AAA75515.1; -; mRNA.
EMBL; U33201; AAA75516.1; -; mRNA.
EMBL; U33202; AAA75517.1; -; mRNA.
EMBL; U33203; AAA75518.1; -; mRNA.
EMBL; AF092844; AAL40179.1; -; mRNA.
EMBL; AF092845; AAL40180.1; -; mRNA.
EMBL; AK290341; BAF83030.1; -; mRNA.
EMBL; BT007258; AAP35922.1; -; mRNA.
EMBL; AF527840; AAM78554.1; -; Genomic_DNA.
EMBL; AC025423; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC009893; -; NOT_ANNOTATED_CDS; mRNA.
EMBL; U28935; AAA82237.1; -; Genomic_DNA.
EMBL; U39736; AAA82061.1; -; Genomic_DNA.
EMBL; AF201370; AAF42995.1; -; mRNA.
EMBL; AJ251943; CAB64448.1; -; Genomic_DNA.
CCDS; CCDS61189.1; -. [Q00987-5]
CCDS; CCDS8986.2; -. [Q00987-11]
PIR; S24354; S24354.
RefSeq; NP_001138811.1; NM_001145339.2.
RefSeq; NP_001265391.1; NM_001278462.1. [Q00987-5]
RefSeq; NP_002383.2; NM_002392.5. [Q00987-11]
RefSeq; XP_005268929.1; XM_005268872.4. [Q00987-1]
RefSeq; XP_006719462.1; XM_006719399.3. [Q00987-8]
UniGene; Hs.484551; -.
UniGene; Hs.733536; -.
PDB; 1RV1; X-ray; 2.30 A; A/B/C=25-109.
PDB; 1T4E; X-ray; 2.60 A; A/B=17-111.
PDB; 1T4F; X-ray; 1.90 A; M=17-125.
PDB; 1YCR; X-ray; 2.60 A; A=17-125.
PDB; 1Z1M; NMR; -; A=1-118.
PDB; 2AXI; X-ray; 1.40 A; A=17-125.
PDB; 2C6A; NMR; -; A=290-335.
PDB; 2C6B; NMR; -; A=290-335.
PDB; 2F1Y; X-ray; 1.70 A; A=224-232.
PDB; 2FOP; X-ray; 2.10 A; B=145-150.
PDB; 2GV2; X-ray; 1.80 A; A=17-125.
PDB; 2HDP; NMR; -; A/B=429-491.
PDB; 2LZG; NMR; -; A=1-125.
PDB; 2M86; NMR; -; B=17-125.
PDB; 2MPS; NMR; -; A=3-109.
PDB; 2RUH; NMR; -; A=6-102.
PDB; 2VJE; X-ray; 2.20 A; A/C=428-491.
PDB; 2VJF; X-ray; 2.30 A; A/C=428-491.
PDB; 3EQS; X-ray; 1.65 A; A=25-109.
PDB; 3G03; X-ray; 1.80 A; A/C=18-125.
PDB; 3IUX; X-ray; 1.65 A; A/C=25-109.
PDB; 3IWY; X-ray; 1.93 A; A/C=25-109.
PDB; 3JZK; X-ray; 2.10 A; A=17-111.
PDB; 3JZR; X-ray; 2.10 A; A=17-125.
PDB; 3JZS; X-ray; 1.78 A; A=24-109.
PDB; 3LBK; X-ray; 2.30 A; A=18-111.
PDB; 3LBL; X-ray; 1.60 A; A/C/E=18-111.
PDB; 3LNJ; X-ray; 2.40 A; A/C/E=25-109.
PDB; 3LNZ; X-ray; 1.95 A; A/C/E/G/I/K/M/O=25-109.
PDB; 3MQS; X-ray; 2.40 A; D=394-403.
PDB; 3TJ2; X-ray; 2.10 A; A/C=18-111.
PDB; 3TPX; X-ray; 1.80 A; A/C/E=25-109.
PDB; 3TU1; X-ray; 1.60 A; A=18-125.
PDB; 3V3B; X-ray; 2.00 A; A/B=24-110.
PDB; 3VBG; X-ray; 2.80 A; A/B/C/D=25-109.
PDB; 3VZV; X-ray; 2.80 A; A/B=25-109.
PDB; 3W69; X-ray; 1.90 A; A/B=25-109.
PDB; 4DIJ; X-ray; 1.90 A; A/B=17-111.
PDB; 4ERE; X-ray; 1.80 A; A/B=17-111.
PDB; 4ERF; X-ray; 2.00 A; A/C/E=17-111.
PDB; 4HBM; X-ray; 1.90 A; A/B/C/D/E/F/G/H=6-125.
PDB; 4HFZ; X-ray; 2.69 A; A/C=17-125.
PDB; 4HG7; X-ray; 1.60 A; A=17-108.
PDB; 4JV7; X-ray; 2.20 A; A=18-111.
PDB; 4JV9; X-ray; 2.50 A; A=18-111.
PDB; 4JVE; X-ray; 2.30 A; A=18-111.
PDB; 4JVR; X-ray; 1.70 A; A/C/E=18-111.
PDB; 4JWR; X-ray; 2.35 A; A/B/C=17-111.
PDB; 4MDN; X-ray; 1.90 A; A=18-110.
PDB; 4MDQ; X-ray; 2.12 A; A=25-110.
PDB; 4OAS; X-ray; 1.70 A; A/C/E=17-111.
PDB; 4OBA; X-ray; 1.60 A; A/B/C=17-111.
PDB; 4OCC; X-ray; 1.80 A; A/C/E=17-111.
PDB; 4ODE; X-ray; 1.80 A; A=6-110.
PDB; 4ODF; X-ray; 2.20 A; A=6-110.
PDB; 4OGN; X-ray; 1.38 A; A=6-110.
PDB; 4OGT; X-ray; 1.54 A; A=6-110.
PDB; 4OGV; X-ray; 2.20 A; A/B/C=17-111.
PDB; 4OQ3; X-ray; 2.30 A; A/B/C/D=17-111.
PDB; 4QO4; X-ray; 1.70 A; A=17-111.
PDB; 4QOC; X-ray; 1.70 A; A/C/E/G/I/K=17-111.
PDB; 4UD7; X-ray; 1.60 A; A/B/C/D=17-125.
PDB; 4UE1; X-ray; 1.45 A; A/B/C/D=17-125.
PDB; 4UMN; X-ray; 1.99 A; A/B=6-125.
PDB; 4WT2; X-ray; 1.42 A; A=6-110.
PDB; 4XXB; X-ray; 2.40 A; B=290-437.
PDB; 4ZFI; X-ray; 2.00 A; A/B/C/D=18-113.
PDB; 4ZGK; X-ray; 2.00 A; A/B=18-114.
PDB; 4ZYC; X-ray; 1.95 A; A/B/C=17-111.
PDB; 4ZYF; X-ray; 1.80 A; A=17-111.
PDB; 4ZYI; X-ray; 1.67 A; A=17-111.
PDB; 5AFG; X-ray; 1.90 A; A=17-108.
PDB; 5C5A; X-ray; 1.15 A; A/B=20-111.
PDB; 5HMH; X-ray; 1.79 A; A/B=21-116.
PDB; 5HMI; X-ray; 1.74 A; A/B=18-116.
PDB; 5HMK; X-ray; 2.17 A; A/B=17-125.
PDB; 5J7F; X-ray; 2.00 A; A/B/C/D=1-125.
PDB; 5J7G; X-ray; 1.85 A; A/B/C/D=18-125.
PDB; 5LAV; X-ray; 1.73 A; A=19-111.
PDB; 5LAW; X-ray; 1.64 A; A=18-111.
PDB; 5LAY; X-ray; 2.71 A; A/B/C/D/E/F=17-111.
PDB; 5LAZ; X-ray; 1.66 A; A=18-111.
PDB; 5LN2; X-ray; 1.58 A; A=17-111.
PDB; 5MNJ; X-ray; 2.16 A; C/G=428-491.
PDB; 5TRF; X-ray; 2.10 A; A/B/C/D/E=10-118.
PDBsum; 1RV1; -.
PDBsum; 1T4E; -.
PDBsum; 1T4F; -.
PDBsum; 1YCR; -.
PDBsum; 1Z1M; -.
PDBsum; 2AXI; -.
PDBsum; 2C6A; -.
PDBsum; 2C6B; -.
PDBsum; 2F1Y; -.
PDBsum; 2FOP; -.
PDBsum; 2GV2; -.
PDBsum; 2HDP; -.
PDBsum; 2LZG; -.
PDBsum; 2M86; -.
PDBsum; 2MPS; -.
PDBsum; 2RUH; -.
PDBsum; 2VJE; -.
PDBsum; 2VJF; -.
PDBsum; 3EQS; -.
PDBsum; 3G03; -.
PDBsum; 3IUX; -.
PDBsum; 3IWY; -.
PDBsum; 3JZK; -.
PDBsum; 3JZR; -.
PDBsum; 3JZS; -.
PDBsum; 3LBK; -.
PDBsum; 3LBL; -.
PDBsum; 3LNJ; -.
PDBsum; 3LNZ; -.
PDBsum; 3MQS; -.
PDBsum; 3TJ2; -.
PDBsum; 3TPX; -.
PDBsum; 3TU1; -.
PDBsum; 3V3B; -.
PDBsum; 3VBG; -.
PDBsum; 3VZV; -.
PDBsum; 3W69; -.
PDBsum; 4DIJ; -.
PDBsum; 4ERE; -.
PDBsum; 4ERF; -.
PDBsum; 4HBM; -.
PDBsum; 4HFZ; -.
PDBsum; 4HG7; -.
PDBsum; 4JV7; -.
PDBsum; 4JV9; -.
PDBsum; 4JVE; -.
PDBsum; 4JVR; -.
PDBsum; 4JWR; -.
PDBsum; 4MDN; -.
PDBsum; 4MDQ; -.
PDBsum; 4OAS; -.
PDBsum; 4OBA; -.
PDBsum; 4OCC; -.
PDBsum; 4ODE; -.
PDBsum; 4ODF; -.
PDBsum; 4OGN; -.
PDBsum; 4OGT; -.
PDBsum; 4OGV; -.
PDBsum; 4OQ3; -.
PDBsum; 4QO4; -.
PDBsum; 4QOC; -.
PDBsum; 4UD7; -.
PDBsum; 4UE1; -.
PDBsum; 4UMN; -.
PDBsum; 4WT2; -.
PDBsum; 4XXB; -.
PDBsum; 4ZFI; -.
PDBsum; 4ZGK; -.
PDBsum; 4ZYC; -.
PDBsum; 4ZYF; -.
PDBsum; 4ZYI; -.
PDBsum; 5AFG; -.
PDBsum; 5C5A; -.
PDBsum; 5HMH; -.
PDBsum; 5HMI; -.
PDBsum; 5HMK; -.
PDBsum; 5J7F; -.
PDBsum; 5J7G; -.
PDBsum; 5LAV; -.
PDBsum; 5LAW; -.
PDBsum; 5LAY; -.
PDBsum; 5LAZ; -.
PDBsum; 5LN2; -.
PDBsum; 5MNJ; -.
PDBsum; 5TRF; -.
DisProt; DP00334; -.
ProteinModelPortal; Q00987; -.
SMR; Q00987; -.
BioGrid; 110358; 463.
DIP; DIP-392N; -.
ELM; Q00987; -.
IntAct; Q00987; 182.
MINT; MINT-101583; -.
STRING; 9606.ENSP00000417281; -.
BindingDB; Q00987; -.
ChEMBL; CHEMBL5023; -.
iPTMnet; Q00987; -.
PhosphoSitePlus; Q00987; -.
DMDM; 266516; -.
EPD; Q00987; -.
MaxQB; Q00987; -.
PaxDb; Q00987; -.
PeptideAtlas; Q00987; -.
PRIDE; Q00987; -.
DNASU; 4193; -.
Ensembl; ENST00000258149; ENSP00000258149; ENSG00000135679. [Q00987-11]
Ensembl; ENST00000299252; ENSP00000299252; ENSG00000135679. [Q00987-5]
Ensembl; ENST00000360430; ENSP00000353611; ENSG00000135679. [Q00987-2]
Ensembl; ENST00000393413; ENSP00000377065; ENSG00000135679. [Q00987-4]
GeneID; 4193; -.
KEGG; hsa:4193; -.
UCSC; uc001sui.6; human. [Q00987-1]
CTD; 4193; -.
DisGeNET; 4193; -.
GeneCards; MDM2; -.
HGNC; HGNC:6973; MDM2.
HPA; CAB000086; -.
HPA; CAB016303; -.
MalaCards; MDM2; -.
MIM; 164785; gene.
MIM; 614401; phenotype.
neXtProt; NX_Q00987; -.
OpenTargets; ENSG00000135679; -.
Orphanet; 99970; Dedifferentiated liposarcoma.
Orphanet; 524; Li-Fraumeni syndrome.
Orphanet; 99971; Well-differentiated liposarcoma.
PharmGKB; PA30718; -.
eggNOG; ENOG410IGXG; Eukaryota.
eggNOG; ENOG41125MP; LUCA.
GeneTree; ENSGT00530000063539; -.
HOVERGEN; HBG013472; -.
InParanoid; Q00987; -.
KO; K06643; -.
OMA; PCVICQS; -.
OrthoDB; EOG091G0FYK; -.
PhylomeDB; Q00987; -.
TreeFam; TF105306; -.
BRENDA; 6.3.2.19; 2681.
Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
Reactome; R-HSA-2559585; Oncogene Induced Senescence.
Reactome; R-HSA-3232118; SUMOylation of transcription factors.
Reactome; R-HSA-399719; Trafficking of AMPA receptors.
Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
Reactome; R-HSA-5689880; Ub-specific processing proteases.
Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
Reactome; R-HSA-6804760; Regulation of TP53 Activity through Methylation.
Reactome; R-HSA-69541; Stabilization of p53.
Reactome; R-HSA-8941858; Regulation of RUNX3 expression and activity.
SignaLink; Q00987; -.
SIGNOR; Q00987; -.
ChiTaRS; MDM2; human.
EvolutionaryTrace; Q00987; -.
GeneWiki; Mdm2; -.
GenomeRNAi; 4193; -.
PMAP-CutDB; Q00987; -.
PRO; PR:Q00987; -.
Proteomes; UP000005640; Chromosome 12.
Bgee; ENSG00000135679; -.
ExpressionAtlas; Q00987; baseline and differential.
Genevisible; Q00987; HS.
GO; GO:0005737; C:cytoplasm; IMP:UniProtKB.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
GO; GO:0005886; C:plasma membrane; TAS:Reactome.
GO; GO:0043234; C:protein complex; IDA:CAFA.
GO; GO:0045202; C:synapse; IEA:Ensembl.
GO; GO:0008097; F:5S rRNA binding; IDA:UniProtKB.
GO; GO:0097718; F:disordered domain specific binding; IPI:CAFA.
GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0016874; F:ligase activity; IDA:UniProtKB.
GO; GO:0061663; F:NEDD8 ligase activity; IMP:CAFA.
GO; GO:0002039; F:p53 binding; IPI:UniProtKB.
GO; GO:0042975; F:peroxisome proliferator activated receptor binding; IEA:Ensembl.
GO; GO:0047485; F:protein N-terminus binding; IPI:CAFA.
GO; GO:0043021; F:ribonucleoprotein complex binding; IDA:UniProtKB.
GO; GO:0097110; F:scaffold protein binding; IEA:Ensembl.
GO; GO:0019789; F:SUMO transferase activity; EXP:Reactome.
GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:CAFA.
GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
GO; GO:1990000; P:amyloid fibril formation; IMP:CAFA.
GO; GO:0003283; P:atrial septum development; IEA:Ensembl.
GO; GO:0003181; P:atrioventricular valve morphogenesis; IEA:Ensembl.
GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
GO; GO:0001974; P:blood vessel remodeling; IEA:Ensembl.
GO; GO:0060411; P:cardiac septum morphogenesis; IEA:Ensembl.
GO; GO:0072717; P:cellular response to actinomycin D; IDA:CAFA.
GO; GO:0071312; P:cellular response to alkaloid; IEA:Ensembl.
GO; GO:0071391; P:cellular response to estrogen stimulus; IEA:Ensembl.
GO; GO:0071480; P:cellular response to gamma radiation; IDA:CAFA.
GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
GO; GO:0071456; P:cellular response to hypoxia; IEP:UniProtKB.
GO; GO:0071375; P:cellular response to peptide hormone stimulus; IEA:Ensembl.
GO; GO:0071494; P:cellular response to UV-C; IEA:Ensembl.
GO; GO:0071301; P:cellular response to vitamin B1; IEA:Ensembl.
GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; IMP:UniProtKB.
GO; GO:0003203; P:endocardial cushion morphogenesis; IEA:Ensembl.
GO; GO:0045184; P:establishment of protein localization; IDA:BHF-UCL.
GO; GO:0071157; P:negative regulation of cell cycle arrest; IDA:BHF-UCL.
GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
GO; GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; IDA:BHF-UCL.
GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:CAFA.
GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl.
GO; GO:0010955; P:negative regulation of protein processing; IEA:Ensembl.
GO; GO:1901797; P:negative regulation of signal transduction by p53 class mediator; IDA:UniProtKB.
GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
GO; GO:0018205; P:peptidyl-lysine modification; IMP:BHF-UCL.
GO; GO:0008284; P:positive regulation of cell proliferation; TAS:BHF-UCL.
GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:UniProtKB.
GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
GO; GO:0046827; P:positive regulation of protein export from nucleus; IEA:Ensembl.
GO; GO:1904754; P:positive regulation of vascular associated smooth muscle cell migration; IEA:Ensembl.
GO; GO:1904707; P:positive regulation of vascular smooth muscle cell proliferation; IEA:Ensembl.
GO; GO:0051865; P:protein autoubiquitination; IMP:ParkinsonsUK-UCL.
GO; GO:0006461; P:protein complex assembly; IDA:UniProtKB.
GO; GO:0031648; P:protein destabilization; IDA:BHF-UCL.
GO; GO:0016579; P:protein deubiquitination; TAS:Reactome.
GO; GO:0034504; P:protein localization to nucleus; IDA:BHF-UCL.
GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IMP:CAFA.
GO; GO:0002027; P:regulation of heart rate; IEA:Ensembl.
GO; GO:0042176; P:regulation of protein catabolic process; IDA:UniProtKB.
GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
GO; GO:0046677; P:response to antibiotic; IEP:UniProtKB.
GO; GO:0042220; P:response to cocaine; IEA:Ensembl.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0045472; P:response to ether; IEA:Ensembl.
GO; GO:1904404; P:response to formaldehyde; IEA:Ensembl.
GO; GO:0010039; P:response to iron ion; IEA:Ensembl.
GO; GO:0032026; P:response to magnesium ion; IEA:Ensembl.
GO; GO:0043278; P:response to morphine; IEA:Ensembl.
GO; GO:0048545; P:response to steroid hormone; IEA:Ensembl.
GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
GO; GO:1990785; P:response to water-immersion restraint stress; IEA:Ensembl.
GO; GO:0036369; P:transcription factor catabolic process; TAS:ParkinsonsUK-UCL.
GO; GO:0007089; P:traversing start control point of mitotic cell cycle; IEA:Ensembl.
GO; GO:0003281; P:ventricular septum development; IEA:Ensembl.
GO; GO:0016032; P:viral process; IEA:UniProtKB-KW.
Gene3D; 1.10.245.10; -; 1.
Gene3D; 3.30.40.10; -; 1.
InterPro; IPR028340; Mdm2.
InterPro; IPR015459; MDM2_E3_ligase.
InterPro; IPR016495; p53_neg-reg_MDM_2/4.
InterPro; IPR003121; SWIB_MDM2_domain.
InterPro; IPR001876; Znf_RanBP2.
InterPro; IPR001841; Znf_RING.
InterPro; IPR013083; Znf_RING/FYVE/PHD.
PANTHER; PTHR13844:SF33; PTHR13844:SF33; 1.
Pfam; PF02201; SWIB; 1.
Pfam; PF00641; zf-RanBP; 1.
PIRSF; PIRSF500700; MDM2; 1.
PIRSF; PIRSF006748; p53_MDM_2/4; 1.
SUPFAM; SSF47592; SSF47592; 2.
SUPFAM; SSF90209; SSF90209; 1.
PROSITE; PS01358; ZF_RANBP2_1; 1.
PROSITE; PS50199; ZF_RANBP2_2; 1.
PROSITE; PS50089; ZF_RING_2; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
Host-virus interaction; Metal-binding; Nucleus; Phosphoprotein;
Proto-oncogene; Reference proteome; Transferase; Ubl conjugation;
Ubl conjugation pathway; Zinc; Zinc-finger.
CHAIN 1 491 E3 ubiquitin-protein ligase Mdm2.
/FTId=PRO_0000157332.
DOMAIN 27 107 SWIB.
ZN_FING 299 328 RanBP2-type. {ECO:0000255|PROSITE-
ProRule:PRU00322}.
ZN_FING 438 479 RING-type. {ECO:0000255|PROSITE-
ProRule:PRU00175}.
REGION 1 110 Necessary for interaction with USP2.
REGION 150 230 Interaction with PYHIN1 and necessary for
interaction with RFFL and RNF34.
{ECO:0000269|PubMed:16479015,
ECO:0000269|PubMed:18382127}.
REGION 170 306 Interaction with MTBP. {ECO:0000250}.
REGION 210 304 ARF-binding.
REGION 223 232 Interaction with USP7.
REGION 242 331 Region II.
REGION 276 491 Necessary for interaction with USP2.
MOTIF 179 185 Nuclear localization signal.
{ECO:0000255}.
MOTIF 190 202 Nuclear export signal.
MOTIF 466 473 Nucleolar localization signal.
{ECO:0000255}.
COMPBIAS 210 215 Poly-Ser.
COMPBIAS 243 301 Asp/Glu-rich (acidic).
MOD_RES 166 166 Phosphoserine; by SGK1.
{ECO:0000244|PubMed:19690332,
ECO:0000244|PubMed:23186163,
ECO:0000269|PubMed:19756449}.
MOD_RES 190 190 Phosphoserine.
{ECO:0000250|UniProtKB:P23804}.
MOD_RES 240 240 Phosphoserine.
{ECO:0000269|PubMed:12167711}.
MOD_RES 242 242 Phosphoserine.
{ECO:0000269|PubMed:12167711}.
MOD_RES 246 246 Phosphoserine.
{ECO:0000269|PubMed:12167711}.
MOD_RES 260 260 Phosphoserine.
{ECO:0000269|PubMed:12167711}.
MOD_RES 262 262 Phosphoserine.
{ECO:0000269|PubMed:12167711}.
MOD_RES 386 386 Phosphoserine; by ATM.
{ECO:0000269|PubMed:19816404}.
MOD_RES 395 395 Phosphoserine; by ATM.
{ECO:0000269|PubMed:19816404}.
MOD_RES 407 407 Phosphoserine; by ATM.
{ECO:0000269|PubMed:19816404}.
MOD_RES 419 419 Phosphothreonine; by ATM.
{ECO:0000269|PubMed:19816404}.
MOD_RES 425 425 Phosphoserine; by ATM.
{ECO:0000269|PubMed:19816404}.
MOD_RES 429 429 Phosphoserine; by ATM.
{ECO:0000269|PubMed:19816404}.
VAR_SEQ 1 61 Missing (in isoform Mdm2-alpha).
{ECO:0000303|PubMed:10597303}.
/FTId=VSP_003207.
VAR_SEQ 1 1 M -> MVRSRQM (in isoform 11).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_037997.
VAR_SEQ 28 300 Missing (in isoform Mdm2-B).
{ECO:0000303|PubMed:8705862}.
/FTId=VSP_003209.
VAR_SEQ 28 222 Missing (in isoform Mdm2-A and isoform
Mdm2-A1). {ECO:0000303|PubMed:15315825,
ECO:0000303|PubMed:8705862}.
/FTId=VSP_003208.
VAR_SEQ 30 388 Missing (in isoform Mdm2-D).
{ECO:0000303|PubMed:8705862}.
/FTId=VSP_003210.
VAR_SEQ 53 222 Missing (in isoform Mdm2-C).
{ECO:0000303|PubMed:8705862}.
/FTId=VSP_003211.
VAR_SEQ 53 97 Missing (in isoform Mdm2-F).
{ECO:0000303|PubMed:11351297}.
/FTId=VSP_022578.
VAR_SEQ 76 102 YCSNDLLGDLFGVPSFSVKEHRKIYTM -> NDCANLFPLV
DLSIRELYISNYITLGI (in isoform Mdm2-E).
{ECO:0000303|PubMed:8705862}.
/FTId=VSP_003212.
VAR_SEQ 103 491 Missing (in isoform Mdm2-E).
{ECO:0000303|PubMed:8705862}.
/FTId=VSP_003213.
VAR_SEQ 115 169 Missing (in isoform Mdm2-G).
{ECO:0000303|PubMed:11351297}.
/FTId=VSP_022579.
VAR_SEQ 275 300 Missing (in isoform Mdm2-A1).
{ECO:0000303|PubMed:15315825}.
/FTId=VSP_003214.
MUTAGEN 305 305 C->S: No loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 374 374 C->T: No loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 438 438 C->L: No loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 441 441 C->G: Fails to interact with MDM4.
{ECO:0000269|PubMed:10608892}.
MUTAGEN 449 449 C->A: Loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10723139}.
MUTAGEN 449 449 C->S: No substantial decrease of
ubiquitin ligase E3 activity.
{ECO:0000269|PubMed:10723139}.
MUTAGEN 452 452 H->A: Loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 455 455 T->A: Significant decrease of ubiquitin
ligase E3 activity.
{ECO:0000269|PubMed:10722742}.
MUTAGEN 457 457 H->S: Loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 461 461 C->S: Loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 464 464 C->A: Loss of ubiquitin ligase E3
activity, enhances protein stability.
Does not inhibit interaction with APEX1,
but inhibits its ubiquitin ligase E3
activity on APEX1.
{ECO:0000269|PubMed:15632057,
ECO:0000269|PubMed:16479015,
ECO:0000269|PubMed:19219073,
ECO:0000269|PubMed:20173098,
ECO:0000269|PubMed:9450543}.
MUTAGEN 475 475 C->G: Loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10722742}.
MUTAGEN 478 478 C->R: Fails to interact with MDM4.
{ECO:0000269|PubMed:10608892}.
MUTAGEN 478 478 C->S: Loss of ubiquitin ligase E3
activity. {ECO:0000269|PubMed:10608892}.
CONFLICT 17 17 S -> P (in Ref. 10; AAA82237).
{ECO:0000305}.
STRAND 7 10 {ECO:0000244|PDB:4WT2}.
STRAND 13 15 {ECO:0000244|PDB:4WT2}.
STRAND 17 19 {ECO:0000244|PDB:2LZG}.
HELIX 23 25 {ECO:0000244|PDB:4OGN}.
STRAND 27 30 {ECO:0000244|PDB:5C5A}.
HELIX 32 41 {ECO:0000244|PDB:5C5A}.
STRAND 46 49 {ECO:0000244|PDB:4OBA}.
HELIX 50 64 {ECO:0000244|PDB:5C5A}.
STRAND 71 76 {ECO:0000244|PDB:5C5A}.
STRAND 78 80 {ECO:0000244|PDB:3LBK}.
HELIX 81 86 {ECO:0000244|PDB:5C5A}.
STRAND 88 92 {ECO:0000244|PDB:5C5A}.
HELIX 96 104 {ECO:0000244|PDB:5C5A}.
STRAND 107 109 {ECO:0000244|PDB:5C5A}.
STRAND 295 297 {ECO:0000244|PDB:2C6A}.
HELIX 299 301 {ECO:0000244|PDB:4XXB}.
TURN 306 308 {ECO:0000244|PDB:4XXB}.
STRAND 314 318 {ECO:0000244|PDB:4XXB}.
TURN 320 322 {ECO:0000244|PDB:4XXB}.
HELIX 433 435 {ECO:0000244|PDB:2VJE}.
TURN 439 441 {ECO:0000244|PDB:2VJE}.
STRAND 442 444 {ECO:0000244|PDB:2VJE}.
STRAND 448 452 {ECO:0000244|PDB:2VJE}.
STRAND 455 460 {ECO:0000244|PDB:2VJE}.
HELIX 462 470 {ECO:0000244|PDB:2VJE}.
TURN 476 478 {ECO:0000244|PDB:2VJE}.
STRAND 484 489 {ECO:0000244|PDB:2VJE}.
SEQUENCE 491 AA; 55233 MW; F37CE163876BC983 CRC64;
MCNTNMSVPT DGAVTTSQIP ASEQETLVRP KPLLLKLLKS VGAQKDTYTM KEVLFYLGQY
IMTKRLYDEK QQHIVYCSND LLGDLFGVPS FSVKEHRKIY TMIYRNLVVV NQQESSDSGT
SVSENRCHLE GGSDQKDLVQ ELQEEKPSSS HLVSRPSTSS RRRAISETEE NSDELSGERQ
RKRHKSDSIS LSFDESLALC VIREICCERS SSSESTGTPS NPDLDAGVSE HSGDWLDQDS
VSDQFSVEFE VESLDSEDYS LSEEGQELSD EDDEVYQVTV YQAGESDTDS FEEDPEISLA
DYWKCTSCNE MNPPLPSHCN RCWALRENWL PEDKGKDKGE ISEKAKLENS TQAEEGFDVP
DCKKTIVNDS RESCVEENDD KITQASQSQE SEDYSQPSTS SSIIYSSQED VKEFEREETQ
DKEESVESSL PLNAIEPCVI CQGRPKNGCI VHGKTGHLMA CFTCAKKLKK RNKPCPVCRQ
PIQMIVLTYF P


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