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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 [2] - 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 a) sufficient for binding p53 & inhibiting its G1 arrest & apoptosis functions b) also binds p73 & E2F1 - region II a) contains most of a central acidic region required for interaction with ribosomal protein L5 & a putative C4-type Zn+2 finger - RING finger domain a) coordinates two Zn+2 b) interacts specifically with RNA whether or not Zn+2 is present c) mediates the heterooligomerization with MDM4 d) 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

Interactions

molecular events

Related

cyclin-dependent kinase inhibitor 2A, isoform 4; p14ARF; p19ARF (MLM) mdm2 proto-oncogene

General

transcription factor (TF) E3 ubiquitin ligase; ubiquitin-ligating enzyme E3; N end-recognizing protein

Properties

SIZE: entity length = 491 aa MW = 55 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: SWIB {27-107} PYHIN1 interaction {150-230} MTBP interaction {170-306} MOTIF: nuclear translocation signal {179-185} nuclear export signal {190-202} binding site SITE: 210-304 FOR-BINDING-OF: cyclin-dependent kinase inhibitor 2A, isoform 4 serine-rich region {210-215} MOTIF: serine residue (SEVERAL) USP7 interaction {223-232} Region II {242-331} MOTIF: acidic region {243-301} MOTIF: acidic residue (SEVERAL) Zinc finger NAME: Zinc finger SITE: 299-328 EFFECTOR-BOUND: Zn+2 RING-finger {438-479} MOTIF: nucleolar localization signal {466-473} EFFECTOR-BOUND: Zn+2 FOR-BINDING-OF: DNA motif

References

  1. Lane DP. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15-6. PMID: 1614522
  2. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: 7677168
  3. Entrez Gene :accession 4193
  4. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/MDM2ID115ch12q15.html
  5. Wikipedia; Note: Mdm2 entry http://en.wikipedia.org/wiki/Mdm2
  6. UniProt :accession Q00987

Component-of

molecular complex

Databases & Figures

OMIM 164785 MORBIDMAP 164785 UniProt Q00987 PFAM correlations Entrez Gene 4193 Kegg hsa:4193 Figures/diagrams/slides/tables related to E3 ubiquitin-protein ligase Mdm2