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Symbol NCOA4 contributors: mct - updated : 15-02-2018
HGNC name nuclear receptor coactivator 4
HGNC id 7671
Corresponding disease
PTC3 papillary thyroid carcinoma 3
Location 10q11.22      Physical location : 51.565.107 - 51.590.733
Synonym name
  • RET-activating gene ELE1
  • androgen receptor-associated protein 70
  • RET-fused
  • Synonym symbol(s) ARA70, RFG, ELE1, RP11-481A12.4, DKFZp762E1112, PTC3
    TYPE functioning gene
    STRUCTURE 25.62 kb     11 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status confirmed
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 3748 73.6 650 . found in the nucleus 2010 20167864
  • ARA70 alpha
  • represses prostate cancer cell proliferation and anchorage-independent growth
  • although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process
  • 11 - 3659 71.4 630 only in testis, localized to the cytosol 2010 20167864
  • ARA70 beta
  • internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion
  • regulator of tumor cell growth and metastasis by affecting gene expression
  • 10 - 3562 69.7 614 - 1996 8643607
    10 - 3502 69.7 614 - 1996 8643607
    10 - 3588 69.7 614 - 1996 8643607
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Reproductivemale systemprostate   
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    cell lineage
    cell lines
    at STAGE
  • a nuclear receptor interaction motif (LXXLL), implicated in the interaction with AR
    CATEGORY regulatory , transcription factor , receptor
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • transcriptional activation of target genes, mediating estrogen-androgen synergism
  • amplifies the activity of several ligand-activated nuclear transcription factors, including the aryl hydrocarbon receptor (AHR) and androgen receptor (AR)
  • coactivator that may play a role in modulating nuclear receptor activity, particularly that of the AHR, during development
  • role for autophagy and NCOA4 in the control of iron homeostasis
  • is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability
  • NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels
  • NCOA4 was a selective cargo receptor for the selective autophagic turnover of ferritin (namely ferritinophagy) in ferroptosis
  • ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis
  • importance of ferritin for the vectorial transfer of imported iron to mitochondria in developing red cells and of PCBP1 and NCOA4 in mediating iron flux through ferritin
  • iron-dependent, highly-specific formation of the remarkably stable FTH1-NCOA4 complex may be important for the characterization of the mechanism of ferritinophagy 7)
  • THRB and NCOA4 regulate terminal erythrocyte differentiation
  • roles of PCBP1 and nuclear coactivator 4 (NCOA4) in mediating the flux of iron through ferritin in developing erythroid cells
  • implicated in ovarian cancer biology in which it could be involved in the transition from precursors to ovarian cancers (OVCAs)
  • CELLULAR PROCESS nucleotide, transcription, regulation
    signaling hormonal
    a component
    small molecule
  • androgen receptor in a ligand-dependent manner
  • retinoid X receptor in a ligand-dependent manner
  • coactivator of the androgen receptor and PPARgamma and repressor of PPARalpha (but coactivator of PPARA in prostate cancer cell lines)
  • interacts with and amplifies AHR action (NCOA4-facilitation of AHR activity was abolished by overexpression of AR, suggesting a potential competition of AHR and AR for NCOA4)
  • both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements
  • NCOA4 interacts directly with AR as a co-activator to enhance AR transcriptional activity
  • KLK2 may cooperate with the AR coregulator,NCOA4, to enhance AR transactivation that may result in alteration of Prostate cancer formation
  • NCOA4 is a minichromosome maintenance 7 (MCM7)-interacting protein that is able to control DNA replication
  • NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex
  • direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes
  • cell & other
    induced by specific induction by androgens
    Other ligand dependent
    regulated in a proteasome- and autophagy-independent manner
    NCOA4 activity also exhibited developmental regulation and regulation by cellular iron levels
    corresponding disease(s) PTC3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells
    Variant & Polymorphism
    Candidate gene
    Therapy target
  • Ncoa4-/- mice are anemic in perinatal periods and fail to respond to TH by enhanced erythropoiesis
  • despite signs of iron overload, Ncoa4-null mice had mild microcytic hypochromic anemia
  • Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells