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NR3C2 (nuclear receptor subfamily 3, group C, member 2)

Identity

Other namesMCR
MGC133092
MLR
MR
HGNC (Hugo) NR3C2
LocusID (NCBI) 4306
Location 4q31.23
Location_base_pair Starts at 148999915 and ends at 149363672 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Genes flanking NR3C2 are Rho GTPase activating protein 10 and argininosuccinate synthetase pseudogene 8.

DNA/RNA

 
  Schematic representation of human mineralocorticoid receptor (MR/NR3C2) structure. The human MR/NR3C2 gene is composed of 10 exons. The first 2 exons (1alpha and 1beta) are untranslated. However, alternative transcription of these exons can give rise to 2 RNA isoforms. The subsequent eight exons encode for the entire MR protein. MR/NR3C2 has three major functional domains: a modulating N-terminal domain (NTD), a central DNA-binding domain (DBD) and a C-terminal steroid ligand-binding domain (LBD). Exon 2 encodes for most of the NTD, exons 3 and 4 encode for each of the two zinc fingers of the DBD and the remaining five exons encode the LBD. AUG: start codon; UGA: stop codon.
Description 10 exons; 363,729 bases DNA.
Transcription Multiple (at least four) mRNA isoforms are generated by alternative transcription or slicing events. Multiple mRNA isoforms are translated into various protein variants.

Protein

Description 984 amino acids. Like all member of the nuclear receptor superfamily, the MR has 3 major domains: an N-terminal domain (NTD), a DNA-binding domain (DBD) and a ligand-binding domain (LBD). The NTD (602 amino acids) is composed of several functional domains (AF-1a, a central domain and AF-1b) that recruit various coregulators responsible for selectively modulating the transcriptional activity of MR. The DBD (66 amino acids) recognizes specific target DNA sequences or hormone response elements. The LBD (251 amino acids) is a multifunctional domain allowing selective hormone binding. The LBD includes the ligand-dependent AF-2 functional domain, which undergoes a rearrangement upon ligand binding.
Expression Ubiquitous. MR expression has been reported in the kidney, colon, breast, salivary glands, sweat glands, liver, cardiomyocytes, endothelial cells, lung, central nervous system (hippocampus, hypothalamus), ocular tissues (retina, iris-ciliary body), adipose tissues (white and brown), inner ear, skin, placenta, uterus, ovaries and testis.
Localisation Cytoplasm, nucleus, endoplasmic reticulum membrane, peripheral membrane: cytoplasmic and nuclear in the absence of ligand; nuclear after ligand-binding. When bound to 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2), it is found associated with the endoplasmic reticulum membrane.
Function Transcription factor activity, receptor activity, protein binding, sequence-specific DNA binding, steroid binding, steroid hormone receptor activity, metal ion binding, zinc ion binding.
Homology Member of the nuclear hormone receptor family, NR3 subfamily.

Mutations

Note Loss-of-function mutations. About 50 distinct mutations in the human MR are known to be responsible for pseudohypoaldosteronism type 1 (PHA1). This is an autosomal genetic disorder caused by loss-of-function mutations. The mutations reported are missense, nonsense, frameshift, splice site mutations and deletions. PHA1 is characterized by salt wasting due to loss-of-function of the MR in the target organs. There are 2 forms of PHA1: the autosomal dominant form, which may be severe at birth, but symptoms remit with age, and the recessive form, which manifests with more severe symptoms persisting into adulthood.
Gain-of-function mutations. Only one mutation, to date, is known to result in a gain-of-function of MR. The single mutation S810L in the LBD leads to a constant MR activation. The inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, with severe exacerbation in pregnancy.

Implicated in

Entity Leukaemia
Note Some of the leukaemic cell lines express both the MR and the amiloride-sensitive sodium channel.
Oncogenesis Some leukemic cell lines respond to mineralocorticoid steroids by an altered growth response that may possibly be linked to apoptosis. The altered sodium flux due to the induction of the amiloride-sensitive sodium channel by mineralocorticoids may cause uncontrolled cell proliferation in cancer.
  
Entity Colorectal carcinoma
Note Reduction of MR mRNA expression is an early event in human sporadic carcinoma progression.
Oncogenesis A significant inverse association between MR and vascular endothelial growth factor receptor-2 (VEGFR-2) expression at the mRNA level has been detected in human colorectal carcinoma, suggesting a potential tumor-suppressive function for MR. The degree of MR underexpression may have a role in the pro-angiogenic switch of colorectal carcinoma.
  
Entity Cervical carcinoma
Note In a study of gene expression profiles in squamous cell cervical carcinoma, NR3C2 was observed to be significantly downregulated, which would suggest that it should be considered as a new putative cervical cancer-related gene.
  
Entity Renal cell neoplasms
Note Using immunohistochemistry, expression of both MR and its related enzyme 11 beta-HSD2 was detected in chromophobe renal cell carcinoma and in oncocytomas. No staining was detected in clear cell renal cell carcinomas. MR and 11 beta-HSD2 may be considered specific immunohistochemical markers of the distal nephron and its related neoplasms (chromophobe renal cell carcinoma and oncocytoma).
  
Entity Lung carcinoma
Note It has been reported that MR and 11 beta-HSD2 seem to be expressed only in adenocarcinomas or in the adenocarcinomatous component of adenosquamous carcinomas. No MR or 11 beta-HSD2 expression was detected in squamous cell carcinomas. MR and 11 beta-HSD2 immunoreactivity have been significantly correlated with the grade of differentiation of adenocarcinomas. Patterns of MR and 11 beta-HSD2 expression as detected with immunohistochemistry may reflect the cellular origin and differentiation status of primary human lung carcinoma, and may serve as a marker of differentiation.
  
Entity Breast carcinoma
Note Expression of MR, as detected with immunohistochemistry, appears to be related to ductal differentiation of breast carcinomas.
  

To be noted

Several studies investigating the role of aldosterone and MR in cardiovascular risk and target organ damage may offer important hints to understand the potential involvement of MR in cancer development. Under particular investigation are the relationship between MR/aldosterone and cellular growth factor receptors expression (such as EGFR or VEGFR).

External links

Nomenclature
HGNC (Hugo)NR3C2   7979
Cards
AtlasNR3C2ID44262ch4q31
Entrez_Gene (NCBI)NR3C2  4306  nuclear receptor subfamily 3, group C, member 2
GeneCards (Weizmann)NR3C2
Ensembl (Hinxton)ENSG00000151623 [Gene_View]  chr4:148999915-149363672 [Contig_View]  NR3C2 [Vega]
ICGC DataPortalENSG00000151623
cBioPortalNR3C2
AceView (NCBI)NR3C2
Genatlas (Paris)NR3C2
WikiGenes4306
SOURCE (Princeton)NM_000901 NM_001166104
Genomic and cartography
GoldenPath (UCSC)NR3C2  -  4q31.23   chr4:148999915-149363672 -  4q31.1   [Description]    (hg19-Feb_2009)
EnsemblNR3C2 - 4q31.1 [CytoView]
Mapping of homologs : NCBINR3C2 [Mapview]
OMIM177735   600983   605115   
Gene and transcription
Genbank (Entrez)AB209056 AJ315514 AJ315515 AK123047 AK304318
RefSeq transcript (Entrez)NM_000901 NM_001166104
RefSeq genomic (Entrez)AC_000136 NC_000004 NC_018915 NG_013350 NT_016354 NW_001838921 NW_004929320
Consensus coding sequences : CCDS (NCBI)NR3C2
Cluster EST : UnigeneHs.163924 [ NCBI ]
CGAP (NCI)Hs.163924
Alternative Splicing : Fast-db (Paris)GSHG0023578
Alternative Splicing GalleryENSG00000151623
Gene ExpressionNR3C2 [ NCBI-GEO ]     NR3C2 [ SEEK ]   NR3C2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP08235 (Uniprot)
NextProtP08235  [Medical]
With graphics : InterProP08235
Splice isoforms : SwissVarP08235 (Swissvar)
Domaine pattern : Prosite (Expaxy)NUCLEAR_REC_DBD_1 (PS00031)    NUCLEAR_REC_DBD_2 (PS51030)   
Domains : Interpro (EBI)Nucl_hormone_rcpt_ligand-bd [organisation]   Nucl_hrmn_rcpt_lig-bd_core [organisation]   Znf_hrmn_rcpt [organisation]   Znf_NHR/GATA [organisation]  
Related proteins : CluSTrP08235
Domain families : Pfam (Sanger)Hormone_recep (PF00104)    zf-C4 (PF00105)   
Domain families : Pfam (NCBI)pfam00104    pfam00105   
Domain families : Smart (EMBL)HOLI (SM00430)  ZnF_C4 (SM00399)  
DMDM Disease mutations4306
Blocks (Seattle)P08235
PDB (SRS)1Y9R    1YA3    2A3I    2AA2    2AA5    2AA6    2AA7    2AAX    2AB2    2ABI    2OAX    3VHU    3VHV    3WFF    3WFG   
PDB (PDBSum)1Y9R    1YA3    2A3I    2AA2    2AA5    2AA6    2AA7    2AAX    2AB2    2ABI    2OAX    3VHU    3VHV    3WFF    3WFG   
PDB (IMB)1Y9R    1YA3    2A3I    2AA2    2AA5    2AA6    2AA7    2AAX    2AB2    2ABI    2OAX    3VHU    3VHV    3WFF    3WFG   
PDB (RSDB)1Y9R    1YA3    2A3I    2AA2    2AA5    2AA6    2AA7    2AAX    2AB2    2ABI    2OAX    3VHU    3VHV    3WFF    3WFG   
Human Protein AtlasENSG00000151623 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP08235
HPRD02991
IPIIPI00027744   IPI00248972   IPI00248973   IPI00248974   IPI00910741   IPI00889527   IPI00889774   IPI00889506   
Protein Interaction databases
DIP (DOE-UCLA)P08235
IntAct (EBI)P08235
FunCoupENSG00000151623
BioGRIDNR3C2
InParanoidP08235
Interologous Interaction database P08235
IntegromeDBNR3C2
STRING (EMBL)NR3C2
Ontologies - Pathways
Ontology : AmiGOsequence-specific DNA binding transcription factor activity  steroid hormone receptor activity  steroid binding  protein binding  nucleoplasm  endoplasmic reticulum membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  signal transduction  zinc ion binding  gene expression  receptor complex  steroid hormone mediated signaling pathway  sequence-specific DNA binding  
Ontology : EGO-EBIsequence-specific DNA binding transcription factor activity  steroid hormone receptor activity  steroid binding  protein binding  nucleoplasm  endoplasmic reticulum membrane  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  signal transduction  zinc ion binding  gene expression  receptor complex  steroid hormone mediated signaling pathway  sequence-specific DNA binding  
Pathways : KEGGAldosterone-regulated sodium reabsorption   
Protein Interaction DatabaseNR3C2
Wikipedia pathwaysNR3C2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)NR3C2
snp3D : Map Gene to Disease4306
SNP (GeneSNP Utah)NR3C2
SNP : HGBaseNR3C2
Genetic variants : HAPMAPNR3C2
Exome VariantNR3C2
1000_GenomesNR3C2 
ICGC programENSG00000151623 
Somatic Mutations in Cancer : COSMICNR3C2 
CONAN: Copy Number AnalysisNR3C2 
Mutations and Diseases : HGMDNR3C2
Mutations and Diseases : intOGenNR3C2
Genomic VariantsNR3C2  NR3C2 [DGVbeta]
dbVarNR3C2
ClinVarNR3C2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM177735    600983    605115   
MedgenNR3C2
GENETestsNR3C2
Disease Genetic AssociationNR3C2
Huge Navigator NR3C2 [HugePedia]  NR3C2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneNR3C2
Homology/Alignments : Family Browser (UCSC)NR3C2
Phylogenetic Trees/Animal Genes : TreeFamNR3C2
Chemical/Protein Interactions : CTD4306
Chemical/Pharm GKB GenePA242
Clinical trialNR3C2
Cancer Resource (Charite)ENSG00000151623
Other databases
Probes
Litterature
PubMed171 Pubmed reference(s) in Entrez
CoreMineNR3C2
iHOPNR3C2
OncoSearchNR3C2

Bibliography

Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor.
Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM.
Science. 1987 Jul 17;237(4812):268-75.
PMID 3037703
 
Human mineralocorticoid receptor genomic structure and identification of expressed isoforms.
Zennaro MC, Keightley MC, Kotelevtsev Y, Conway GS, Soubrier F, Fuller PJ.
J Biol Chem. 1995 Sep 8;270(36):21016-20.
PMID 7673127
 
Localization of mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase type II in human breast and its disorders.
Sasano H, Frost AR, Saitoh R, Matsunaga G, Nagura H, Krozowski ZS, Silverberg SG.
Anticancer Res. 1997 May-Jun;17(3C):2001-7.
PMID 9216657
 
Demonstration of the mineralocorticoid hormone receptor and action in human leukemic cell lines.
Mirshahi M, Mirshahi S, Golestaneh N, Mishal Z, Nicolas C, Hecquet C, Agarwal MK.
Leukemia. 2000 Jun;14(6):1097-104.
PMID 10865975
 
Expression of 11 beta-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor in primary lung carcinomas.
Suzuki S, Suzuki T, Tsubochi H, Koike K, Tateno H, Krozowski ZS, Sasano H.
Anticancer Res. 2000 Jan-Feb;20(1A):323-8.
PMID 10769675
 
Aldosterone stimulates epidermal growth factor receptor expression.
Krug AW, Grossmann C, Schuster C, Freudinger R, Mildenberger S, Govindan MV, Gekle M.
J Biol Chem. 2003 Oct 31;278(44):43060-6. Epub 2003 Aug 25.
PMID 12939263
 
Dissecting mineralocorticoid receptor structure and function.
Rogerson FM, Brennan FE, Fuller PJ.
J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):389-96. (REVIEW)
PMID 12943727
 
Aldosterone signaling modifies capillary formation by human bone marrow endothelial cells.
Chen W, Valamanesh F, Mirshahi T, Soria J, Tang R, Agarwal MK, Mirshahi M.
Vascul Pharmacol. 2004 Jan;40(6):269-77.
PMID 15063830
 
Aldosterone impairs bone marrow-derived progenitor cell formation.
Marumo T, Uchimura H, Hayashi M, Hishikawa K, Fujita T.
Hypertension. 2006 Sep;48(3):490-6. Epub 2006 Jul 17.
PMID 16847146
 
Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis.
Choi YW, Bae SM, Kim YW, Lee HN, Kim YW, Park TC, Ro DY, Shin JC, Shin SJ, Seo JS, Ahn WS.
Int J Gynecol Cancer. 2007 May-Jun;17(3):687-96.
PMID 17504382
 
Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression.
Di Fabio F, Alvarado C, Majdan A, Gologan A, Voda L, Mitmaker E, Beitel LK, Gordon PH, Trifiro M.
J Gastrointest Surg. 2007 Nov;11(11):1521-8. Epub 2007 Aug 17.
PMID 17703341
 
Aldosterone, mineralocorticoid receptors, and vascular inflammation.
Fiebeler A, Muller DN, Shagdarsuren E, Luft FC.
Curr Opin Nephrol Hypertens. 2007 Mar;16(2):134-42. (REVIEW)
PMID 17293689
 
Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter.
Grossmann C, Krug AW, Freudinger R, Mildenberger S, Voelker K, Gekle M.
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1790-800. Epub 2007 Feb 20.
PMID 17311890
 
Is the vascular endothelium under the control of aldosterone? Facts and hypothesis.
Oberleithner H.
Pflugers Arch. 2007 May;454(2):187-93. Epub 2007 Feb 7. (REVIEW)
PMID 17285301
 
The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.
Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombes M.
Nucl Recept Signal. 2007 Nov 30;5:e012. (REVIEW)
PMID 18174920
 
Nongenotropic aldosterone effects and the EGFR: interaction and biological relevance.
Grossmann C, Gekle M.
Steroids. 2008 Oct;73(9-10):973-8. Epub 2007 Dec 23. (REVIEW)
PMID 18249428
 
Mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type II expression in renal cell neoplasms: a tissue microarray and quantitative RT-PCR study.
Yakirevich E, Morris DJ, Tavares R, Meitner PA, Lechpammer M, Noble L, de Rodriguez AF, Gomez-Sanchez CE, Wang LJ, Sabo E, Delellis RA, Resnick MB.
Am J Surg Pathol. 2008 Jun;32(6):874-83.
PMID 18408592
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written12-2008Francesco Di Fabio, Bruce Gottlieb, Lenore K Beitel, Mark Trifiro
Cattedra di Chirurgia Generale, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy (FDF); Lady Davis Institute for Medical Research-Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada (BG, LKB, MT)

Citation

This paper should be referenced as such :
Di, Fabio F ; Gottlieb, B ; Beitel, LK ; Trifiro, M
NR3C2 (nuclear receptor subfamily 3, group C, member 2)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):858-860.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/NR3C2ID44262ch4q31.html

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indexed on : Sat Oct 4 13:04:03 CEST 2014

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