Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

NCOA4 (Nuclear Receptor Coactivator 4)

Identity

Other namesARA70
DKFZp762E1112
ELE1
PTC3
RFG
HGNC (Hugo) NCOA4
LocusID (NCBI) 8031
Location 10q11.23
Location_base_pair Starts at 51565108 and ends at 51590734 bp from pter ( according to hg19-Feb_2009)  [Mapping]

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

Entity inv(10)(q11q11) 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.
  

External links

Nomenclature
HGNC (Hugo)NCOA4   7671
Cards
AtlasNCOA4ID218ch10q11
Entrez_Gene (NCBI)NCOA4  8031  nuclear receptor coactivator 4
GeneCards (Weizmann)NCOA4
Ensembl (Hinxton)ENSG00000138293 [Gene_View]  chr10:51565108-51590734 [Contig_View]  NCOA4 [Vega]
AceView (NCBI)NCOA4
Genatlas (Paris)NCOA4
WikiGenes8031
SOURCE (Princeton)NM_001145260 NM_001145261 NM_001145262 NM_001145263 NM_005437
Genomic and cartography
GoldenPath (UCSC)NCOA4  -  10q11.23   chr10:51565108-51590734 +  10q11.2   [Description]    (hg19-Feb_2009)
EnsemblNCOA4 - 10q11.2 [CytoView]
Mapping of homologs : NCBINCOA4 [Mapview]
OMIM188550   601984   
Gene and transcription
Genbank (Entrez)AB064669 AK129911 AK130612 AK292480 AK293978
RefSeq transcript (Entrez)NM_001145260 NM_001145261 NM_001145262 NM_001145263 NM_005437
RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NG_023372 NT_030059 NW_001837979 NW_003871068 NW_004929376
Consensus coding sequences : CCDS (NCBI)NCOA4
Cluster EST : UnigeneHs.709644 [ NCBI ]
CGAP (NCI)Hs.709644
Alternative Splicing : Fast-db (Paris)GSHG0003361
Alternative Splicing GalleryENSG00000138293
Gene ExpressionNCOA4 [ NCBI-GEO ]     NCOA4 [ SEEK ]   NCOA4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13772 (Uniprot)
NextProtQ13772  [Medical]
With graphics : InterProQ13772
Splice isoforms : SwissVarQ13772 (Swissvar)
Domains : Interpro (EBI)ARA70   
Related proteins : CluSTrQ13772
Domain families : Pfam (Sanger)ARA70 (PF12489)   
Domain families : Pfam (NCBI)pfam12489   
DMDM Disease mutations8031
Blocks (Seattle)Q13772
PDB (SRS)1T5Z   
PDB (PDBSum)1T5Z   
PDB (IMB)1T5Z   
PDB (RSDB)1T5Z   
Human Protein AtlasENSG00000138293
Peptide AtlasQ13772
HPRD03584
IPIIPI00015145   IPI00221177   IPI01015333   IPI01010219   IPI00953684   IPI00922559   IPI00922102   IPI00844206   IPI00514382   
Protein Interaction databases
DIP (DOE-UCLA)Q13772
IntAct (EBI)Q13772
FunCoupENSG00000138293
BioGRIDNCOA4
InParanoidQ13772
Interologous Interaction database Q13772
IntegromeDBNCOA4
STRING (EMBL)NCOA4
Ontologies - Pathways
Ontology : AmiGOtranscription coactivator activity  nucleus  transcription, DNA-templated  male gonad development  response to hormone  androgen receptor signaling pathway  positive regulation of transcription, DNA-dependent  androgen receptor binding  
Ontology : EGO-EBItranscription coactivator activity  nucleus  transcription, DNA-templated  male gonad development  response to hormone  androgen receptor signaling pathway  positive regulation of transcription, DNA-dependent  androgen receptor binding  
Pathways : KEGGPathways in cancer    Thyroid cancer   
REACTOMENCOA4
Protein Interaction DatabaseNCOA4
Wikipedia pathwaysNCOA4
Gene fusion - rearrangments
Rearrangement : TICdbNCOA4 [10q11.23]  -  NCOA4 [10q11.23]
Rearrangement : TICdbNCOA4 [10q11.23]  -  NCOA4 [10q11.23]
Rearrangement : TICdbNCOA4 [10q11.23]  -  RET [10q11.21]
Rearrangement : TICdbRET [10q11.21]  -  NCOA4 [10q11.23]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)NCOA4
SNP (GeneSNP Utah)NCOA4
SNP : HGBaseNCOA4
Genetic variants : HAPMAPNCOA4
1000_GenomesNCOA4 
ICGC programENSG00000138293 
Cancer Gene: CensusNCOA4 
Somatic Mutations in Cancer : COSMICNCOA4 
CONAN: Copy Number AnalysisNCOA4 
Mutations and Diseases : HGMDNCOA4
OMIM188550    601984   
GENETestsNCOA4
Disease Genetic AssociationNCOA4
Huge Navigator NCOA4 [HugePedia]  NCOA4 [HugeCancerGEM]
Genomic VariantsNCOA4  NCOA4 [DGVbeta]
Exome VariantNCOA4
dbVarNCOA4
ClinVarNCOA4
snp3D : Map Gene to Disease8031
General knowledge
Homologs : HomoloGeneNCOA4
Homology/Alignments : Family Browser (UCSC)NCOA4
Phylogenetic Trees/Animal Genes : TreeFamNCOA4
Chemical/Protein Interactions : CTD8031
Chemical/Pharm GKB GenePA31473
Clinical trialNCOA4
Cancer Resource (Charite)ENSG00000138293
Other databases
Probes
Litterature
PubMed62 Pubmed reference(s) in Entrez
CoreMineNCOA4
iHOPNCOA4

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
RET oncogene activation in papillary thyroid carcinoma.
Tallini G, Asa S L.
Adv Anat Pathol. 2001 Nov;8(6):345-54.
PMID 11707626
 
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
 
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
 
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
 
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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written10-2008Dario de Biase, Luca Morandi, Giovanni Tallini
Bologna University School of Medicine, Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy

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. October 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/NCOA4ID218ch10q11.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44559/1/10-2008-NCOA4ID218ch10q11.pdf   [ Bibliographic record ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Apr 18 17:25:49 CEST 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.