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NCOA4 (Nuclear Receptor Coactivator 4)

Written2008-10Dario de Biase, Luca Morandi, Giovanni Tallini
Bologna University School of Medicine, Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)ARA70
DKFZp762E1112
ELE1
PTC3
RFG
HGNC (Hugo) NCOA4
HGNC Alias symbARA70
RFG
ELE1
PTC3
DKFZp762E1112
HGNC Alias nameRET-activating gene ELE1
LocusID (NCBI) 8031
Atlas_Id 218
Location 10q11.23  [Link to chromosome band 10q11]
Location_base_pair Starts at 46005088 and ends at 46023458 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping NCOA4.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
MSMB (10q11.22)::NCOA4 (10q11.22)MSMB (10q11.23)::NCOA4 (10q11.23)NCOA4 (10q11.22)::OR13A1 (10q11.21)
NCOA4 (10q11.22)::RET (10q11.21)NCOA4 (10q11.23)::NCOA4 (10q11.23)NCOA4 (10q11.23)::OR13A1 (10q11.21)
NCOA4 (10q11.23)::PCDH15 (10q21.1)NCOA4 (10q11.23)::RET (10q11.21)RET (10q11.21)::NCOA4 (10q11.22)
RET (10q11.21)::NCOA4 (10q11.23)

DNA/RNA

Description 10 exons, 3431bp.
Transcription Isoforms due to alternative splicing.

Protein

Description Two isoforms:
- Isoform alfa (614 aa, mass around 70kD)
- Isoform beta: missing of aa 239-565 (mass around 32kD)
Expression NCOA4 is widely expressed in several tissues, including testis, adrenal and thyroid glands, thymus, prostate. A truncated NCOA4 corresponding to the beta isoform is fused to RET exon 12 and is aberrantly expressed in papillary thyroid carcinoma as a consequence of intrachromosomal rearrangements at 10q11.2 (RET/NCOA4).
Function NCOA4 is involved in the androgen receptor signaling pathway and in the development of the male gonade. It is a ligand-dependent associated protein for the androgen receptor (AR), that functions as coactivator to enhance AR transcriptional activity (7-10 fold in human prostate cancer cells) and protein stability. NCOA4 also enhances the agonist activity of anti-androgens in human prostate cancer cells (3-30 fold in the prostate cancer cell line DU145), with relevant implications for hormonal treatment of prostate cancer. Albeit to a lesser degree (up to 2-fold), NCO4 also enhances transcription activity of other steroid receptors, such as glucocorticoid receptor (GR), progesterone receptor (PR) and oestrogen receptor (ER).
In addition to the interaction with steroid hormone receptors, NCOA4 functions as coactivator of peroxisome proliferator-activated receptor gamma (PPARG). PPARG is a peroxisome proliferator-activated receptor and as such belongs to the nuclear hormone receptor superfamily. PPARG is highly expressed in adipose tissue (were it is involved in adipogenesis and in the regulation of adipocyte-specific genes), as well as in other human tissues. Interestingly, PPARG is rearranged with PAX8 in a subset of follicular thyroid tumors.
Unlike the AR-NCOA4 interaction, which requires the presence of androgen, the PPARG-NCOA4 interaction can occur in the absence of exogenous ligand. However, the presence of the ligand enhances PPARG-NCOA4 transactivation and NCOA4 is thus regarded as a ligand-enhanced coactivator of PPARG.
 
  Ligand-specific interaction between AR (Androgen receptor), NCOA4, and the androgen receptor ligand DHT (dihydrotestosterone).

Mutations

Germinal LINE S94L; F154L; C350R; P474R; L561P.
Somatic NCOA4 breakpoint for rearrangement to form RET/NCOA4 oncogene at cDNA bp791, corresponding to aa 238-239.

Implicated in

Note
  
Entity with RET/NCOA4 rearrangement in thyroid cancer
Disease Papillary thyroid carcinoma. RET/NCOA4 may occur in non radiation-associated carcinomas but it is particularly common in radiation-associated tumors like those linked to the Chernobyl nuclear accident (1986).
Prognosis RET/NCOA4 may be associated with aggressive behaviour. Among post-Chernobyl papillary carcinomas, RET/NCOA4 has been associated with tumors that were of shorter latency after radiation exposure, of larger size, with extrathyroidal extension, and that were classified as solid variant papillary carcinomas.
Cytogenetics Simple karyotypes with balanced chromosomal inversions due to structural rearrangement of NCOA4 and RET gene on chromosome 10 [inv(10)(q11.2-q21)], resulting in RET/NCOA4.
Hybrid/Mutated Gene RET/NCOA4
Abnormal Protein NCOA4/RET (RP3)
 
Diagram of RET/NCOA4 oncogene. The red arrow indicates the breakpoint region.
Oncogenesis RET/PTC oncogenes are generated by chromosomal rearrangements resulting in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5'-terminal region of heterologous genes (e.g. H4, RIa, RFG5, hTIF1, RFG7, ELKS). All are balanced inversions or translocations which involve the 3.0 kb intron 11 of RET. RET-fused genes are widely expressed in human tissues, including thyroid follicular cells, and have putative dimerization domains. As the chimeric forms of RET-TK are translated into fusion proteins, these domains of the translocated amino terminal regions allow dimerization and thus ligand independent activation of RET-TK, which is considered essential for the transformation of thyroid cells. To date, at least 16 chimeric mRNAs involving 10 different genes have been reported, of which RET/PTC1 (consisting in the fusion of RET with H4) and RET/NCOA4 (consisting in the fusion of RET with NCOA4) are by far the most common.
ANIMAL MODELS RET/NCOA4 transgenic mice have been generated by Powell and coworkers using a construct with the RET/NCOA4 fusion gene downstream and under the control of the bovine thyroglobulin gene regulatory region; they express RET/NCOA4 selectively in the thyroid gland and develop thyroid hyperplasia and solid tumor variants of papillary carcinomas.
  

Bibliography

Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an Internally deleted ELE1 beta isoform.
Alen P, Claessens F, Schoenmakers E, Swinnen JV, Verhoeven G, Rombauts W, Peeters B.
Mol Endocrinol. 1999 Jan;13(1):117-28.
PMID 9892017
 
Expression and function of androgen receptor coactivators in prostate cancer.
Culig Z, Comuzzi B, Steiner H, Bartsch G, Hobisch A.
J Steroid Biochem Mol Biol. 2004 Nov;92(4):265-71.
PMID 15663989
 
Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma.
Heinlein CA, Ting HJ, Yeh S, Chang C.
J Biol Chem. 1999 Jun 4;274(23):16147-52.
PMID 10347167
 
Functional interaction of nuclear receptor coactivator 4 with aryl hydrocarbon receptor.
Kollara A, Brown TJ.
Biochem Biophys Res Commun. 2006 Jul 28;346(2):526-34.
PMID 16762319
 
Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells.
Miyamoto H, Yeh S, Wilding G, Chang C.
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7379-84.
PMID 9636157
 
Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70.
Peng Y, Li CX, Chen F, Wang Z, Ligr M, Melamed J, Wei J, Gerald W, Pagano M, Garabedian MJ, Lee P.
Am J Pathol. 2008 Jan;172(1):225-35.
PMID 18156210
 
The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.
Powell DJ Jr, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A, Rothstein JL.
Cancer Res. 1998 Dec 1;58(23):5523-8.
PMID 9850089
 
Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications.
Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, Klugbauer S.
Clin Cancer Res. 2000 Mar;6(3):1093-103.
PMID 10741739
 
Molecular characterization of RET/PTC3: a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma.
Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G, Fusco A.
Oncogene. 1994 Feb;9(2):509-16.
PMID 8290261
 
Direct regulation of androgen receptor-associated protein 70 by thyroid hormone and its receptors.
Tai PJ, Huang YH, Shih CH, Chen RN, Chen CD, Chen WJ, Wang CS, Lin KH.
Endocrinology. 2007 Jul;148(7):3485-95.
PMID 17412801
 
RET oncogene activation in papillary thyroid carcinoma.
Tallini G, Asa S L.
Adv Anat Pathol. 2001 Nov;8(6):345-54.
PMID 11707626
 
Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.
Yeh S, Chang C.
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5517-21.
PMID 8643607
 

Citation

This paper should be referenced as such :
de, Biase D ; Morandi, L ; Tallini, G
NCOA4 (Nuclear Receptor Coactivator 4)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):654-656.
Free journal version : [ pdf ]   [ DOI ]


External links

 

Nomenclature
HGNC (Hugo)NCOA4   7671
Cards
AtlasNCOA4ID218ch10q11
Entrez_Gene (NCBI)NCOA4    nuclear receptor coactivator 4
AliasesARA70; ELE1; PTC3; RFG
GeneCards (Weizmann)NCOA4
Ensembl hg19 (Hinxton)ENSG00000266412 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000266412 [Gene_View]  ENSG00000266412 [Sequence]  chr10:46005088-46023458 [Contig_View]  NCOA4 [Vega]
ICGC DataPortalENSG00000266412
TCGA cBioPortalNCOA4
AceView (NCBI)NCOA4
Genatlas (Paris)NCOA4
SOURCE (Princeton)NCOA4
Genetics Home Reference (NIH)NCOA4
Genomic and cartography
GoldenPath hg38 (UCSC)NCOA4  -     chr10:46005088-46023458 -  10q11.22   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NCOA4  -     10q11.22   [Description]    (hg19-Feb_2009)
GoldenPathNCOA4 - 10q11.22 [CytoView hg19]  NCOA4 - 10q11.22 [CytoView hg38]
ImmunoBaseENSG00000266412
Genome Data Viewer NCBINCOA4 [Mapview hg19]  
OMIM601984   
Gene and transcription
Genbank (Entrez)AB064669 AK129911 AK130612 AK292480 AK293978
RefSeq transcript (Entrez)NM_001145260 NM_001145261 NM_001145262 NM_001145263 NM_005437
Consensus coding sequences : CCDS (NCBI)NCOA4
Gene ExpressionNCOA4 [ NCBI-GEO ]   NCOA4 [ EBI - ARRAY_EXPRESS ]   NCOA4 [ SEEK ]   NCOA4 [ MEM ]
Gene Expression Viewer (FireBrowse)NCOA4 [ Firebrowse - Broad ]
GenevisibleExpression of NCOA4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8031
GTEX Portal (Tissue expression)NCOA4
Human Protein AtlasENSG00000266412-NCOA4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13772   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13772  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13772
PhosPhoSitePlusQ13772
Domains : Interpro (EBI)ARA70    NCoA-4   
Domain families : Pfam (Sanger)ARA70 (PF12489)   
Domain families : Pfam (NCBI)pfam12489   
Conserved Domain (NCBI)NCOA4
PDB (RSDB)1T5Z   
PDB Europe1T5Z   
PDB (PDBSum)1T5Z   
PDB (IMB)1T5Z   
Structural Biology KnowledgeBase1T5Z   
SCOP (Structural Classification of Proteins)1T5Z   
CATH (Classification of proteins structures)1T5Z   
SuperfamilyQ13772
AlphaFold pdb e-kbQ13772   
Human Protein Atlas [tissue]ENSG00000266412-NCOA4 [tissue]
HPRD03584
Protein Interaction databases
DIP (DOE-UCLA)Q13772
IntAct (EBI)Q13772
BioGRIDNCOA4
STRING (EMBL)NCOA4
ZODIACNCOA4
Ontologies - Pathways
QuickGOQ13772
Ontology : AmiGOtranscription coactivator activity  nucleus  protein targeting to lysosome  cellular iron ion homeostasis  male gonad development  response to hormone  intracellular estrogen receptor signaling pathway  autolysosome  positive regulation of transcription, DNA-templated  cellular response to estrogen stimulus  cellular response to testosterone stimulus  
Ontology : EGO-EBItranscription coactivator activity  nucleus  protein targeting to lysosome  cellular iron ion homeostasis  male gonad development  response to hormone  intracellular estrogen receptor signaling pathway  autolysosome  positive regulation of transcription, DNA-templated  cellular response to estrogen stimulus  cellular response to testosterone stimulus  
Pathways : KEGGPathways in cancer    Thyroid cancer   
NDEx NetworkNCOA4
Atlas of Cancer Signalling NetworkNCOA4
Wikipedia pathwaysNCOA4
Orthology - Evolution
OrthoDB8031
GeneTree (enSembl)ENSG00000266412
Phylogenetic Trees/Animal Genes : TreeFamNCOA4
Homologs : HomoloGeneNCOA4
Homology/Alignments : Family Browser (UCSC)NCOA4
Gene fusions - Rearrangements
Fusion : MitelmanMSMB::NCOA4 [10q11.23/10q11.23]  
Fusion : MitelmanNCOA4::OR13A1 [10q11.23/10q11.21]  
Fusion : MitelmanNCOA4::RET [10q11.23/10q11.21]  
Fusion : MitelmanRET::NCOA4 [10q11.21/10q11.23]  
Fusion : COSMICRET [10q11.21]  -  NCOA4 [10q11.22]  [fusion_1494]  [fusion_1495]  [fusion_1496]  [fusion_1497]  [fusion_1502]  
Fusion : QuiverNCOA4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNCOA4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NCOA4
dbVarNCOA4
ClinVarNCOA4
MonarchNCOA4
1000_GenomesNCOA4 
Exome Variant ServerNCOA4
GNOMAD BrowserENSG00000266412
Varsome BrowserNCOA4
ACMGNCOA4 variants
VarityQ13772
Genomic Variants (DGV)NCOA4 [DGVbeta]
DECIPHERNCOA4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNCOA4 
Mutations
ICGC Data PortalNCOA4 
TCGA Data PortalNCOA4 
Broad Tumor PortalNCOA4
OASIS PortalNCOA4 [ Somatic mutations - Copy number]
Cancer Gene: CensusNCOA4 
Mutations and Diseases : HGMDNCOA4
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaNCOA4
DgiDB (Drug Gene Interaction Database)NCOA4
DoCM (Curated mutations)NCOA4
CIViC (Clinical Interpretations of Variants in Cancer)NCOA4
OncoKBNCOA4
NCG (London)NCOA4
Cancer3DNCOA4
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601984   
Orphanet905   
DisGeNETNCOA4
MedgenNCOA4
Genetic Testing Registry NCOA4
NextProtQ13772 [Medical]
GENETestsNCOA4
Target ValidationNCOA4
Huge Navigator NCOA4 [HugePedia]
ClinGenNCOA4
Clinical trials, drugs, therapy
MyCancerGenomeNCOA4
Protein Interactions : CTDNCOA4
Pharm GKB GenePA31473
PharosQ13772
Clinical trialNCOA4
Miscellaneous
canSAR (ICR)NCOA4
HarmonizomeNCOA4
DataMed IndexNCOA4
Probes
Litterature
PubMed87 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXNCOA4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:23:28 CEST 2021

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