SUBUNIT: Binds p53/TP53, TP73/p73, ARF/P14, PML, RBL5 and RP11, and 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, MTBP, RFWD3, TBRG1, USP7, PYHIN1, UBXN6, and RBBP6. Isoform Mdm2-F does not interact with p53/TP53. Interacts with and ubiquitinates HIV-1 Tat. 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; 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 MDM2 and ERBB4 in the complex.

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; 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: Phosphorylated in response to ionizing radiation in an ATM- dependent manner.

PTM: Auto-ubiquitinated; which leads to proteasomal degradation. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitinilation and degradation of p53/TP53. Deubiquitinated by USP7; leading to stabilize it.

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.

SIMILARITY: Contains 1 RanBP2-type zinc finger.

SIMILARITY: Contains 1 RING-type zinc finger.

SIMILARITY: Contains 1 SWIB domain. 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="http://en.wikipedia.org/wiki/Mdm2";

COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.