P56950 (MDM2_CANFA) Reviewed, UniProtKB/Swiss-Prot
Last modified June 11, 2014. Version 115. History...
Names and origin
|Protein names||Recommended name:|
E3 ubiquitin-protein ligase Mdm2
Double minute 2 protein
p53-binding protein Mdm2
|Organism||Canis familiaris (Dog) (Canis lupus familiaris) [Reference proteome]|
|Taxonomic identifier||9615 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Carnivora › Caniformia › Canidae › Canis ›|
|Sequence length||487 AA.|
|Protein existence||Evidence at transcript level|
General annotation (Comments)
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 By similarity.
Binds p53/TP53, TP73/p73, ARF/P14, PML, RBL5 and RP11 and specifically to RNA. Can interact also with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, MTBP, RFWD3, TBRG1, USP7, PYHIN1, UBXN6, and RBBP6. Isoform Mdm2-Fdoes not interact with p53/TP53. Interacts with ARRB1 and ARRB2. Interacts (isoform 2)with PSMA3. Found in a trimeric complex with MDM2, MDM4 and UPB2. 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; the interaction leads 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 By similarity.
Nucleus › nucleoplasm By similarity. Cytoplasm By similarity. Nucleus › nucleolus By similarity. 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 Ain the nucleus By similarity.
Isoform Mdm2-alpha is present in lymphoid and testicular tissues.
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 By similarity. Interacts with IGF1R By similarity.
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 By similarity.
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.
Belongs to the MDM2/MDM4 family.
Contains 1 RanBP2-type zinc finger.
Contains 1 RING-type zinc finger.
Contains 1 SWIB domain.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform Mdm2 (identifier: P56950-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform Mdm2-alpha (identifier: P56950-2) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 487||487||E3 ubiquitin-protein ligase Mdm2||PRO_0000157329|
|Domain||27 – 107||81||SWIB|
|Zinc finger||299 – 328||30||RanBP2-type|
|Zinc finger||434 – 475||42||RING-type|
|Region||150 – 230||81||Interaction with PYHIN1 and necessary for interaction with RFFL By similarity|
|Region||170 – 306||137||Interaction with MTBP By similarity|
|Region||210 – 304||95||ARF-binding|
|Region||223 – 232||10||Interaction with USP7 By similarity|
|Region||242 – 331||90||Region II|
|Motif||179 – 185||7||Nuclear localization signal Potential|
|Motif||190 – 202||13||Nuclear export signal|
|Motif||462 – 469||8||Nucleolar localization signal Potential|
|Compositional bias||210 – 215||6||Poly-Ser|
|Compositional bias||243 – 301||59||Asp/Glu-rich (acidic)|
Amino acid modifications
|Modified residue||166||1||Phosphoserine; by SGK1 By similarity|
|Modified residue||240||1||Phosphoserine By similarity|
|Modified residue||242||1||Phosphoserine By similarity|
|Modified residue||246||1||Phosphoserine By similarity|
|Modified residue||260||1||Phosphoserine By similarity|
|Modified residue||262||1||Phosphoserine By similarity|
|Modified residue||382||1||Phosphoserine; by ATM By similarity|
|Modified residue||391||1||Phosphoserine; by ATM By similarity|
|Modified residue||403||1||Phosphoserine; by ATM By similarity|
|Modified residue||415||1||Phosphothreonine; by ATM By similarity|
|Modified residue||425||1||Phosphoserine; by ATM By similarity|
|Alternative sequence||1 – 61||61||Missing in isoform Mdm2-alpha.||VSP_003206|
|Sequence conflict||11||1||G → D in AAG42840. Ref.2|
|Sequence conflict||238 – 239||2||QD → HH in AAG42840. Ref.2|
|||"Cloning, sequence analysis and expression of the cDNAs encoding the canine and equine homologues of the mouse double minute 2 (mdm2) proto-oncogene."|
Nasir L., Burr P.D., McFarlane S.T., Gault E., Thompson H., Argyle D.J.
Cancer Lett. 152:9-13(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-484.
|||"A novel exon within the mdm2 gene modulates translation initiation in vitro and disrupts the p53-binding domain of mdm2 protein."|
Veldhoen N., Metcalfe S., Milner J.
Oncogene 18:7026-7033(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2 AND MDM2-ALPHA).
|AF100705 mRNA. Translation: AAF67833.1.|
AF322416 mRNA. Translation: AAG42840.1.
|RefSeq||NP_001003103.1. NM_001003103.2. |
3D structure databases
|SMR||P56950. Positions 1-118, 290-335, 428-487. |
Protocols and materials databases
Genome annotation databases
Family and domain databases
|Gene3D||126.96.36.199. 1 hit. |
188.8.131.52. 1 hit.
|InterPro||IPR028340. Mdm2. |
|PANTHER||PTHR10360:SF11. PTHR10360:SF11. 1 hit. |
|Pfam||PF02201. SWIB. 1 hit. |
PF00641. zf-RanBP. 1 hit.
|PIRSF||PIRSF500700. MDM2. 1 hit. |
PIRSF006748. p53_MDM_2/4. 1 hit.
|SMART||SM00184. RING. 1 hit. |
|SUPFAM||SSF47592. SSF47592. 2 hits. |
|PROSITE||PS01358. ZF_RANBP2_1. 1 hit. |
PS50199. ZF_RANBP2_2. 1 hit.
PS50089. ZF_RING_2. 1 hit.
|Accession||Primary (citable) accession number: P56950|
Secondary accession number(s): Q95KN5
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families