MDM2_MOUSE
ID MDM2_MOUSE Reviewed; 489 AA.
AC P23804; Q61040; Q64330; Q91XK7;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 218.
DE RecName: Full=E3 ubiquitin-protein ligase Mdm2;
DE EC=2.3.2.27 {ECO:0000269|PubMed:14642282};
DE AltName: Full=Double minute 2 protein;
DE AltName: Full=Oncoprotein Mdm2;
DE AltName: Full=RING-type E3 ubiquitin transferase Mdm2 {ECO:0000305};
DE AltName: Full=p53-binding protein Mdm2;
GN Name=Mdm2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MDM2-P90).
RX PubMed=2026149; DOI=10.1002/j.1460-2075.1991.tb07676.x;
RA Fakharzadeh S.S., Trusko S.P., George D.L.;
RT "Tumorigenic potential associated with enhanced expression of a gene that
RT is amplified in a mouse tumor cell line.";
RL EMBO J. 10:1565-1569(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM MDM2-P90).
RC STRAIN=129/Sv;
RX PubMed=8917101; DOI=10.1016/0378-1119(96)00151-5;
RA Jones S.N., Ansari-Lari M.A., Hancock A.R., Jones W.J., Gibbs R.A.,
RA Donehower L.A., Bradley A.;
RT "Genomic organization of the mouse double minute 2 gene.";
RL Gene 175:209-213(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM MDM2-P90).
RC STRAIN=129/Sv;
RX PubMed=8660994; DOI=10.1006/geno.1996.0210;
RA de Oca Luna R.M., Tabor A.D., Eberspaecher H., Hulboy D.L., Worth L.L.,
RA Colman M.S., Finlay C.A., Lozano G.;
RT "The organization and expression of the mdm2 gene.";
RL Genomics 33:352-357(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE (ISOFORMS MDM2-P90 AND MDM2-P76), TISSUE SPECIFICITY,
RP AND INDUCTION.
RX PubMed=10075719; DOI=10.1074/jbc.274.12.8161;
RA Saucedo L.J., Myers C.D., Perry M.E.;
RT "Multiple murine double minute gene 2 (MDM2) proteins are induced by
RT ultraviolet light.";
RL J. Biol. Chem. 274:8161-8168(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Lung, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOLAR LOCALIZATION SIGNAL.
RX PubMed=10713175; DOI=10.1128/mcb.20.7.2517-2528.2000;
RA Weber J.D., Kuo M.-L., Bothner B., DiGiammarino E.L., Kriwacki R.W.,
RA Roussel M.F., Sherr C.J.;
RT "Cooperative signals governing ARF-mdm2 interaction and nucleolar
RT localization of the complex.";
RL Mol. Cell. Biol. 20:2517-2528(2000).
RN [8]
RP PHOSPHORYLATION BY ATM.
RX PubMed=10611322; DOI=10.1073/pnas.96.26.14973;
RA Khosravi R., Maya R., Gottlieb T., Oren M., Shiloh Y., Shkedy D.;
RT "Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in
RT response to DNA damage.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:14973-14977(1999).
RN [9]
RP INTERACTION WITH MTBP.
RX PubMed=10906133; DOI=10.1074/jbc.m004252200;
RA Boyd M.T., Vlatkovic N., Haines D.S.;
RT "A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that
RT is suppressed by MDM2.";
RL J. Biol. Chem. 275:31883-31890(2000).
RN [10]
RP FUNCTION, AND INTERACTION WITH AARB2.
RX PubMed=11588219; DOI=10.1126/science.1063866;
RA Shenoy S.K., McDonald P.H., Kohout T.A., Lefkowitz R.J.;
RT "Regulation of receptor fate by ubiquitination of activated beta 2-
RT adrenergic receptor and beta-arrestin.";
RL Science 294:1307-1313(2001).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
RX PubMed=14642282; DOI=10.1016/s0896-6273(03)00687-1;
RA Colledge M., Snyder E.M., Crozier R.A., Soderling J.A., Jin Y.,
RA Langeberg L.K., Lu H., Bear M.F., Scott J.D.;
RT "Ubiquitination regulates PSD-95 degradation and AMPA receptor surface
RT expression.";
RL Neuron 40:595-607(2003).
RN [12]
RP FUNCTION, INTERACTION WITH PML AND RPL11, AND SUBCELLULAR LOCATION.
RX PubMed=15195100; DOI=10.1038/ncb1147;
RA Bernardi R., Scaglioni P.P., Bergmann S., Horn H.F., Vousden K.H.,
RA Pandolfi P.P.;
RT "PML regulates p53 stability by sequestering Mdm2 to the nucleolus.";
RL Nat. Cell Biol. 6:665-672(2004).
RN [13]
RP INTERACTION WITH TBRG1.
RX PubMed=17110379; DOI=10.1074/jbc.m609612200;
RA Tompkins V.S., Hagen J., Frazier A.A., Lushnikova T., Fitzgerald M.P.,
RA di Tommaso A.D., Ladeveze V., Domann F.E., Eischen C.M., Quelle D.E.;
RT "A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains
RT chromosomal stability.";
RL J. Biol. Chem. 282:1322-1333(2007).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, Pancreas, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [15]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RPL11.
RX PubMed=21804542; DOI=10.1038/nm.2392;
RA Sasaki M., Kawahara K., Nishio M., Mimori K., Kogo R., Hamada K., Itoh B.,
RA Wang J., Komatsu Y., Yang Y.R., Hikasa H., Horie Y., Yamashita T.,
RA Kamijo T., Zhang Y., Zhu Y., Prives C., Nakano T., Mak T.W., Sasaki T.,
RA Maehama T., Mori M., Suzuki A.;
RT "Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar
RT RPL11.";
RL Nat. Med. 17:944-951(2011).
RN [16]
RP FUNCTION, AND INDUCTION.
RX PubMed=25088421; DOI=10.1016/j.celrep.2014.06.056;
RA Yoshihara S., Takahashi H., Nishimura N., Kinoshita M., Asahina R.,
RA Kitsuki M., Tatsumi K., Furukawa-Hibi Y., Hirai H., Nagai T., Yamada K.,
RA Tsuboi A.;
RT "Npas4 regulates Mdm2 and thus Dcx in experience-dependent dendritic spine
RT development of newborn olfactory bulb interneurons.";
RL Cell Rep. 8:843-857(2014).
RN [17]
RP INTERACTION WITH ADGRB1.
RX PubMed=25751059; DOI=10.1172/jci74603;
RA Zhu D., Li C., Swanson A.M., Villalba R.M., Guo J., Zhang Z., Matheny S.,
RA Murakami T., Stephenson J.R., Daniel S., Fukata M., Hall R.A., Olson J.J.,
RA Neigh G.N., Smith Y., Rainnie D.G., Van Meir E.G.;
RT "BAI1 regulates spatial learning and synaptic plasticity in the
RT hippocampus.";
RL J. Clin. Invest. 125:1497-1508(2015).
RN [18]
RP FUNCTION, INTERACTION WITH NDUFS1, AND MUTAGENESIS OF GLY-58.
RX PubMed=30879903; DOI=10.1016/j.molcel.2019.02.012;
RA Elkholi R., Abraham-Enachescu I., Trotta A.P., Rubio-Patino C.,
RA Mohammed J.N., Luna-Vargas M.P.A., Gelles J.D., Kaminetsky J.R.,
RA Serasinghe M.N., Zou C., Ali S., McStay G.P., Pfleger C.M., Chipuk J.E.;
RT "MDM2 Integrates Cellular Respiration and Apoptotic Signaling through
RT NDUFS1 and the Mitochondrial Network.";
RL Mol. Cell 74:452-465(2019).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of
CC p53/TP53, leading to its degradation by the proteasome
CC (PubMed:15195100, PubMed:21804542). Inhibits p53/TP53- and p73/TP73-
CC mediated cell cycle arrest and apoptosis by binding its transcriptional
CC activation domain (By similarity). Also acts as a ubiquitin ligase E3
CC toward itself, ARRB1 and ARBB2 (PubMed:11588219). Permits the nuclear
CC export of p53/TP53 (By similarity). Promotes proteasome-dependent
CC ubiquitin-independent degradation of retinoblastoma RB1 protein (By
CC similarity). Inhibits DAXX-mediated apoptosis by inducing its
CC ubiquitination and degradation (By similarity). Component of the
CC TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53 (By
CC similarity). Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex
CC which links growth factor and DNA damage response pathways (By
CC similarity). Mediates ubiquitination and subsequent proteasome
CC degradation of DYRK2 in nucleus (By similarity). Ubiquitinates IGF1R
CC and SNAI1 and promotes them to proteasomal degradation (By similarity).
CC Ubiquitinates DCX, leading to DCX degradation and reduction of the
CC dendritic spine density of olfactory bulb granule cells
CC (PubMed:25088421). Ubiquitinates DLG4, leading to proteasomal
CC degradation of DLG4 which is required for AMPA receptor endocytosis
CC (PubMed:14642282). Negatively regulates NDUFS1, leading to decreased
CC mitochondrial respiration, marked oxidative stress, and commitment to
CC the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1
CC leading to its cytosolic retention rather than mitochondrial
CC localization resulting in decreased supercomplex assembly (interactions
CC between complex I and complex III), decreased complex I activity, ROS
CC production, and apoptosis (PubMed:30879903).
CC {ECO:0000250|UniProtKB:Q00987, ECO:0000269|PubMed:11588219,
CC ECO:0000269|PubMed:14642282, ECO:0000269|PubMed:15195100,
CC ECO:0000269|PubMed:21804542, ECO:0000269|PubMed:25088421,
CC ECO:0000269|PubMed:30879903}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:14642282};
CC -!- SUBUNIT: Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds
CC specifically to RNA. Can interact with RB1, E1A-associated protein
CC EP300 and the E2F1 transcription factor. Forms a ternary complex with
CC p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1 and
CC RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a
CC trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-
CC terminus and C-terminus). Interacts with MDM4. Part of a complex with
CC MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and
CC USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus)
CC with RASSF1 isoform A (via N-terminus); the interaction is independent
CC of TP53. Interacts with APEX1; leading to its ubiquitination and
CC degradation. Interacts with RYBP; this inhibits ubiquitination of TP53.
CC Identified in a complex with RYBP and p53/TP53. Also a component of the
CC TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53
CC stabilization and activity. Binds directly both p53/TP53 and TRIM28.
CC Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting
CC growth factor responses with DNA damage. Interacts directly with both
CC TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with
CC IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2
CC leading to its proteasomal degradation. Interacts with SNAI1; this
CC interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via
CC intracellular domain). Interacts with FHIT. Interacts with RFFL and
CC RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and
CC CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53.
CC Interacts with MTA1 (By similarity). Interacts with AARB2
CC (PubMed:11588219). Interacts with MTBP (PubMed:10906133). Interacts
CC with PML (PubMed:15195100). Interacts with TBRG1 (PubMed:17110379).
CC Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and
CC RPL11; the interaction is direct occurs in the nucleoplasm and
CC negatively regulates MDM2-mediated TP53 ubiquitination and degradation
CC (PubMed:15195100, PubMed:21804542). Interacts with ADGRB1; the
CC interaction results in inhibition of MDM2-mediated ubiquitination and
CC degradation of DLG4/PSD95, promoting DLG4 stability and regulating
CC synaptic plasticity (PubMed:25751059). Interacts with RPL23A; this
CC interaction may promote p53/TP53 polyubiquitination (By similarity).
CC Interacts with NDUFS1 (PubMed:30879903). {ECO:0000250|UniProtKB:Q00987,
CC ECO:0000269|PubMed:10906133, ECO:0000269|PubMed:11588219,
CC ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:17110379,
CC ECO:0000269|PubMed:21804542, ECO:0000269|PubMed:25751059,
CC ECO:0000269|PubMed:30879903}.
CC -!- INTERACTION:
CC P23804; Q8BWG8: Arrb1; NbExp=4; IntAct=EBI-641788, EBI-641778;
CC P23804; Q62108: Dlg4; NbExp=3; IntAct=EBI-641788, EBI-300895;
CC P23804; O88904: Hipk1; NbExp=3; IntAct=EBI-641788, EBI-692945;
CC P23804; Q5EBH1: Rassf5; NbExp=3; IntAct=EBI-641788, EBI-960530;
CC P23804; Q9CXW4: Rpl11; NbExp=4; IntAct=EBI-641788, EBI-1548890;
CC P23804; P62830: Rpl23; NbExp=2; IntAct=EBI-641788, EBI-2365752;
CC P23804; P47962: Rpl5; NbExp=3; IntAct=EBI-641788, EBI-773940;
CC P23804; Q8BSK8: Rps6kb1; NbExp=2; IntAct=EBI-641788, EBI-646423;
CC P23804; P02340: Tp53; NbExp=9; IntAct=EBI-641788, EBI-474016;
CC P23804; P62991: Ubc; NbExp=2; IntAct=EBI-641788, EBI-413074;
CC P23804; P53350: PLK1; Xeno; NbExp=2; IntAct=EBI-641788, EBI-476768;
CC P23804-1; O35618: Mdm4; NbExp=2; IntAct=EBI-3386476, EBI-2603376;
CC P23804-1; P02340: Tp53; NbExp=2; IntAct=EBI-3386476, EBI-474016;
CC P23804-2; O35618: Mdm4; NbExp=2; IntAct=EBI-3386480, EBI-2603376;
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleoplasm
CC {ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:21804542}. Cytoplasm
CC {ECO:0000269|PubMed:15195100}. Nucleus, nucleolus
CC {ECO:0000269|PubMed:15195100}. Nucleus {ECO:0000250|UniProtKB:Q00987}.
CC Note=Colocalizes with RASSF1 isoform A in the nucleus (By similarity).
CC Expressed predominantly in the nucleoplasm. Interaction with ARF(P14)
CC results in the localization of both proteins to the nucleolus. The
CC nucleolar localization signals in both ARF(P14) and MDM2 may be
CC necessary to allow efficient nucleolar localization of both proteins.
CC {ECO:0000250|UniProtKB:Q00987}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=2;
CC Name=Mdm2-p90;
CC IsoId=P23804-1; Sequence=Displayed;
CC Name=Mdm2-p76;
CC IsoId=P23804-2; Sequence=VSP_003215;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed at low-level throughout
CC embryo development and in adult tissues. MDM2-p90 is much more abundant
CC than MDM2-p76 in testis, brain, heart, and kidney, but in the thymus,
CC spleen, and intestine, the levels of the MDM2 proteins are roughly
CC equivalent. {ECO:0000269|PubMed:10075719}.
CC -!- INDUCTION: By UV light (PubMed:10075719). Down-regulated by NPAS4
CC (PubMed:25088421). {ECO:0000269|PubMed:10075719,
CC ECO:0000269|PubMed:25088421}.
CC -!- DOMAIN: Region I is sufficient for binding p53 and inhibiting its G1
CC arrest and apoptosis functions. It also binds p73 and E2F1. Region II
CC contains most of a central acidic region required for interaction with
CC ribosomal protein L5 and a putative C4-type zinc finger. The RING
CC finger domain which coordinates two molecules of zinc interacts
CC specifically with RNA whether or not zinc is present and mediates the
CC heterooligomerization with MDM4. It is also essential for its ubiquitin
CC ligase E3 activity toward p53 and itself.
CC -!- PTM: Phosphorylation on Ser-163 by SGK1 activates ubiquitination of
CC p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM
CC upon DNA damage; this prevents oligomerization and E3 ligase
CC processivity and impedes constitutive p53/TP53 degradation (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Autoubiquitination leads to proteasomal degradation; resulting in
CC p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by
CC TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases
CC deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7
CC leading to its stabilization (By similarity).
CC {ECO:0000250|UniProtKB:Q00987}.
CC -!- DISRUPTION PHENOTYPE: Loss of Dlg4 ubiquitination.
CC {ECO:0000269|PubMed:14642282}.
CC -!- MISCELLANEOUS: [Isoform Mdm2-p76]: Does not bind to p53. Can be
CC produced by alternative initiation at Met-50 of isoform Mdm2-p90, but
CC is produced more efficiently by alternative splicing. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the MDM2/MDM4 family. {ECO:0000305}.
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DR EMBL; X58876; CAA41684.1; -; mRNA.
DR EMBL; U40145; AAA91167.1; -; Genomic_DNA.
DR EMBL; U47944; AAB09030.1; -; Genomic_DNA.
DR EMBL; U47935; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47936; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47937; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47938; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47939; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47940; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47941; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47942; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47943; AAB09030.1; JOINED; Genomic_DNA.
DR EMBL; U47934; AAB09031.1; -; mRNA.
DR EMBL; AK004719; BAB23502.1; -; mRNA.
DR EMBL; AK088638; BAC40470.1; -; mRNA.
DR EMBL; BC050902; AAH50902.1; -; mRNA.
DR CCDS; CCDS24194.1; -. [P23804-1]
DR CCDS; CCDS70110.1; -. [P23804-2]
DR PIR; S15349; S15349.
DR RefSeq; NP_001275515.1; NM_001288586.2. [P23804-2]
DR RefSeq; NP_034916.1; NM_010786.4. [P23804-1]
DR AlphaFoldDB; P23804; -.
DR SMR; P23804; -.
DR BioGRID; 201372; 91.
DR CORUM; P23804; -.
DR DIP; DIP-24174N; -.
DR DIP; DIP-24196N; -.
DR IntAct; P23804; 23.
DR MINT; P23804; -.
DR STRING; 10090.ENSMUSP00000020408; -.
DR BindingDB; P23804; -.
DR ChEMBL; CHEMBL3600279; -.
DR iPTMnet; P23804; -.
DR PhosphoSitePlus; P23804; -.
DR jPOST; P23804; -.
DR MaxQB; P23804; -.
DR PaxDb; P23804; -.
DR PeptideAtlas; P23804; -.
DR PRIDE; P23804; -.
DR ProteomicsDB; 292177; -. [P23804-1]
DR ProteomicsDB; 292178; -. [P23804-2]
DR Antibodypedia; 3664; 1834 antibodies from 47 providers.
DR DNASU; 17246; -.
DR Ensembl; ENSMUST00000020408; ENSMUSP00000020408; ENSMUSG00000020184. [P23804-1]
DR Ensembl; ENSMUST00000105263; ENSMUSP00000100898; ENSMUSG00000020184. [P23804-2]
DR GeneID; 17246; -.
DR KEGG; mmu:17246; -.
DR UCSC; uc007hdl.2; mouse. [P23804-1]
DR CTD; 4193; -.
DR MGI; MGI:96952; Mdm2.
DR VEuPathDB; HostDB:ENSMUSG00000020184; -.
DR eggNOG; ENOG502QQNV; Eukaryota.
DR GeneTree; ENSGT00530000063539; -.
DR HOGENOM; CLU_043544_0_0_1; -.
DR InParanoid; P23804; -.
DR OMA; LGELPCK; -.
DR OrthoDB; 1329283at2759; -.
DR PhylomeDB; P23804; -.
DR TreeFam; TF105306; -.
DR Reactome; R-MMU-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-MMU-2559585; Oncogene Induced Senescence.
DR Reactome; R-MMU-3232142; SUMOylation of ubiquitinylation proteins.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-MMU-6804757; Regulation of TP53 Degradation.
DR Reactome; R-MMU-6804760; Regulation of TP53 Activity through Methylation.
DR Reactome; R-MMU-69541; Stabilization of p53.
DR Reactome; R-MMU-8941858; Regulation of RUNX3 expression and activity.
DR BioGRID-ORCS; 17246; 15 hits in 76 CRISPR screens.
DR ChiTaRS; Mdm2; mouse.
DR PRO; PR:P23804; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P23804; protein.
DR Bgee; ENSMUSG00000020184; Expressed in animal zygote and 278 other tissues.
DR ExpressionAtlas; P23804; baseline and differential.
DR Genevisible; P23804; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0045202; C:synapse; ISO:MGI.
DR GO; GO:0017053; C:transcription repressor complex; ISO:MGI.
DR GO; GO:0008097; F:5S rRNA binding; ISS:UniProtKB.
DR GO; GO:0097718; F:disordered domain specific binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0016874; F:ligase activity; ISO:MGI.
DR GO; GO:0061663; F:NEDD8 ligase activity; ISO:MGI.
DR GO; GO:0002039; F:p53 binding; IPI:BHF-UCL.
DR GO; GO:0042975; F:peroxisome proliferator activated receptor binding; ISO:MGI.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0047485; F:protein N-terminus binding; ISO:MGI.
DR GO; GO:0033612; F:receptor serine/threonine kinase binding; ISO:MGI.
DR GO; GO:0043021; F:ribonucleoprotein complex binding; ISS:UniProtKB.
DR GO; GO:0019789; F:SUMO transferase activity; ISO:MGI.
DR GO; GO:0043130; F:ubiquitin binding; ISS:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:MGI.
DR GO; GO:0008270; F:zinc ion binding; ISO:MGI.
DR GO; GO:1990000; P:amyloid fibril formation; ISO:MGI.
DR GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR GO; GO:0003283; P:atrial septum development; IGI:MGI.
DR GO; GO:0003181; P:atrioventricular valve morphogenesis; IGI:MGI.
DR GO; GO:0001568; P:blood vessel development; IMP:MGI.
DR GO; GO:0001974; P:blood vessel remodeling; IMP:MGI.
DR GO; GO:0060411; P:cardiac septum morphogenesis; IGI:MGI.
DR GO; GO:0072717; P:cellular response to actinomycin D; ISO:MGI.
DR GO; GO:0071480; P:cellular response to gamma radiation; ISO:MGI.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; ISO:MGI.
DR GO; GO:0003203; P:endocardial cushion morphogenesis; IMP:MGI.
DR GO; GO:0045184; P:establishment of protein localization; ISO:MGI.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:0003170; P:heart valve development; IGI:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; ISO:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; ISO:MGI.
DR GO; GO:0010977; P:negative regulation of neuron projection development; ISO:MGI.
DR GO; GO:0010955; P:negative regulation of protein processing; ISO:MGI.
DR GO; GO:1901797; P:negative regulation of signal transduction by p53 class mediator; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0045787; P:positive regulation of cell cycle; IGI:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISO:MGI.
DR GO; GO:0051149; P:positive regulation of muscle cell differentiation; IMP:CACAO.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISO:MGI.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; ISO:MGI.
DR GO; GO:1904754; P:positive regulation of vascular associated smooth muscle cell migration; ISO:MGI.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI.
DR GO; GO:0031648; P:protein destabilization; ISO:MGI.
DR GO; GO:0034504; P:protein localization to nucleus; ISO:MGI.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0065003; P:protein-containing complex assembly; ISO:MGI.
DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; ISO:MGI.
DR GO; GO:0051726; P:regulation of cell cycle; ISO:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0002027; P:regulation of heart rate; IGI:MGI.
DR GO; GO:0042176; P:regulation of protein catabolic process; ISO:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:1990785; P:response to water-immersion restraint stress; ISO:MGI.
DR GO; GO:0007089; P:traversing start control point of mitotic cell cycle; IDA:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:MGI.
DR GO; GO:0003281; P:ventricular septum development; IGI:MGI.
DR CDD; cd16783; mRING-HC-C2H2C4_MDM2; 1.
DR Gene3D; 1.10.245.10; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR028340; Mdm2.
DR InterPro; IPR015459; MDM2_E3_ligase.
DR InterPro; IPR044080; MDM2_mRING-HC-C2H2C4.
DR InterPro; IPR016495; p53_neg-reg_MDM_2/4.
DR InterPro; IPR036885; SWIB_MDM2_dom_sf.
DR InterPro; IPR003121; SWIB_MDM2_domain.
DR InterPro; IPR001876; Znf_RanBP2.
DR InterPro; IPR036443; Znf_RanBP2_sf.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR13844:SF15; PTHR13844:SF15; 1.
DR Pfam; PF02201; SWIB; 1.
DR Pfam; PF00641; zf-RanBP; 1.
DR PIRSF; PIRSF500700; MDM2; 1.
DR PIRSF; PIRSF006748; p53_MDM_2/4; 1.
DR SUPFAM; SSF47592; SSF47592; 2.
DR SUPFAM; SSF90209; SSF90209; 1.
DR PROSITE; PS51925; SWIB_MDM2; 1.
DR PROSITE; PS01358; ZF_RANBP2_1; 1.
DR PROSITE; PS50199; ZF_RANBP2_2; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Alternative splicing; Apoptosis; Cytoplasm;
KW Metal-binding; Nucleus; Phosphoprotein; Proto-oncogene; Reference proteome;
KW Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..489
FT /note="E3 ubiquitin-protein ligase Mdm2"
FT /id="PRO_0000018650"
FT DOMAIN 26..109
FT /note="SWIB/MDM2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01273"
FT ZN_FING 297..326
FT /note="RanBP2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00322"
FT ZN_FING 436..477
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 1..110
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT REGION 1..101
FT /note="Sufficient to promote the mitochondrial pathway of
FT apoptosis"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 114..183
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 147..228
FT /note="Interaction with PYHIN1 and necessary for
FT interaction with RFFL and RNF34"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 167..304
FT /note="Interaction with MTBP"
FT /evidence="ECO:0000269|PubMed:10906133"
FT REGION 197..235
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 208..302
FT /note="ARF-binding"
FT REGION 221..230
FT /note="Interaction with USP7"
FT /evidence="ECO:0000250"
FT REGION 240..329
FT /note="Region II"
FT REGION 250..271
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 274..489
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT REGION 342..426
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 176..182
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 183..195
FT /note="Nuclear export signal"
FT MOTIF 464..471
FT /note="Nucleolar localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 159..183
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 199..216
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 217..235
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 250..268
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 342..386
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 387..408
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 409..423
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 163
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 183
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 238
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 240
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 244
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 258
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 260
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 394
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 406
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 417
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 423
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 427
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT VAR_SEQ 1..49
FT /note="Missing (in isoform Mdm2-p76)"
FT /evidence="ECO:0000305"
FT /id="VSP_003215"
FT MUTAGEN 58
FT /note="G->I: Reduced interaction with NDUFS1, ROS
FT production and apoptosis."
FT /evidence="ECO:0000269|PubMed:30879903"
FT CONFLICT 203
FT /note="S -> T (in Ref. 1; CAA41684)"
FT /evidence="ECO:0000305"
FT CONFLICT 419
FT /note="D -> H (in Ref. 1; CAA41684)"
FT /evidence="ECO:0000305"
FT CONFLICT 486
FT /note="T -> S (in Ref. 1; CAA41684 and 2; AAA91167)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 489 AA; 54558 MW; 4ABF489A82038DF4 CRC64;
MCNTNMSVST EGAASTSQIP ASEQETLVRP KPLLLKLLKS VGAQNDTYTM KEIIFYIGQY
IMTKRLYDEK QQHIVYCSND LLGDVFGVPS FSVKEHRKIY AMIYRNLVAV SQQDSGTSLS
ESRRQPEGGS DLKDPLQAPP EEKPSSSDLI SRLSTSSRRR SISETEENTD ELPGERHRKR
RRSLSFDPSL GLCELREMCS GGSSSSSSSS SESTETPSHQ DLDDGVSEHS GDCLDQDSVS
DQFSVEFEVE SLDSEDYSLS DEGHELSDED DEVYRVTVYQ TGESDTDSFE GDPEISLADY
WKCTSCNEMN PPLPSHCKRC WTLRENWLPD DKGKDKVEIS EKAKLENSAQ AEEGLDVPDG
KKLTENDAKE PCAEEDSEEK AEQTPLSQES DDYSQPSTSS SIVYSSQESV KELKEETQDK
DESVESSFSL NAIEPCVICQ GRPKNGCIVH GKTGHLMSCF TCAKKLKKRN KPCPVCRQPI
QMIVLTYFN
