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FLASH GENE

Symbol

NR1I2

contributors: mct/npt - updated : 10-01-2016

HGNC name	nuclear receptor subfamily 1, group I, member 2
HGNC id	7968

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	38.01 kb     9 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site
text structure	proximal region of 1.5-kb from the transcription start site conferred a promoter activity
	putative HNF1 binding element is essential for the transcriptional activity

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_022002 9 - 2772 NP_071285 - 473 - 2006 16328955 isoform 2 NM_003889 9 - 4446 NP_003880 49.7 434 - 2006 16328955 isoform 1 NM_033013 9 - 4335 NP_148934 - 397 - 2006 16328955 isoform 3

EXPRESSION

Type	restricted

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 liver       highly   stomach

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a nuclear receptor DNA-binding domain
	a ligand binding domain (LBD) that uses a novel sequence insert to form a homodimer unique to the nuclear receptor superfamily
	a AF2 domain necessary for binding with PROX1

mono polymer

heteromer , dimer

HOMOLOGY

interspecies	homolog to murine Nr1i2 (77.4pc)
	homolog to rattus Nr1i2 (76.9pc)

Homologene

FAMILY	nuclear hormone receptor family
	nuclear receptor superfamily

CATEGORY

transcription factor , receptor nuclear

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
text	nuclear translocation observed as an essential regulatory event for transcription of its target genes such as CYP3A4

basic FUNCTION	detoxification of cholestatic bile acids
	regulating the expression of genes involved in the biosynthesis transport and metabolism of bile acids
	playing a key role in the regulation of both drug metabolism and efflux by inducing the expression of CYP3A4 and MDR1 gene
	key regulator of genes encoding several major cytochrome P450 enzymes and transporters
	potential role in breast cancer resistance to drug treatments
	ligand-activated transcription factor regulating genes central to drug and hormone metabolism in the liver
	necessary for IL6-mediated repression of the CYP3A4 expression in human hepatocytes
	transcription factor that induces hepatic drug metabolism by activating cytochrome P450 genes (21127053)
	may have a function in prediction and treatment of esophageal disease
	important regulator of xenobiotic metabolism and intestinal integrity
	co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

an FGF21-NR1I2 signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in Nonalcoholic fatty liver disease (NAFLD)

a component	heterodimerizing with RXR
	forms a tryptophan zipper-mediated homodimer, playing a role in the function of this nuclear xenobiotic receptor
	NR1I2 and RXRA form a heterotetramer unprecedented in the nuclear receptor family of ligand-regulated transcription factors

INTERACTION

DNA	binding to a response element in CYP3A4

RNA

small molecule

protein	immune-regulatory role in T lymphocytes and SOCS1 is an early signal in NR1I2-mediated T lymphocyte suppression
	GADD45B is a direct target for NR1I2, eliciting cell signals to regulate various cellular functions
	eliciting MAPK14 phosphorylation for cell migration
	NR1I2 promoter methylation is involved in the regulation of intestinal NR1I2 and CYP3A4 mRNA expression and might be associated with the inter-individual variability of the drug responses of colon cancer cells
	NR1I2 represses SULT1E1, possibly attenuating the inactivation of estrogen
	PROX1 could negatively regulate NR1I2 signals in some tumor cells, such as hepatocellular carcinoma (HCC) cells, where both NR1I2 and PROX1 are expressed
	RBCK1 ubiquitinates NR1I2, and this may target NR1I2 for degradation by the ubiquitin-proteasome pathway
	both ELANE and PRTN3 cleave the human NR1I2 N terminus at sites distinct from the thrombin cleavage site
	regulates innate immunity via activation of NLRP3 inflammasome in vascular endothelial cells
	cross-talk between NR1I2 and AHR plays a role in the regulation of CYP3A4 gene expression
	NR1I2 plays a central role in cortisol-mediated induction of CYP3A4 activity during pregnancy

cell & other

REGULATION

activated by

pregnanes, toxic bile acid, lithocholic acid

induced by

catatoxic steroids

Other	SUMOylated to repress the inflammatory response
	post-translational regulation of NR1I2 via phosphorylation-facilitated ubiquitination by DYRK2 and UBR5

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in adenocarcinoma tissue and columnar Barrett epithelium

Susceptibility

to ulcerative colitis (UC)

Variant & Polymorphism SNP	rs2276707 was weakly associated with UC susceptibility

Candidate gene
Marker	prognostic factor in epithelial ovarian cancer and may represent a useful marker to identify patients at risk of recurrence or death
Therapy target

ANIMAL & CELL MODELS

Pxr-deficient mice exhibit an exaggerated T lymphocyte proliferation and increased CD25 expression