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FLASH GENE
Symbol MDM4 contributors: mct/ - updated : 02-04-2014
HGNC name Mdm4 p53 binding protein homolog (mouse)
HGNC id 6974
Location 1q32.1      Physical location : 204.485.510 - 204.527.247
Synonym name
  • p53 binding protein
  • Mdm4, transformed 3T3 cell double minute 4, p53 binding protein (mouse)
  • MDM4-related protein 1
  • double minute 4, human homolog of; p53-binding protein
  • protein Mdmx
  • Synonym symbol(s) MDMX, MRP1, MGC132766, HDMX, DKFZp781B1423
    DNA
    TYPE functioning gene
    STRUCTURE 110.62 kb     11 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure
  • a TP53-responsive promoter in its first intron that drives the expression of mRNA transcripts with quantitatively and qualitatively different translation potential, which participate in an autoregulatory feedback loop to control the abundance and activity of TP53 in cancer cells
  • MAPPING cloned Y linked N status provisional
    Physical map
    C1orf37 1q31.1 chromosome 1 open reading frame 37 PPFIA4 1q32.1 protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 4 MYOG 1q31-q41 myogenin (myogenic factor 4) ADORA1 1q32.1 adenosine A1 receptor MYBPH 1q32.1 myosin binding protein H CHI3L1 1q31-q32 chitinase 3-like 1 (cartilage glycoprotein-39) CHIT1 1q31-q32 chitinase 1 (chitotriosidase) LOC388729 1 LOC388729 BTG2 1q32 BTG family, member 2 FMOD 1q32.1 fibromodulin ATP2B4 1q32 ATPase, Ca++ transporting, plasma membrane 4 MGC5457 1q32.1 hypothetical protein MGC5457 LAX 1q32.1 hypothetical protein FLJ20340 KIAA0663 1q32.1 hypothetical protein FLJ20340 SNRPE 1q32 small nuclear ribonucleoprotein polypeptide E LOC391155 1 similar to KRT8 protein FLJ40343 1q32.1 hypothetical protein FLJ40343 SOX13 1q31.3-q32.1 SRY (sex determining region Y)-box 13 FLJ10761 1q32.1 putative ethanolamine kinase REN 1q32 renin KISS1 1q32 KiSS-1 metastasis-suppressor FLJ42654 1q32.1 FLJ42654 protein PEPP3 1q32.1 phosphoinositol 3-phosphate-binding protein-3 PPP1R15B 1q32.1 protein phosphatase 1, regulatory (inhibitor) subunit 15B PIK3C2B 1q32 phosphoinositide-3-kinase, class 2, beta polypeptide MDM4 1q32 Mdm4, transformed 3T3 cell double minute 4, p53 binding protein (mouse) GAC1 NFASC 1q32.1 Mdm4, transformed 3T3 cell double minute 4, p53 binding protein (mouse) CNTN2 1q32.1 contactin 2 (axonal) LOC388730 1 similar to RIKEN cDNA 4930429O20 RBBP5 1q32 retinoblastoma binding protein 5 KIAA0472 HUCEP11 1q32.1 retinoblastoma binding protein 5 SNARK 1q32 Homo sapiens likely ortholog of rat SNF1/AMP-activated protein kinase (SNARK), mRNA. FLJ10748 1q32.1 hypothetical protein FLJ10748 LOC93273 1q32.1 hypothetical protein LOC93273 PCTK3 1q31-q32 PCTAIRE protein kinase 3 DKFZp761N1114 1q32.1 hypothetical protein DKFZp761N1114 ELK4 1q32 ELK4, ETS-domain protein (SRF accessory protein 1) Prostein 1q32.1 prostein protein NUCKS 1q31.1 prostein protein RAB7L1 1q32 RAB7, member RAS oncogene family-like 1 SLC41A1 1q32.1 solute carrier family 41, member 1
    RNA
    TRANSCRIPTS type messenger
    text is regulated at the posttranscriptional level by alternative splicing (PMID: 24127580)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 10090 54 490 highly in thymus 2012 2401879
    MDM4-FL or HDMX
    - - - - 508 - 2012 2401879
  • transcribed from the HDMX-P2 promoter in response to TP53-activating signals.
  • an additional 18 AAs at its N terminus
  • retains the ability to cooperate with MDM2 in the ubiquitination of TP53 but has reduced capacity to inhibit TP53 activity and TP53-induced antiproliferative responses
  • 10 - 9940 - 440 - 2012 2401879
    MDM4-A or HDMX-A
    10 - 100022 - 127 transformed cell lines 2012 2401879
  • MDM4-S, HDMX-S, or HDMX-E, product of exon 6 skipping
  • truncated form, potent TP53 repressor
  • lacks the central and C-terminal regions, but containing the NTD and 17 additional amino acids
  • is likely to play a key role in the regulation of cell proliferation and apoptosis in a way distinct from MDM4
  • 7 - 9611 - 116 - 2012 2401879
    MDM4-ALT1, XALT1, or HDMX-ALT1
    5 - 9421 - 267 - 2012 2401879
  • MDM4-ALT2, XALT2, or HDMX-ALT2
  • 8 - 9796 - 392 - 2012 2401879
    MDM4-G or HDMX-G
    3 - 9112 - 164 - 2012 2401879
    DM4-211 or HDMX211
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymph node   highly
     spleen   highly
     thymus   highly
    Reproductivemale systemtestis  highly
    Visualeyeretina    Homo sapiensFetal
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Lymphoid    
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal pocket, globular SWIB-like domain (NTD) that binds to the primary transactivation domain of TP53 , binds tightly to the N-terminal domain of TP53 and inhibits it
  • a RANBP2-type zinc finger and a RING-type zinc finger
  • a regulatory element (the “WWW element”), AAs 190–210 in that intrinsically disordered region constitute an inhibitory module that binds to its own N-terminal domain and prevents MDM4 from binding to TP53
  • HOMOLOGY
    interspecies homolog to murine Mdm4 (84.4pc)
    homolog to rattus Mdm4 (84.6pc)
    intraspecies homolog to to TP53-binding protein MDM2
    Homologene
    FAMILY
  • MDM2/MDM4 family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus
    basic FUNCTION
  • ubiquitin E3 ligase, involved in the apoptosis
  • may act as a negative regulator of TP53 levels and activity
  • can effectively function to promote cellular MDM2 E3 ubiquitin ligase activity when cellular MDM2 concentrations are limiting
  • different roles of MDM2 and MDM4 in the regulation of TP53 activities
  • mitochondrial MDM4 binds to BCL2, facilitates the mitochondrial localization of p53Ser46(P) and promotes binding between BCL2 and p53Ser46(P), release of cytochrome C and apoptosis
  • inhibits p73-mediated cell cycle arrest and apoptosis
  • inhibits degradation of MDM2
  • having a TP53-independent role in suppressing oncogenic cell transformation, proliferation, and tumorigenesis by promoting centrosome clustering and bipolar mitosis
  • structurally related TP53-binding proteins that function as critical negative regulators of TP53 activity in embryonic and adult tissue
  • regulates TP53 abundance by modulating the levels and activity of MDM2
  • with MDM4, bind TP53 and inhibit its function by distinct nonredundant mechanisms
  • cooperated with MDM2 to control TP53 activity
  • key modulator of TP53 activity in differentiating embryonic stem cells
  • can suppress TP53, which is through transcriptional activation of TP53 principal negative regulator, MDM2
  • is one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to activate the TP53 response
  • having TP53- and MDM2-independent oncogenic function providing new insight into the many cancers that overexpress MDM4
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • 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
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • TP53 binding and repressor
  • binding to BCL2 in mitochondria
  • binding to TP73 and MDM2
  • YWHAG binds to the MDM4 domain adjacent to CDKN1A binding suggesting that YWHAG may affect MDM4-mediated CDKN1A proteasomal turnover
  • critical role for noncoding 5S rRNA in modulating the TP53-MDM4-MDM2 axis
  • CSNK1A1 stably associates with MDM4, stimulates MDM4-TP53 binding, and cooperates with MDM4 to inactivate TP53
  • intricate interplay between MDM2 and MDM4 in TP53 regulation
  • RPL37, RPS15 and RPS20 regulate the MDM2-TP53-MDM4 network
  • may contribute to the regulation of TP53 independently of MDM2
  • JMJD6 antagonizes TP53 acetylation, promotes the association of TP53 with its negative regulator MDM4, and represses transcriptional activity of TP53
  • cell & other
    REGULATION
    Phosphorylated by AMPK, that phosphorylates and inactivates MDM4, resulting in TP53 stabilization and activation
    Other can be deubiquitinated by USP2 (Allende-Vega 2010)
    regulated through its subcellular localization (in many proliferating cells is primarily cytoplasmic)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   amplification    
    strongly selected for during tumour progression as a mechanism to suppress the TP53 response in RB1-deficient retinal cells
    tumoral     --over  
    in malignant glioma escaping TP53 dependent growth control
    tumoral     --low  
    downregulation of MDM4 expression associates with cisplatin resistance in ovarian cancers
    constitutional   deletion    
    induces multipolar mitotic spindle formation and the loss of chromosomes from hyperploid TP53-null cells
    tumoral   amplification    
    in breast carcinomas, colon carcinomas, lung carcinomas, and a smaller percentage of gliomas
    constitutional     --over  
    in fibroblast-like synoviocyte, may contribute to the hyperplasia phenotype of rheumatoid arthritis synovial tissues
    tumoral     --over  
    in retinoblastoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancereye 
    specific chemotherapeutic target for treating retinoblastoma
    cancereye 
    MDM4 inhibitor, SJ-172550, and can efficiently kill MDM4-amplified retinoblastoma cells
    cancerskin 
    is a promising target for antimelanoma combination therapy
    ANIMAL & CELL MODELS