E3 ubiquitin-protein ligase Mdm2; p53-binding protein Mdm2; oncoprotein Mdm2; double minute 2 protein; Hdm2 (MDM2)

Function

• inhibits TP53/p53- & TP73/p73-mediated cell cycle arrest & apoptosis by binding its transcriptional activation domain
• functions as a ubiquitin ligase E3 in the presence of E1 & E2, toward p53 & itself
• permits the nuclear export of p53 & targets it for proteasome-mediated proteolysis
• binds p53, p73, ARF(P14), ribosomal protein L5 & specifically to RNA
• interact with RB protein & alters binding properties of the Rb pocket
• interacts with E1A-associated protein EP300 & E2F1 transcription factor
• forms a ternary complex with TP53/p53 & WWOX
• interacts with CDKN2AIP, MTBP, TRBG1 & USP7
• isoform Mdm2-F does not interact with TP53/p53
• interacts with PYHIN1
• interacts with, & ubiquitinates HIV-1 Tat
• may also bind DNA with its Zn finger(s)
• phosphorylated in response to ionizing radiation (ATM-dependent)
• auto-ubiquitinated; which leads to proteasomal degradation

Structure

• region I
  • sufficient for binding p53 & inhibiting its G1 arrest & apoptosis functions
  • also binds p73 & E2F1
• region II
  • contains most of a central acidic region required for interaction with ribosomal protein L5 & a putative C4-type Zn+2 finger
• RING finger domain
  • coordinates two Zn+2
  • interacts specifically with RNA whether or not Zn+2 is present
  • mediates the heterooligomerization with MDM4
  • essential for its ubiquitin ligase E3 activity toward p53 & itself
• belongs to the MDM2/MDM4 family
• contains 1 RanBP2-type Zn+2 finger
• contains 1 RING-type Zn+2 finger
• contains 1 SWIB domain

Compartment

• nucleus, nucleoplasm, nucleolus, cytoplasm
• expressed predominantly in the nucleoplasm
• interaction with p14ARF results in the localization of both proteins to the nucleolus; he nucleolar localization signals in both p14ARF & MDM2 may be necessary to allow efficient nucleolar localization of both proteins

Alternative splicing

named isoforms=10

Expression

• ubiquitous
• induced by DNA damage

Pathology

• seems to be amplified in certain tumors including soft tissue sarcomas, osteosarcomas & gliomas)
• higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage & high-grade ovarian carcinoma & bladder carcinomas
• four of the splice variants show loss of p53 binding
• isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F & isoform Mdm2-G are observed in a range of cancers but absent in normal tissues
• MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells

More general terms

• transcription factor (TF)
• E3 ubiquitin ligase

Additional terms

• cyclin-dependent kinase inhibitor 2A, isoform 4; p14ARF; p19ARF (MLM)

Database

• UniProt: http://www.uniprot.org/uniprot/Q00987.html
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4193
• OMIM: https://mirror.omim.org/entry/164785
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4193