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FLASH GENE

Symbol

NR3C1

contributors: mct/npt - updated : 10-05-2016

HGNC name	nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
HGNC id	7978

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	GRL cortisol resistance, primary
Location	5q31.3      Physical location : 142.657.496 - 142.815.077
Synonym name	glucocorticoid receptor
Synonym symbol(s)	GR, GCR, GRL, GCCR

DNA

TYPE	functioning gene
STRUCTURE	455.83 kb     9 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	see ADRB2 ,CSF1R

RNA

TRANSCRIPTS	type	messenger

text	seven spliced variants : five encoding for isoform Alpha, one for isoform Bêta and one for isoform Gamma 11 splice variants of the hGR exon 1, based on seven exon 1s, and four (1-D to 1-F and 1-H)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001018077 9 splicing 7286 NP_001018087 85 777 - 2007 17438138 containing exon 1a (longer than 1b & 1c) containing exon 5b (shorter than 5a) containing exon 11a (longer than 11b) lacking exons 2 & 3 longest transcript variant 1 encoding the isoform Alpha NM_001018074 9 splicing 6614 NP_001018084 85 777 - 2007 17438138 containing exon 1b containing exon 5b (shorter than 5a) containing exon 11a (longer than 11b) lacking exons 2 & 3 variant 2 encoding the isoform Alpha NM_001018075 9 splicing 6517 NP_001018085 85 777 - 2007 17438138 containing exon 1c (shorter than 1a & 1b) containing exon 5b (shorter than 5a) containing exon 11a (longer than 11b) lacking exons 2 & 3 variant 3 encoding the isoform Alpha NM_001018076 9 splicing 6410 NP_001018086 85 777 - 2007 17438138 containing exon 5b (shorter than 5a) containing exon 11a (longer than 11b) lacking exons 1 & 3 variant 4 encoding the isoform Alpha NM_000176 9 splicing 6784 NP_000167 85 777 - 2007 17438138 containing exon 5b (shorter than 5a) containing exon 11a (longer than 11b) lacking exons 1 & 2 variant 5 encoding the isoform Alpha NM_001020825 9 splicing 4154 NP_001018661 81 742 - 2007 17438138 containing exon 5b (shorter than 5a) containing exon 11b (shorter than 11a) lacking exons 1 & 2 encoding the isoform Beta influences positively and negatively the transcriptional activity of large subsets of genes, most of which are not responsive to glucocorticoids, in addition to its well-known dominant negative effect against GRalpha-mediated transcriptional activity NM_001024094 9 splicing 6787 NP_001019265 85 778 - 2007 17438138 containing exon 5a (longer than 5b) containing exon 11a (longer than 11b) lacking exons 1 & 2 encoding for the isoform Gamma variant 1G - - 547 isoform 1G - 145 - 2007 17438138 NM_001204261 9 - 6801 NP_001191190 - 680 - 2007 17438138 variant 1C3, alpha-C3, also known as GR-C3 NM_001204260 9 - 6802 NP_001191189 - 688 - 2007 17438138 variant 1C2, alpha-C2, also known as GR-C2 NM_001204259 9 - 6801 NP_001191188 - 692 - 2007 17438138 alpha-C1, also known as GR-C1 variant 1H - - 585 isoform 1H - 145 in the hippocampus, also detected in the immune system, in the liver, lung and smooth muscle 2007 17438138 variant 1F - - 511 isoform 1F - - in the hippocampus, also detected in the immune system 2007 17438138 variant 1E - - 498 isoform 1E - 145 in the hippocampus, also detected in the immune system 2007 17438138 NM_001204262 9 - 6801 NP_001191191 - 462 only in the hippocampus 2007 17438138 variant 1D, alpha-D1, also known as GR-D1 NM_001204258 9 - 6801 NP_001191187 - 751 - 2007 17438138 alpha-B, also known as GR-B NM_001204263 9 - 6801 NP_001191192 - 447 - 2007 17438138 alpha-D2, also known as GR-D2) NM_001204264 9 - 6801 NP_001191193 - 442 - 2007 17438138 alpha-D3, also known as GR-D3 NM_001204265 - - 4104 NP_001191194 - 676 - 2007 17438138 GR-P

EXPRESSION

Type	ubiquitous

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 Cardiovascular vessel       highly Digestive esophagus       moderately Endocrine pancreas       moderately   parathyroid       moderately Lymphoid/Immune lymph node       highly Nervous brain limbic system hippocampus   predominantly Homo sapiens   nerve cranial nerve     moderately Reproductive female system placenta     moderately   male system testis     moderately Urinary kidney       moderately

tissue

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

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text	placenta, embryonic tissue

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	receptor composed of a N terminal modulator domain
	a hinge region homologous only with those of the oxosteroid receptors
	a central bipartite zinc finger DNA binding domain followed by a nuclear localization signal (NLS)
	activation function 1 (AF1) in the N-terminal half of NR3C1
	C terminal ligand binding domain including a transactivation and dimerization domain (important in conferring transactivational activity), the AF2 domain in the C-terminal ligand-binding domain (LBD)

HOMOLOGY

interspecies	homolog to rattus Nr3c1 (90.83 pc)
	homolog to murine Nr3c1 (90.44 pc)

Homologene

FAMILY	nuclear hormone receptor family
	NR3 subfamily

CATEGORY

transcription factor , signaling hormone , receptor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,matrix
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,nucleolus

basic FUNCTION	nuclear hormone receptor that regulates multiple physiological and pathophysiological processes (Niu 2009)
	inhibit erythroid maturation not only through a transcriptional mechanism, but also through a rapid membrane-associated pathway that interferes with EPO receptor signaling (Stellacci 2009)
	regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes (Meijsing 2009)
	coactivation of NR3C1 and NFKB alters signaling pathways that are regulated by each factor separately and provide insight into the networks underlying the NR3C1 and NFKB crosstalk
	endothelial NR3C1 is a critical regulator of NFKB1 activation and nitric oxide synthesis in sepsis
	in the brain, has been implicated, amongst others, in feedback regulation of the hypothalamic-pituitary-adrenal axis, with potential deficits during aging and in depression
	is required for fetal heart maturation
	ligand-dependent transcription factor of the nuclear receptor superfamily
	NR3C1 -dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages
	both NR3C1 and FOXO1 are required for ANGPTL4 transcription activation, and FOXO1 negatively mediates the suppressive effect of insulin

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

inflammation

PATHWAY

metabolism

signaling

signal transduction

a component

INTERACTION

DNA

RNA

small molecule

protein	interacting with tissue-specific transcriptional activators required for receptor actin (see HNFS)
	upregulating HIF1 gene expression under hypoxic conditions
	transcriptional activity suppressed with association yoGbetagamma complexes
	PMF1 binds to the glucocorticoid receptor (NR3C1), and represses glucocorticoid-induced transcription
	ANGPTL4 is a direct target that participates in glucocorticoid-regulated triglyceride metabolism (Koliwad 2009)
	interacting with SKA2 in cancer cells (Rice 2008)
	NUP62 and NR3C1 were able to interact in a more efficient manner when chaperoned by the HSP90-based heterocomplex
	role for GPR50 in NR3C1 signalling through interaction with kat5
	FOXA1 is a potent enhancer of NR3C1-induced transcription
	molecular interplay of NR3C1 and MEF2A in the control of genes important for neuronal plasticity
	GSK3B is important for NR3C1 transactivation activity and GSK3B inhibition suppresses NR3C1-stimulated gene expression
	FOXO3 is an immediate early glucocorticoid receptor (NR3C1) target, whose transcription is even further enhanced by conditions that mimic metabolic stress
	AGRP is a common orexigenic target gene of NR3C1 and BSX
	mutual antagonism between NR4A3 and NR3C1 to be a key rheostat for peripheral metabolic signals to centrally control energy balance
	NR3C1-induced expression of HNF4A may likely contribute to indirect SLC22A1 gene up-regulation by dexamethasone in primary human hepatocytes, but not in hepatocyte-derived tumor cell lines
	BUD23 is a novel regulator of chromatin structure affecting NR3C1 recruitment and function, contributing to loss of NR3C1 sensitivity in inflammation, with suppressed expression in pulmonary disease
	NR1D1 influences the stability and nuclear localization of NR3C1
	MDFIC is a binding partner for NR3C1, and NR3C1 directly represses the MDFIC gene, revealing a negative feedback loop by which glucocorticoids limit MDFIC activity

cell & other

REGULATION

activated by

ligand-induced activity of N3C1 is enhanced by DAP3

Other	phosphorylated by activated JNK (phosphorylates NR3C1 at Ser226, enhances its nuclear export after withdrawal of a ligand for NR3C1, dexamethasone, and may contribute to termination of NR3C1-mediated transcription) (Itoh 2002)
	GSK3B regulates NR3C1 response by genomic and nongenomic mechanisms

ASSOCIATED DISORDERS

corresponding disease(s)

GRL

related resource

Glucocorticoid Receptor Resource database

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral         NR3C1 gene inactivated through promoter hypermethylation in colorectal tumor development

Susceptibility

Variant & Polymorphism

Candidate gene	DNA methylation markers of Gastric cancer (GC), which may serve as useful markers that may identify a distinct subset of GC (Kang 2008)
Marker
Therapy target

ANIMAL & CELL MODELS