Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

NCOA4

contributors: mct - updated : 15-02-2018

HGNC name	nuclear receptor coactivator 4
HGNC id	7671

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

DNA

TYPE	functioning gene
STRUCTURE	25.62 kb     11 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001145260 12 - 3748 NP_001138732 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 NM_001145261 11 - 3659 NP_001138733 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 NM_001145263 10 - 3562 NP_001138735 69.7 614 - 1996 8643607 NM_005437 10 - 3502 NP_005428 69.7 614 - 1996 8643607 NM_001145262 10 - 3588 NP_001138734 69.7 614 - 1996 8643607

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Reproductive male system prostate

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

a nuclear receptor interaction motif (LXXLL), implicated in the interaction with AR

HOMOLOGY

Homologene

FAMILY

CATEGORY

regulatory , transcription factor , receptor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,nucleus

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

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

hormonal

a component

INTERACTION

DNA

RNA

small molecule

protein	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

REGULATION

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

ASSOCIATED DISORDERS

corresponding disease(s)

PTC3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	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