MDM4_MOUSE
ID MDM4_MOUSE Reviewed; 489 AA.
AC O35618; Q9CYG1;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Protein Mdm4;
DE AltName: Full=Double minute 4 protein;
DE AltName: Full=Mdm2-like p53-binding protein;
DE AltName: Full=Protein Mdmx;
DE AltName: Full=p53-binding protein Mdm4;
GN Name=Mdm4; Synonyms=Mdmx;
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 LONG).
RC TISSUE=Embryo;
RX PubMed=8895579; DOI=10.1002/j.1460-2075.1996.tb00919.x;
RA Shvarts A., Steegenga W.T., Riteco N., Van Laar T., Dekker P., Bazuine M.,
RA Van Ham R.C.A., Van der Houven van Oordt W., Hateboer G., Van der Eb A.J.,
RA Jochemsen A.G.;
RT "MDMX: a novel p53-binding protein with some functional properties of
RT MDM2.";
RL EMBO J. 15:5349-5357(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RA Jochemsen A.G., Shvarts A., Steegenga W.T., Riteco N., Van Laar T.,
RA Dekker P., Bazuine M., Van Ham R.C.A., van Oordt W., Hateboer G.,
RA der Eb A.J.;
RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT).
RX PubMed=10075736; DOI=10.1074/jbc.274.12.8299;
RA Rallapalli R., Strachan G., Cho B., Mercer W.E., Hall D.J.;
RT "A novel MDMX transcript expressed in a variety of transformed cell lines
RT encodes a truncated protein with potent p53 repressive activity.";
RL J. Biol. Chem. 274:8299-8308(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RA Yang Y.;
RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG).
RC STRAIN=C57BL/6J; TISSUE=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 GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest
CC and apoptosis by binding its transcriptional activation domain.
CC Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of
CC TP53 while maintaining suppression of TP53 transactivation and
CC apoptotic functions. The short isoform is a more potent inhibitor of
CC TP53 activity than the long isoform.
CC -!- SUBUNIT: Found in a trimeric complex with USP2, MDM2 and MDM4.
CC Interacts with USP2. Interacts (phosphorylated) with YWHAG; negatively
CC regulates MDM4 activity toward TP53 (By similarity). Interacts with
CC MDM2, TP53 and TP73. {ECO:0000250}.
CC -!- INTERACTION:
CC O35618; P23804-1: Mdm2; NbExp=2; IntAct=EBI-2603376, EBI-3386476;
CC O35618; P23804-2: Mdm2; NbExp=2; IntAct=EBI-2603376, EBI-3386480;
CC O35618; Q93009: USP7; Xeno; NbExp=4; IntAct=EBI-2603376, EBI-302474;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=O35618-1; Sequence=Displayed;
CC Name=Short; Synonyms=MdmX-S;
CC IsoId=O35618-2; Sequence=VSP_003216, VSP_003217;
CC -!- TISSUE SPECIFICITY: In all tissues tested. The short isoform is
CC expressed in a variety of transformed cell lines.
CC -!- DOMAIN: Region I is sufficient for binding TP53 and inhibiting its G1
CC arrest and apoptosis functions. It also binds TP73. Region II contains
CC most of a central acidic region and a putative C4-type zinc finger. The
CC RING finger domain which coordinates two molecules of zinc mediates the
CC heterooligomerization with MDM2.
CC -!- PTM: Phosphorylated. Phosphorylation at Ser-367 promotes interaction
CC with YWHAG and subsequent ubiquitination and degradation.
CC Phosphorylation at Ser-341 also induces ubiquitination and degradation
CC but to a lower extent (By similarity). {ECO:0000250}.
CC -!- PTM: Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on
CC the other hand stabilizes the MDM4 protein (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the MDM2/MDM4 family. {ECO:0000305}.
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DR EMBL; AF007110; AAB62927.1; -; mRNA.
DR EMBL; EU568360; ACB69756.1; -; mRNA.
DR EMBL; AK017719; BAB30893.1; -; mRNA.
DR EMBL; AK083349; BAC38879.1; -; mRNA.
DR EMBL; CH466520; EDL39660.1; -; Genomic_DNA.
DR EMBL; CH466520; EDL39662.1; -; Genomic_DNA.
DR CCDS; CCDS15290.1; -. [O35618-1]
DR PIR; S71955; S71955.
DR RefSeq; NP_001289730.1; NM_001302801.1.
DR RefSeq; NP_001289731.1; NM_001302802.1.
DR RefSeq; NP_001289732.1; NM_001302803.1. [O35618-1]
DR RefSeq; NP_001289733.1; NM_001302804.1.
DR RefSeq; NP_032601.2; NM_008575.4. [O35618-1]
DR AlphaFoldDB; O35618; -.
DR SMR; O35618; -.
DR BioGRID; 201373; 10.
DR DIP; DIP-24201N; -.
DR IntAct; O35618; 5.
DR STRING; 10090.ENSMUSP00000068661; -.
DR iPTMnet; O35618; -.
DR PhosphoSitePlus; O35618; -.
DR jPOST; O35618; -.
DR MaxQB; O35618; -.
DR PaxDb; O35618; -.
DR PRIDE; O35618; -.
DR ProteomicsDB; 295986; -. [O35618-1]
DR ProteomicsDB; 295987; -. [O35618-2]
DR Antibodypedia; 20673; 762 antibodies from 38 providers.
DR DNASU; 17248; -.
DR Ensembl; ENSMUST00000067429; ENSMUSP00000070411; ENSMUSG00000054387. [O35618-1]
DR Ensembl; ENSMUST00000188090; ENSMUSP00000140609; ENSMUSG00000054387. [O35618-1]
DR GeneID; 17248; -.
DR KEGG; mmu:17248; -.
DR UCSC; uc007cpk.2; mouse. [O35618-1]
DR CTD; 4194; -.
DR MGI; MGI:107934; Mdm4.
DR VEuPathDB; HostDB:ENSMUSG00000054387; -.
DR eggNOG; ENOG502QQNV; Eukaryota.
DR GeneTree; ENSGT00530000063539; -.
DR HOGENOM; CLU_043544_2_0_1; -.
DR InParanoid; O35618; -.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-MMU-2559585; Oncogene Induced Senescence.
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 BioGRID-ORCS; 17248; 8 hits in 76 CRISPR screens.
DR ChiTaRS; Mdm4; mouse.
DR PRO; PR:O35618; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; O35618; protein.
DR Bgee; ENSMUSG00000054387; Expressed in secondary oocyte and 243 other tissues.
DR ExpressionAtlas; O35618; baseline and differential.
DR Genevisible; O35618; MM.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0017053; C:transcription repressor complex; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0002039; F:p53 binding; IBA:GO_Central.
DR GO; GO:0003283; P:atrial septum development; IGI:MGI.
DR GO; GO:0003181; P:atrioventricular valve morphogenesis; IGI:MGI.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0003203; P:endocardial cushion morphogenesis; IGI:MGI.
DR GO; GO:0003170; P:heart valve development; IGI:MGI.
DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IMP:UniProtKB.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:MGI.
DR GO; GO:0065003; P:protein-containing complex assembly; ISO:MGI.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:InterPro.
DR GO; GO:0002027; P:regulation of heart rate; IGI:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0003281; P:ventricular septum development; IGI:MGI.
DR Gene3D; 1.10.245.10; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR015458; MDM4.
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:SF20; PTHR13844:SF20; 1.
DR Pfam; PF02201; SWIB; 1.
DR Pfam; PF00641; zf-RanBP; 1.
DR PIRSF; PIRSF500699; MDM4; 1.
DR PIRSF; PIRSF006748; p53_MDM_2/4; 1.
DR SUPFAM; SSF47592; SSF47592; 1.
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 splicing; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..489
FT /note="Protein Mdm4"
FT /id="PRO_0000157337"
FT DOMAIN 25..108
FT /note="SWIB/MDM2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01273"
FT ZN_FING 299..328
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 131..166
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 246..331
FT /note="Region II"
FT REGION 392..489
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT MOTIF 441..444
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOD_RES 179
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5XIN1"
FT MOD_RES 341
FT /note="Phosphoserine; by CHEK2"
FT /evidence="ECO:0000250|UniProtKB:O15151"
FT MOD_RES 367
FT /note="Phosphoserine; by CHEK1 and CHEK2"
FT /evidence="ECO:0000250|UniProtKB:O15151"
FT VAR_SEQ 115..127
FT /note="DAAQTLALAQDHT -> ARCNRILQSQKKN (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:10075736"
FT /id="VSP_003216"
FT VAR_SEQ 128..489
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:10075736"
FT /id="VSP_003217"
FT CONFLICT 112
FT /note="I -> N (in Ref. 1; AAB62927)"
FT /evidence="ECO:0000305"
FT CONFLICT 475
FT /note="A -> V (in Ref. 1; AAB62927)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 489 AA; 54963 MW; 85A7602AA9AAFD52 CRC64;
MTSHSTSAQC SASDSACRIS SEQISQVRPK LQLLKILHAA GAQGEVFTMK EVMHYLGQYI
MVKQLYDQQE QHMVYCGGDL LGDLLGCQSF SVKDPSPLYD MLRKNLVTSA SINTDAAQTL
ALAQDHTMDF PSQDRLKHGA TEYSNPRKRT EEEDTHTLPT SRHKCRDSRA DEDLIEHLSQ
DETSRLDLDF EEWDVAGLPW WFLGNLRNNC IPKSNGSTDL QTNQDIGTAI VSDTTDDLWF
LNETVSEQLG VGIKVEAANS EQTSEVGKTS NKKTVEVGKD DDLEDSRSLS DDTDVELTSE
DEWQCTECKK FNSPSKRYCF RCWALRKDWY SDCSKLTHSL STSNITAIPE KKDNEGIDVP
DCRRTISAPV VRPKDGYLKE EKPRFDPCNS VGFLDLAHSS ESQEIISSAR EQTDIFSEQK
AETESMEDFQ NVLKPCSLCE KRPRDGNIIH GKTSHLTTCF HCARRLKKSG ASCPACKKEI
QLVIKVFIA
