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

Home Page

FLASH GENE

Symbol

NOX4

contributors: mct - updated : 05-01-2017

HGNC name	NADPH oxidase 4
HGNC id	7891

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	11q14.3      Physical location : 89.057.523 - 89.322.779
Synonym name	renal NADPH oxidase
	kidney superoxide-producing NADPH oxidase
Synonym symbol(s)	KOX, KOX-1, RENOX
EC.number	1.6.3.-

DNA

TYPE	functioning gene
STRUCTURE	173.84 kb     19 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001143836 17 - 4270 NP_001137308 - 538 in lung 2005 15721269 isoform b lacks the first NAD(P)H binding site having dominant negative characteristics for ROS generation variant 4 - - 1292 isoform 4 - 224 lung 2005 15721269 also called NOX4C lacks all FADH and NAD(P)H binding sites having dominant negative characteristics for ROS generation variant 5 - - 816 isoform 5 - 271 lung 2005 15721269 also called NOX4D lack the transmembrane domains, suggesting these as non-membrane associated isoform contains all FADH and NAD(P)H binding domains variant 6 - - 696 isoform 6 - 231 lung 2005 15721269 also called NOX4E lack the transmembrane domains, suggesting these as non-membrane associated isoform NM_016931 17 - 4390 NP_058627 66.9 578 - 2007 17940286 isoform a NM_001143837 19 - 4615 NP_001137309 - 554 - - isoform c

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 Digestive mouth       highly Nervous nerve       moderately Reproductive male system prostate     moderately Urinary kidney tubule convoluted tubule proximal tubule highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Muscular striatum cardiac     Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Muscular myocyte Homo sapiens not specific adipocyte not specific chondrocyte Homo sapiens Urinary epithelial cell

cell lineage
cell lines	renal carcinoma cell lines
	glioblastoma cell lines
fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	kidney, placenta, liver
	highly expressed in proliferating chondrocytes and prehypertrophic chondrocytes

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	5-6 conserved transmembrane alpha-helices
	a ferric oxidoreductase domain
	FADH and NAD(P)H binding sites

HOMOLOGY

interspecies

homolog to murine Nox4

Homologene

FAMILY

CATEGORY

enzyme , transport

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus
text	localized within the cytoplasm of endothelial cells, in the perinuclear space not in nucleus
	localizes to mitochondria
	colocalized with proteins of the endoplasmic reticulum
	partially localized in mitochondria in cardiac myocytes

basic FUNCTION	generating reactive oxygen species (ROS) that function in host defense and cellular signaling
	critical catalytic component for superoxide production in quiescent vascular smooth muscle cells
	may be involved in increased superoxide generation in vascular smooth muscle cells under proinflammatory conditions
	with CYBB mediate proliferative response in endothelial cells
	major Nox isoform in endothelial cells, forming an active complex with CYBA
	contributes to angiotensin II and transforming growth factor-beta redox signaling
	central mediator that controls oxidative stress that may lead to mitochondrial dysfunction and cell injury in diseases such as diabetes
	increasing oxidative damage leading to loss of replicative potential in HUVECs
	in cardiac myocytes is potentially a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during pressure overload
	with DUOX2, are required for platelet-derived growth factor (PDGF) induced RB1 phosphorylation in normal fibroblasts
	NOX4 and DUOX2 regulate cell cycle entry as part of a p53-dependent checkpoint for proliferation
	reactive oxygen species generated by NADPH oxidase 2 and 4 (CYBB and NOX4)are required for chondrogenic differentiation
	unique inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress
	unique stress-inducible regulator of myocardial angiogenesis that facilitates adaptation to cardiac overload stress
	might be involved in the pathophysiology of lung artery hypertrophy in idiopathic pulmonary fibrosis (
	acts as an intermediary in the signaling of TGFB1 to facilitate collagen synthesis
	is involved in the local stimulatory effects of TGFB1 on collagen accumulation
	central role of NOX4 as a mediator of renal cell injury in diabetic kidney disease
	expression of NLRP5 and NOX4 proteins are closely related to the follicular development and ovulation with particular regard for ovarian aging
	integrin engagement during cell attachment activates POLDIP2/NOX4 to oxidize actin, which modulates focal adhesion (FA) assembly

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

electron transport

PATHWAY

metabolism

signaling

	pathway of redox-sensitive signaling via NOX4 and MAPK14 in endothelial cells
	novel redox signaling pathway, involving NOX4-PPP1R15A interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains EIF2S1 phosphorylation to protect tissues under stress

a component

subunit of NADPH oxidase

INTERACTION

DNA

RNA

small molecule

protein	interacts with protein disulfide isomerase
	interacts with, relocalizes and stabilizes CYBA/p22phox
	interacts with TLR4
	cooperative action of KCNK3 and NADPH oxidase-4 (NOX4) mediated the O2-sensitive K+ current response
	SP3 plays a key role in the expression of NOX4 in various cell lineages in humans
	upregulation of NOX4 leads to an upregulation of PDE4A, PDE4B, and PDE4D and increased hydrolysis of cAMP which in turn augments cell replication and angiogenesis
	is a critical mediator in oncogenic HRAS-induced DNA damage and subsequent senescence
	UTS2 and NOX4 stimulated FOXO2, FOXO3 activity and MMP2 is a target gene of FOXO3
	plays an essential role in mediating cysteine oxidation and nuclear exit of HDAC4, thereby mediating cardiac hypertrophy in response to PE (Phenylephrine) and pressure overload
	TGFB1 induces myofibroblast differentiation and lung fibrosis by activation of the reactive oxygen species-generating enzyme NADPH oxidase 4 (NOX4)
	endogenous TGFB1I1 suppresses senescence and profibrotic activities of myofibroblasts by down-regulating NOX4 protein expression
	POLDIP2 interacts with NADPH oxidase 4 (NOX4) and regulates migration
	TGFB1I1 and HSPB1, HSPB2 are effectors of NOX4 required for TGFB1-stimulated Focal adhesions (FAs) formation, adhesion strength and migration in vascular smooth muscle cell
	NOX4 is a positive transcriptional regulator of CTH in endothelial cells and propose that it may in turn contribute to the regulation of vascular tone via the modulation of H2S production
	PDGFA-induced migration of mesenchymal cells requires NOX4 and DUOX1/2 enzymes, which mediate redox-sensitive activation of PI3-kinase pathway and PKB/AKT1
	overexpression of LCLAT1 attenuated TGFB1-induced mitochondrial and intracellular oxidative stress, NOX4 expression and differentiation of human lung fibroblasts
	POLDIP2, a novel regulator of NOX4, plays a significant role in reactive oxygen species production and cytoskeletal remodeling

cell & other

REGULATION

Other

regulated by NFkappaB (NF-kappaB is an essential regulator of NOX1- and NOX4-containing NADPH oxidase in smooth muscle cells)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in vascular smooth muscle cells exposed to hypoxia and in lungs from patients with idiopathic pulmonary arterial hypertension

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed diabete     primary target for the design of new therapeutic strategies to counteract oxidant-mediated deleterious effects associated with various diseases characterized by oxidative stress cardiovascular aquired heart failure could be a target of future treatments for heart failure respiratory lung   might be a target for the treatment of pulmonary fibrosis dermatology skin   targeting TGFB1 downstream via the profibrotic mediator NOX4 could be a potential anti-fibrotic therapy

ANIMAL & CELL MODELS

	In a rat model of diabetes, mitochondrial Nox4 expression is increased in kidney cortex (Block 2009)
	in c-Nox4(-/-) mice, reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes
	Nox4-null mice developed exaggerated contractile dysfunction, hypertrophy, and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected