NCOA4 (Nuclear Receptor Coactivator 4)

2008-10-01 Dario de Biase , Luca Morandi , Giovanni Tallini Affiliation

Bologna University School of Medicine, Anatomia Patologica, Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy

Identity

HGNC

NCOA4

LOCATION

10q11.23

LOCUSID

8031

ALIAS

ARA70,ELE1,PTC3,RFG

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

10 exons, 3431bp.

Transcription

Isoforms due to alternative splicing.

Proteins

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 name

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 gene

RET/NCOA4

Fusion 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

Pubmed ID	Last Year	Title	Authors
9892017	1999	Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform.	Alen P et al
15663989	2004	Expression and function of androgen receptor coactivators in prostate cancer.	Culig Z et al
10347167	1999	Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma.	Heinlein CA et al
16762319	2006	Functional interaction of nuclear receptor coactivator 4 with aryl hydrocarbon receptor.	Kollara A et al
9636157	1998	Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells.	Miyamoto H et al
18156210	2008	Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70.	Peng Y et al
9850089	1998	The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.	Powell DJ Jr et al
10741739	2000	Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications.	Rabes HM et al
8290261	1994	Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma.	Santoro M et al
17412801	2007	Direct regulation of androgen receptor-associated protein 70 by thyroid hormone and its receptors.	Tai PJ et al
11707626	2001	RET oncogene activation in papillary thyroid carcinoma.	Tallini G et al
8643607	1996	Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.	Yeh S et al

Other Information

Locus ID:

NCBI: 8031
MIM: 601984
HGNC: 7671
Ensembl: ENSG00000266412

Variants:

dbSNP: 8031
ClinVar: 8031
TCGA: ENSG00000266412
COSMIC: NCOA4

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000266412	ENST00000578454	Q13772
ENSG00000266412	ENST00000579039	Q13772
ENSG00000266412	ENST00000580070	B4DZ85
ENSG00000266412	ENST00000581486	Q13772
ENSG00000266412	ENST00000581486	A0A024QZI5
ENSG00000266412	ENST00000583565	Q13772
ENSG00000266412	ENST00000583565	A0A024QZI5
ENSG00000266412	ENST00000585056	B4DF87
ENSG00000266412	ENST00000585132	Q13772
ENSG00000266412	ENST00000585132	A0A024QZI5

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Thyroid cancer	KEGG	ko05216
Pathways in cancer	KEGG	hsa05200
Thyroid cancer	KEGG	hsa05216
Ferroptosis	KEGG	ko04216
Ferroptosis	KEGG	hsa04216

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
24695223	2014	Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy.	221
25327288	2014	Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.	154
27245739	2016	Autophagy promotes ferroptosis by degradation of ferritin.	120
16385451	2006	A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.	69
26436293	2015	Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis.	64
19730683	2009	The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.	59
21085629	2010	Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.	44
15772083	2005	Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells.	31
18660489	2008	Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.	26
12881713	2003	Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors.	23

Citation

Dario de Biase ; Luca Morandi ; Giovanni Tallini

NCOA4 (Nuclear Receptor Coactivator 4)

Atlas Genet Cytogenet Oncol Haematol. 2008-10-01

Online version: http://atlasgeneticsoncology.org/gene/218/ncoa4-(nuclear-receptor-coactivator-4)