MDM2_CANLF
ID MDM2_CANLF Reviewed; 487 AA.
AC P56950; Q95KN5;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=E3 ubiquitin-protein ligase Mdm2;
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:P23804};
DE AltName: Full=Double minute 2 protein;
DE Short=Cdm2;
DE AltName: Full=RING-type E3 ubiquitin transferase Mdm2 {ECO:0000305};
DE AltName: Full=p53-binding protein Mdm2;
GN Name=MDM2;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-484.
RX PubMed=10754200; DOI=10.1016/s0304-3835(99)00427-9;
RA Nasir L., Burr P.D., McFarlane S.T., Gault E., Thompson H., Argyle D.J.;
RT "Cloning, sequence analysis and expression of the cDNAs encoding the canine
RT and equine homologues of the mouse double minute 2 (mdm2) proto-oncogene.";
RL Cancer Lett. 152:9-13(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2 AND MDM2-ALPHA).
RX PubMed=10597303; DOI=10.1038/sj.onc.1203182;
RA Veldhoen N., Metcalfe S., Milner J.;
RT "A novel exon within the mdm2 gene modulates translation initiation in
RT vitro and disrupts the p53-binding domain of mdm2 protein.";
RL Oncogene 18:7026-7033(1999).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of
CC p53/TP53, leading to its degradation by the proteasome. Inhibits
CC p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by
CC binding its transcriptional activation domain. Also acts as a ubiquitin
CC ligase E3 toward itself and ARRB1. Permits the nuclear export of
CC p53/TP53. Promotes proteasome-dependent ubiquitin-independent
CC degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated
CC apoptosis by inducing its ubiquitination and degradation. Component of
CC the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53.
CC Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links
CC growth factor and DNA damage response pathways. Mediates ubiquitination
CC and subsequent proteasome degradation of DYRK2 in nucleus.
CC Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal
CC degradation. Ubiquitinates DCX, leading to DCX degradation and
CC reduction of the dendritic spine density of olfactory bulb granule
CC cells. Ubiquitinates DLG4, leading to proteasomal degradation of DLG4
CC which is required for AMPA receptor endocytosis (By similarity).
CC Negatively regulates NDUFS1, leading to decreased mitochondrial
CC respiration, marked oxidative stress, and commitment to the
CC mitochondrial pathway of apoptosis (By similarity). 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 (By similarity).
CC {ECO:0000250|UniProtKB:P23804, ECO:0000250|UniProtKB:Q00987}.
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:0000250|UniProtKB:P23804};
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. Interacts with AARB2. Interacts with MTBP.
CC Interacts with PML. Interacts with RPL11. Interacts with TBRG1.
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 Interacts with ADGRB1; the interaction results in inhibition of MDM2-
CC mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4
CC stability and regulating synaptic plasticity. Interacts with RPL23A;
CC this interaction may promote p53/TP53 polyubiquitination (By
CC similarity). Interacts with NDUFS1 (By similarity).
CC {ECO:0000250|UniProtKB:P23804, ECO:0000250|UniProtKB:Q00987}.
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleoplasm
CC {ECO:0000250|UniProtKB:P23804}. Cytoplasm
CC {ECO:0000250|UniProtKB:P23804}. Nucleus, nucleolus
CC {ECO:0000250|UniProtKB:P23804}. Nucleus {ECO:0000250|UniProtKB:Q00987}.
CC Note=Expressed predominantly in the nucleoplasm. Interaction with
CC ARF(P14) results in the localization of both proteins to the nucleolus.
CC The nucleolar localization signals in both ARF(P14) and MDM2 may be
CC necessary to allow efficient nucleolar localization of both proteins.
CC Colocalizes with RASSF1 isoform A in the nucleus (By similarity).
CC {ECO:0000250|UniProtKB:P23804, ECO:0000250|UniProtKB:Q00987}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Mdm2;
CC IsoId=P56950-1; Sequence=Displayed;
CC Name=Mdm2-alpha;
CC IsoId=P56950-2; Sequence=VSP_003206;
CC -!- TISSUE SPECIFICITY: Isoform Mdm2-alpha is present in lymphoid and
CC testicular tissues.
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 (By similarity). Interacts
CC with IGF1R (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylation on Ser-166 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. {ECO:0000250|UniProtKB:Q00987}.
CC -!- SIMILARITY: Belongs to the MDM2/MDM4 family. {ECO:0000305}.
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DR EMBL; AF100705; AAF67833.1; -; mRNA.
DR EMBL; AF322416; AAG42840.1; -; mRNA.
DR RefSeq; NP_001003103.1; NM_001003103.2.
DR AlphaFoldDB; P56950; -.
DR BMRB; P56950; -.
DR SMR; P56950; -.
DR STRING; 9612.ENSCAFP00000000608; -.
DR BindingDB; P56950; -.
DR ChEMBL; CHEMBL3600278; -.
DR PaxDb; P56950; -.
DR Ensembl; ENSCAFT00030016129; ENSCAFP00030014077; ENSCAFG00030007887. [P56950-2]
DR Ensembl; ENSCAFT00845029644; ENSCAFP00845023282; ENSCAFG00845016387. [P56950-2]
DR GeneID; 403693; -.
DR KEGG; cfa:403693; -.
DR CTD; 4193; -.
DR eggNOG; ENOG502QQNV; Eukaryota.
DR GeneTree; ENSGT00530000063539; -.
DR InParanoid; P56950; -.
DR OrthoDB; 1329283at2759; -.
DR Reactome; R-CFA-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-CFA-399719; Trafficking of AMPA receptors.
DR Reactome; R-CFA-5689880; Ub-specific processing proteases.
DR Reactome; R-CFA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-CFA-6804757; Regulation of TP53 Degradation.
DR Reactome; R-CFA-6804760; Regulation of TP53 Activity through Methylation.
DR Reactome; R-CFA-69541; Stabilization of p53.
DR Reactome; R-CFA-8941858; Regulation of RUNX3 expression and activity.
DR Proteomes; UP000002254; Chromosome 10.
DR Bgee; ENSCAFG00000000418; Expressed in keratinocyte and 46 other tissues.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0008097; F:5S rRNA binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0002039; F:p53 binding; IBA:GO_Central.
DR GO; GO:0043021; F:ribonucleoprotein complex binding; ISS:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; ISS:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:InterPro.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0065008; P:regulation of biological quality; IEA:UniProt.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:InterPro.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
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 2: Evidence at transcript level;
KW Alternative splicing; Apoptosis; Cytoplasm; Metal-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..487
FT /note="E3 ubiquitin-protein ligase Mdm2"
FT /id="PRO_0000157329"
FT DOMAIN 26..109
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 434..475
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 1..101
FT /note="Sufficient to promote the mitochondrial pathway of
FT apoptosis"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 114..188
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 150..230
FT /note="Interaction with PYHIN1 and necessary for
FT interaction with RFFL and RNF34"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 170..306
FT /note="Interaction with MTBP"
FT /evidence="ECO:0000250"
FT REGION 210..304
FT /note="ARF-binding"
FT REGION 211..237
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 223..232
FT /note="Interaction with USP7"
FT /evidence="ECO:0000250"
FT REGION 242..331
FT /note="Region II"
FT REGION 252..275
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 369..397
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 179..185
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 190..202
FT /note="Nuclear export signal"
FT MOTIF 462..469
FT /note="Nucleolar localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 114..128
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 129..144
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 145..161
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 162..188
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 211..225
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 252..271
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 369..383
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 166
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 190
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P23804"
FT MOD_RES 240
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 242
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 246
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 262
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 382
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 391
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 403
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 415
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 425
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT VAR_SEQ 1..61
FT /note="Missing (in isoform Mdm2-alpha)"
FT /evidence="ECO:0000303|PubMed:10597303"
FT /id="VSP_003206"
FT CONFLICT 11
FT /note="G -> D (in Ref. 2; AAG42840)"
FT /evidence="ECO:0000305"
FT CONFLICT 238..239
FT /note="QD -> HH (in Ref. 2; AAG42840)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 487 AA; 54696 MW; 60CDB470A32A8E69 CRC64;
MCNTNMSVST GGAVSTSQIP ASEQETLVRP KPLLLKLLKS VGAQKDTYTM KEVIFYLGQY
IMTKRLYDEK QQHIVYCSND LLGDLFGVPS FSVKEHRKIY TMIYRNLVVV NQHEPSDSGT
SVSENSCHRE GGSDQKDPVQ ELQEEKPSSS DLISRPSTSS RRRTISETEE HADDLPGERQ
RKRHKSDSIS LSFDESLALC VIREICCERS SSSESTGTPS NPDLDAGVSE HSGDWLDQDS
VSDQFSVEFE VESLDSEDYS LSEEGQELSD EDDEVYRVTV YQAGESDTDS FEEDPEISLA
DYWKCTSCNE MNPPLPPHCN RCWALRENWL PEDKGKIPEK ATPENSTQVE EGFDVPDCKK
AAASDSRESC AEEIDDKITQ ASHSQESEDY SQPSTSNSII YSSQEDVKEF EREETQDKEE
IVESSFPLNA IEPCVICQGR PKNGCIVHGK TGHLMACFTC AKKLKKRNKP CPVCRQPIQM
IVLTYFP
