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FLASH GENE
Symbol ETV4 contributors: mct - updated : 27-08-2016
HGNC name ets variant 4
HGNC id 3493
Location 17q21.31      Physical location : 41.605.211 - 41.623.762
Synonym name
  • ets variant gene 4 (E1A enhancer binding protein, E1AF)
  • E1A enhancer binding protein
  • stimulating transcription from matrix metalloproteinase gene promoters
  • adenovirus E1A enhancer-binding protein
  • polyomavirus enhancer activator-3
  • EWS protein/E1A enhancer binding protein chimera
  • Synonym symbol(s) E1AF, PEAR, E1A-F, PEA3, PEAS3
    DNA
    TYPE functioning gene
    SPECIAL FEATURE arranged in tandem
    STRUCTURE 18.55 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (CAAT box)
    Binding site   transcription factor
    text structure
  • variation in exon 1, which depends on the cell type
  • no typical TATA box in the 5'-flanking region, but putative binding sites of a number of transcription factors including PEA3 as well as CAAT boxes
  • housekeeping gene, whose expression is controlled in specific tissues
  • SUMO-mediated recycling plays a role in ETV4 -mediated promoter activation (Guo 2009)
  • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 - 2298 54 484 - 2006 16297865
    13 - 2431 54 484 - 2006 16297865
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon highly
     stomach   highly
    Endocrineneuroendocrinepituitary  highly
    Reproductivefemale systemovary  highly
    Skin/Tegumentskin   highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text mammary gland in development, fetal kidney
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two repeat homolog to EWSR1
  • helix-turn-helix superfamily
  • two functional domains
  • an acidic domain
  • CR1 domain (which alone is insufficient to bind EP300) sufficient for repression of MITF, while the N-terminus, through which E1A binds the EP300 proteins and other coactivators, was unable to repress
  • the DNA binding ETS domain, PEA3 subgroup
  • HOMOLOGY
    interspecies homolog to adenovirus E1A enhancer binding protein
    homolog to murine Pea3
    Homologene
    FAMILY
  • divergent member of the winged helix-turn-helix superfamily
  • PEA3 subfamily of ETS transcription factors
  • CATEGORY transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • transcription regulator, activating matrix metalloproteinase genes
  • involved in in progenitor cell renewal or terminal differentiation
  • acting in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in well differentiated cells
  • play critical roles in tumor metastasis via directly binding to the promoter of genes involved in tumor migration and invasion
  • pivotal and complementary roles of ETV4 and ETV5 transcription factors in events crucial to mammary tumorigenesis
  • sumoylation plays a positive role in ETV4-mediated transcriptional activation and the ERK MAP kinase pathway cooperates with rather than antagonizes this process
  • with ETV5, are key components of a gene network downstream of Ret that promotes and controls renal branching morphogenesis
  • is involved in tumorigenesis especially during the metastatic process
  • increased the morphogenetic and tumorigenic capacity of mammary epithelial cells by modulating their cell morphology, proliferation, and migration potential
  • ETV4 and ETV5 are essential molecules of the transcriptional program linking neurotrophin signaling to sensory neuronal differentiation, suggesting that they can be involved in NGF-mediated target innervation
  • might potentially play an essential role in the activation of the PTK2 gene during tumor metastasis
  • oncogenic factor ETV4 regulates POU5F1 gene expression as a transcriptional activator
  • ETV4 and ETV5, potentially through regulation of GBX2 and TCF15, are involved in the ES cell proliferation and induction of differentiation-associated genes in ES cells
  • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA binding to sequences containing the consensus pentanucleotide 5'-CGGA(AT)-3'
    RNA
    small molecule
    protein
  • up-regulate the epithelial marker MUC4 and down-regulate the ERBB2 oncogene (is a key regulator of the differentiation/proliferation balance in pancreatic cancer)
  • increases cell cycle progression via upregulation of interacting with CCND3 (increases cell cycle progression via upregulation of CCND3 transcription, which elicits a new mechanism of breast cancer growth and a new mechanism of CCND3 transcription)
  • interacting with E2F1 (activation of ETV4 provides a means for E2F1 to induce cell apoptosis in response to DNA damage)
  • interaction with MMP1, and PTGS2 (its sumoylation is required for maximal activation of target gene promoters, including MMP1 and PTGS2)
  • MYOD1 or ETV4 could bind to the E-box and ETV4 sites on the ABCB1 promoter and activate its transcription
  • RFWD2 is a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5
  • CCND2 is a new ETV4 target gene involved in the control of cellular proliferation and migration, a finding that highlights a new negative regulatory loop between ETV4 and CCND2
  • ETV4 is able to transactivate PTK2 expression through binding to the promoter region of PTK2
  • ETV4 and cAMP response elements play a role in the transcriptional regulation of PANX1 in the epididymis
  • ACACA and ACLY regulate the levels of ETV4 under hypoxia via increased alpha-ketoglutarate
  • cell & other
    REGULATION
    activated by by E1AF itself and estrogen receptor
    Other modified by SUMO on multiple sites in its N-terminal region
    (activation of the ERK MAP kinase pathway promotes this sumoylation)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    translocated with EWSR1 in t(17;22) (q12;q12) in Ewing sarcoma
    tumoral fusion      
    with TMPRSS2 in prostate carcinoma
    tumoral     --over  
    correlated significantly with tumor progression of rectal cancer and may be an important factor in rectal cancer progression
    tumoral     --low  
    reduction of ETV4 expression in colorectal cancer cells significantly impaired their invasive capacity
    constitutional        
    motility defects observed in ETV4-null cells are due to altered adhesion signaling
    tumoral     --over  
    in gastric adenocarcinomas and the simultaneous upregulation of ETV4 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS