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FLASH GENE
Symbol MDM2 contributors: mct/shn/pgu - updated : 02-04-2020
HGNC name Mdm2 p53 binding protein homolog (mouse)
HGNC id 6973
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestivemouthtongue  highly
 salivary gland   highly
Lymphoid/Immunelymph node   highly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Epithelialbarrier/lining   
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES acid
STRUCTURE
motifs/domains
  • a N terminal TP53 binding domain, involved in interaction with S100 proteins , a high affinity TP53-binding domain at the N terminus, interacting with the PTB domain of NUMB
  • a hydrophobic pocket involved in both its transrepressor and E3-ubiqutin ligase functions
  • a central acid domain that recognizes a ubiquitination signal in the core DNA binding domain of TP53, and necessary for binding to GORAB , domain required to induce TP53 conformational change and inhibiting TP53 DNA binding
  • a nuclear localization signal (NLS)
  • a C4 type motif, a nuclear export signal (NES)
  • a Ring finger domain
  • a second binding site for TP53 in its acidic domain and part of the zinc finger domain, stabilizing the interaction between MDM2 and Tp53 during Tp53 degradation
  • C-terminal AAs are required for dimerization and for activity, with a single aromatic AA located 3 AAs from the C terminus , and a C2H2C4 RING finger domain that is required for E2 enzyme-binding and ATP-dependent molecular chaperone activity
  • a C-terminal RING domain that recruits E2 ubiquitin conjugating enzymes , and C-terminal AAs of the RING directly contribute to MDM2 E3 ligase activity, a feature unique to MDM2 and absent in the RCHY1 RING domain
    • conjugated PhosphoP
    mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Mdm2, Mus musculus
    ortholog to Mdm2, Rattus norvegicus
    ortholog to mdm2, Danio rerio
    ortholog to MDM2, Pan troglodytes
    intraspecies homolog to Mdm4 p53 binding protein homolog (mouse)
    Homologene
    FAMILY
  • MDM2/MDM4 family
    • CATEGORY enzyme , regulatory , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm
    text
  • predominantly in the nucleoplasm, translocated to the nucleus after phosphorylation, after mitogen-induced activation of PI3 kinase and its target AKT1
  • nuclear translocation upon VEGF stimulation
    • basic FUNCTION
  • plays an important role in regulating the stability and function of the p53 tumor suppressor protein
  • plays a key role in GRK2 degradation
  • acting as an E3 ubiquitin ligase directly transfering ubiquitin and targeting TP53 to proteasome complex for ubiquitin degradation
  • commun component of the ubiquitin and NEDD8 conjugation pathway and controling the function of substrate proteins
  • playing a pathogenic role in neuroblastoma
  • involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation
  • key negative regulator of TP53, also binds to and inhibits TP73
  • in the absence of ATP, was able to catalyse inhibition of the DNA-binding function of E2F1
  • structurally related TP53-binding proteins that function as critical negative regulators of TP53 activity in embryonic and adult tissue
  • having a key role in regulating TP53 abundance
  • modulation of HDM2 expression could play an important role in tumor angiogenesis and the metastatic process via transcriptional regulation of VEGFA
  • has ability to ubiquitinate XRCC6
  • ubiquitin E3 ligase activity, downstream of TP53 to regulate the degradation of mammalian Foxo factors
  • functions as a specific E3 ubiquitin ligase for HEXIM1, suggesting a possible role for HEXIM1 ubiquitination in the regulation of CCNT1 activity
  • with MDM4, bind TP53 and inhibit its function by distinct nonredundant mechanisms
  • may be facilitating, or at least enhancing, the association of TP53 with the proteasome (phosphorylation of its central domain regulates this process)
  • it is likely that MDM2 might facilitate the recruitment of ITCH/TP73 complex to proteasome, and thereby promoting the proteasomal degradation of TP73 in HeLa cells
  • involved in regulation of subcellular localization and function of ARRB2
  • essential role of MDM2 E3 ligase activity in determining ARRB2 subcellular localization and corresponding signaling
  • may, under some conditions, actively repress basal activity of TP53 target genes by recruiting corepressors to promoters
  • can play a TP53-independent role in the regulation of VEGFA, which may promote tumor growth and metastasis
  • master regulator of TP53 for proteasomal degradation, restraining the potent activity of TP53 and enabling cell survival and proliferation
  • E3 ligases, that can also ubiquitinate itself
  • MDM4/MDM2-TP53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
  • UBE2A-MDM2 ubiquitin ligase machinery is critical for the degradation of chromatin-related proteins
  • critical role played by the MDM2/MDM4-TP53 nexus on nephrogenesis
  • RNF2 is required to support DNA replication, similar to MDM2
  • chromatin modification by MDM2 and PRC1 ensures smooth DNA replication through the avoidance of R-loop formation
    • CELLULAR PROCESS cell cycle, checkpoint
    PHYSIOLOGICAL PROCESS
    text plays an important role in the regulation of the G(1) checkpoint of the cell cycle through its interaction with p53
    PATHWAY
    metabolism
    signaling
    unique MYB-DHRS2-MDM2-TP53 mitochondria-to-nucleus signaling pathway that may have functional significance for ER-positive breast cancers
    a component
  • component of a ternary complex with TP53 and EP300
  • MDM2 and MDM4 can form a heterodimer through their Ring domains, and this may regulate MDM2-mediated degradation of TP53
  • most oncogenic form of these proteins is the MDM2–MDM4 heterodimer
  • HDM2-HDM2 homodimers
  • promotes the formation of a ternary complex between TP53, MDM2, and the proteasome
  • S100B formed a complex with TP53 in the presence of MDM2
  • NUMB forming a trimeric complex with MDM2 and TP53 and has been shown to play a role in the stabilization of TP53 in cells
  • CDKN2A-MDM2-TP53 and the RPL11-MDM2-TP53 pathways are likely functionally connected
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • ribosomal L5 protein, RPL5
  • target for transcriptional activation by the TP53 tumor suppressor gene product (Zaubermann 1995)
  • retinoblastoma protein, RB
  • TAF1 RNA polymerase II, TATA box binding protein (TBP)-associated factor 250kDa, TAFII250
  • Ink4a tumor suppressor gene product, p19Arf
  • numb gene homolog (Drosophila), NUMB
  • E1A binding protein p300, EP300
  • tumor protein p73, TP73
  • MDMX
  • Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse) binding protein, 104kDa, MTPB
  • C-terminus of the catalytic subunit of DNA polymerase epsilon, POLE
  • a direct activator of ERalpha function
  • Tat interacting protein, 60kDa, TIP60
  • p300/CBP-associated factor, PCAF
  • c-Abl binds and phosphorylates Mdm2 in vivo and in vitro
  • AKT
  • histone deacetylase 1, HDAC1
  • arrestin, beta 2, ARRB2
  • cyclin G1, CCND1
  • hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor), HIF1A
  • insulin-like growth factor 1 receptor, IGF-1R
  • ribosomal protein L11
  • C-terminal binding protein 2, CTBP2
  • nucleophosmin (nucleolar phosphoprotein B23, numatrin), NPM1
  • Yin Yang 1, YY1
  • Directly interacts and inhibits the p53 tumor suppressor protein
  • CHK2 checkpoint homolog (S. pombe), CHEK2
  • Hdmx protein
  • promyelocytic leukaemia, PML
  • Seladin-1
  • Gankyrin
  • nuclear corepressor KAP1
  • ubiquitin specific peptidase 7 (herpes virus-associated), USP7
  • titin-cap (telethonin), TCAP
  • death domain-associated protein, Daxx
  • cadherin 1, type 1, E-cadherin (epithelial), CDH1
  • ubiquitin specific peptidase 2, USP2
  • stratifin, SFN
  • wild-type p53-induced phosphatase 1, WIP1
  • TAF1 (downregulates MDM2 auto-ubiquitylation, leading to MDM2 stabilization, and promotes TP53-MDM2 association through a recently defined second binding site in the acidic domain of MDM2)
  • binding to the TP53 amino terminus, inhibiting its transactivation function and targeting it for proteasomal degradation, and regulates the TP53 tumor suppressor by promoting its proteasome-mediated degradation
  • FK506 binding protein 3, 25kDa, FKBP3
  • COP9 constitutive photomorphogenic homolog subunit 5 (Arabidopsis), COPS5
  • can also target itself and MDM4 for degradation
  • proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki), PA28gamma
  • dihydrofolate reductase, DHFR
  • MDM2-RPL26 interaction represents an additional important component of the autoregulatory feedback loop that dictates cellular TP53 levels and activity
  • insulin-like growth factor receptor, IGF-IR
  • GNAS complex locus, GNAS
  • IRF2
  • FOXO1 and FOXO3 and promotes their ubiquitination and degradation
  • MDM2 ubiquitination of RPSS7 is involved in sustaining the TP53 response
  • stable complex of DYRK2 with MDM2 at the nucleus (nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation)
  • associates with the proteasome and this interaction strongly enhanced the association of TP53 with the degradation machinery
  • RYBP
  • ATF3 (MDM2 via its C-terminal RING finger can bind to the Basic region of ATF3 and mediate the addition of ubiquitin moieties to the ATF3 leucine zipper domain)
  • histone methyltransferases SUV39H1 and EHMT1
  • interacting with GORAB, which promoted MDM2 self-ubiquitination and induced MDM2 protein degradation
  • intricate interplay between MDM2 and MDM4 in TP53 regulation
  • MDM2-TP53 interaction is decreased upon deletion, mutation or acetylation of the TP53 C terminus
  • GNL3L binds MDM2 and displays the same function as nucleostemin in stabilizing MDM2 protein and preventing its ubiquitylation
  • SENP2-dependent regulation of MDM2 is sensitive to its TP53-binding activity
  • SENP3 interacts with TP53 and MDM2, desumoylates both proteins and bound to the acidic domain of MDM2, which also mediates the TP53 interaction, and competed with TP53 for binding
  • UBE4B physically interacts with TP53 and MDM2
  • regulates TP53 predominantly by promoting TP53 ubiquitination
  • SUV39H1 is targeted to TP53 target promoters by binding MDM2 acidic domain and neutralizing its TP53 conformational effect, forming a TP53-MDM2-SUV39H1 complex capable of DNA binding and transcription repression
  • MDM2 expression causes the loss of NME2 cell motility regulatory function
  • UBE4B, an E3 and E4 ubiquitin ligase with a U-box domain, interacting physically with both TP53 and MDM2
  • upon catecholamine stimulation, ARRB1 promotes the interaction of MDM2 and TP53 by acting as an E3 ligase adaptor that facilitates ubiquitination of p53
  • BAIAP2L1 interacted with MDM2 and promoted low levels of MDM2-mediated TP53 ubiquitination
  • specific interaction between RPL11 and the zinc finger of MDM2 via hydrophilic AAs as well as a molecular foundation for better understanding RPL11 inhibition of MDM2 function
  • promotes SUMO-2/3 modification of TP53 to modulate transcriptional activity
  • critical role for noncoding 5S rRNA in modulating the TP53-MDM4-MDM2 axis
  • major regulator of TP53 by acting as a ubiquitin E3 ligase
  • activator of APOC3 promoter which is antagonized by TP53 and NR0B2 inhibition
  • direct binding to MDM2 E3 ligase and NEDDylation of RPL11 are critical regulators for RPL11 promoter recruitment
  • MDM4 can suppress TP53, which is through transcriptional activation of TP53 principal negative regulator, MDM2
  • MDM2 acid domain binds NUMB and is critical for NUMB ubiquitination
  • interacts directly with TTF1 and regulates its cellular abundance by targeting it for degradation by the proteasome
  • SKI enhances MDM2-mediated TP53 ubiquitination
  • RPS25-MDM2-TP53 regulatory feedback loop, which may have an important role in cancer development and progression
  • GORAB can directly induce MDM2 transcription, whereas inhibiting the function of MDM2 by specific small interfering RNAs results in partial rescue of neurite outgrowth and neuronal morphogenesis defects induced by GORAB
  • DNAJC7 is associated with TP53 in mammalian cells, and stabilizes TP53 by inhibiting complex formation between TP53 and MDM2
  • RPS14 binds to and inactivates MDM2, consequently leading to TP53-dependent cell-cycle arrest and growth inhibition
  • RPS26 has the ability to interact with MDM2 and inhibits MDM2-mediated TP53 ubiquitination that leads to TP53 stabilization upon overexpression
  • can inhibit AXIN1-stimulated TP53-dependent apoptosis by suppressing TP53 phosphorylation at Ser 46 and apoptosis-related TP53 transactivational activity
  • RPL37, RPS15 and RPS20 regulate the MDM2-TP53-MDM4 network
  • RASSF6 binds MDM2 and facilitates its ubiquitination
  • for the maintenance of self-renewal, PCID2 binds to EID1 to impede the association with MDM2
  • DNAJB1 was found to specifically bind to MDM2
  • TP53&
    • 8209;PIAS3 interaction through the 1-52 amino acid region of TP53, reduces TP53&
    8209;MDM2 complex formation, which not only increases the half-life of TP53, but also its transactivation of target genes
  • MDM4 may contribute to the regulation of TP53 independently of MDM2
  • AKT1S1 negatively regulates the RPL11-MDM2-TP53 nucleolar stress response pathway and suppresses induction of T53-mediated cellular senescence
  • FUBP1 is a positive splicing regulatory factor of MDM2 . FUBP1 is also a strong positive splicing regulator that facilitates efficient splicing of the MDM2 pre-mRNA by binding its introns
  • XAF1 binds directly to the N-terminal proline-rich domain of TP53 and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of TP53
  • suppression of TP53 by NOTCH3 is mediated by CCNG1 and sustained by MDM2 in hepatocellular carcinoma
  • MDM2 binds to and is involved in conjugating either ubiquitin or NEDD8 to TP53
  • MDM2-dependent NEDD8 conjugation of TP53 results in transcriptionally inactive TP53, a process that is reversed with a small molecule inhibitor to either SRC or UBE2M
  • HSP90B1 interacts with both TP53 and MDM2 to enhance MDM2-mediated TP53 ubiquitination and degradation
  • interaction of ADGRB1 with MDM2 in the brain modulates DLG4 levels and thereby regulates synaptic plasticity
  • RBBP6 interacts with TP53 and enhances the activity of MDM2, the prototypical negative regulator of TP53
  • TRIM65 binds to the N-terminus of TP53 tumor suppressor and thus competes with MDM2 for TP53 binding
  • RPS2 interacts with MDM2 through the RING finger domain of MDM2, and RPS2 is ubiquitinated by MDM2 and the ubiquitinated status of RPS2 regulates the stability of TP53
  • ZEB2 interacted with MDM2 to promote brain microvascular endothelial cells (BMECs) dysfunction and brain damage after intracerebral hemorrhage (ICH)
    • cell & other
    REGULATION
    activated by RANGAP1 and protected against self-ubiquitination
    SKI that positively regulates MDM2 protein
    induced by p53 and DNA damage
    inhibited by homeodomain interacting protein kinase 2, HIPK2
    retinoblastoma protein, Rb
    small molecules (HLI98)
    tumor susceptibility gene 101, TSG101
    repressed by Sumoylated by protein inhibitor of activated STAT (PIAS) and RanBP2
    Other regulated by nuclear PIM1 and MYCN
    modulation by HIPK2 of its activity at transcriptional and posttranscriptional levels
    phophorylated by v-akt murine thymoma viral oncogene homolog 1, AKT1
    stabilized by CARP1 and CARP2
    regulated by COP9 signalosome complex subunit 5, CSN5
    phosphorylated by MAPKAP kinase 2, MK2
    negatively regulated by Ribosomal protein L11 )
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   amplification    
    in sarcoma, malignant glioma,angiosarcoma, liposarcoma well differentiated and anaplastic astrocytoma, and diffuse large B cell lymphoma
    tumoral     --over  
    in leukemias
    tumoral   amplification    
    consistently amplified in classic and dedifferentiated low-grade osteosarcoma (LGOS) but not in their histologic mimics
    tumoral     --low  
    combinatory inhibition of TRIM65 and MDM2 in lung cancer cells
    tumoral     --over  
    MDM2 up-regulation in renal cancer cells can act in a dominant manner to abrogate the function of a potent suppressor of motility and metastasis
    Susceptibility
  • to early onset in age of tumour in Li-Fraumeni syndrome
  • to gastric carcinoma with poor prognosis
    • Variant & Polymorphism SNP SNP309 G allele lowering the age of tumour onset in germline TP53 mutation carriers, this effect may be amplified by the TP53 72Arg allele
  • promoter polymorphism SNP309 is associated with both gastric carcinoma and increased susceptibility
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    antagonists of the TP53-MDM2 interaction showing good efficacy against tumors with normal MDM2 expression
    cancerskin 
    Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes
    cancer  
    targeting the acidic domain of MDM2 on its own or in combination with other drugs may be a useful therapeutic strategy for the prevention of cancer
    ANIMAL & CELL MODELS
  • Knockout of MDM2 in mice results in embryonic lethality because of ectopic activation of p53