Nomenclature: Testicular receptor 2

Systematic Nomenclature: NR2C1

Family: 2C. Testicular receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 603 12q22 NR2C1 nuclear receptor subfamily 2, group C, member 1 2
Mouse 590 10 52.0 cM Nr2c1 nuclear receptor subfamily 2, group C, member 1 12
Rat 590 7q13 Nr2c1 nuclear receptor subfamily 2, group C, member 1 10
Previous and Unofficial Names
TR2-11
TR2
Psg4
nuclear receptor subfamily 2 group C member 1
nuclear receptor subfamily 2, group C, member 1
nuclear receptor subfamily 2, group H, member 1
orphan nuclear receptor TR2
orphan receptor
orphan receptor, TR2-11
pregnancy specific beta-1-glycoprotein 4
Eenr
4831444H07Rik
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Comments: Orphan
DNA Binding
Structure:  Homodimer, Heterodimer
HRE core sequence:  AGGTCA n AGGTCA
Response element:  DR1, DR2, DR3, DR4, DR5, Other DR, Other - see comments
DNA Binding Comments
TR2 is able to form heterodimers with TR4 on a DR5 element. TR2 interact with DR element with different spacing with the following preference: DR1>DR2>DR5=DR4=DR6>DR3
Co-binding Partners
Name Interaction Effect Reference
Androgen receptor Physical, Functional DNA binding and AR can heterodimerize with TR2, and function as a repressor to down-regulate TR2 target genes by preventing the binding of TR2 to those genes. Reciprocally, TR2 can repress AR target gene expression. 10
Testicular receptor 4 Physical, Functional DNA binding, TR2 and TR4 form heterodimers. The dimerization interface is localized in the ligand-binding domains, and three leucine residues in helix H10 are critical for this interaction. Coexpression of TR2 and TR4 exerts a stronger repressive activity than expressing either receptor alone in a reporter gene assay. 12
Estrogen receptor-α Physical, Functional DNA binding 5
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NRIP1 Co-repressor No No Yes 6
HDAC3 Co-repressor No No No 9
HDAC4 Co-repressor Yes No No 9
Main Target Genes
Name Species Effect Technique Comments References
EPO Human Repressed Transient transfection, EMSA EPO: A TR2RE-EPO has been identified in the 3 minimal hypoxia-inducible enhancer of the human erythropoietin (EPO) gene. 8
histamine receptor H1 Human Repressed Transient transfection, EMSA, Other Histamine H1 receptor: A DNA response element (TR2RE-HR) in the 3 flanking region of the human histamine H1 receptor (HR) gene was identified as a target for human TR2 7
CNTFRa Human Activated Transient transfection, EMSA 12
Aldolase A Human Activated Transient transfection, EMSA Aldolase A: TR2 was identified as an M1 site binding protein of the muscle-specific pM promoter in the human aldolase A gene 3
Main Target Genes Comments
Human papillomavirus type 16:- TR2 can bind to a DR4 response element in the HPV-16 promoter, and potentiate HPV transcriptional activity in a dose-dependent manner [4].
Tissue Distribution
Prostate, liver, testis, seminal vesicle, kidney
Expression level:  High
Species:  Rat
Technique:  Northern, in situ, other
References:  1-2
Tissue Distribution Comments
The first studies on rat TR2 gene expression detected a transcript of 2.5 kb in prostate, liver, testis, seminal vesicle and kidney and suggest that the transcript observed in prostate was negatively regulated by androgens. A prominent testis expression was described in mouse although the expression was also observed in numerous other tissues. The very high expression in testis was confirmed by subsequent studies that also demonstrate that TR2 expression starts at E8.5 days of development, reaches a maximal level at E12.5 and declines at E14.5. The corresponding protein was located in the seminiferous tubules where advanced germ cells reside. In situ hybridisation located TR2 expression in many mouse tissues including kidney and intestine during late embryogenesis. It was shown that TR2 expression is down-regulated by ionising irradiation and that this effect is mediated by p53 which behaves as a down-regulator of TR2 expression. A regulation of TR2 expression by retinoic acid was suggested since mice fed with vitamin-A depleted diet exhibit no germ cells and no TR2 expression in testis.
Physiological Consequences of Altering Gene Expression
TR2 -/- mice:- Male mice lacking TR2 have functional testes, including normal sperm number and motility, and both male and female mice lacking TR2 are fertile.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  11
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr2c1tm1Chc Nr2c1tm1Chc/Nr2c1tm1Chc
involves: 129S5/SvEvBrd
MGI:1352465  MP:0001588 abnormal hemoglobin PMID: 17431400 
Nr2c1tm1Chc Nr2c1tm1Chc/Nr2c1tm1Chc
involves: 129S5/SvEvBrd * C57BL/6
MGI:1352465  MP:0002169 no abnormal phenotype detected PMID: 12052874 
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  TR2-9 (nuclear receptor subfamily 2 group C member 1 isoform b): - has a shorter ligandbinding domain. This isoform was isolated by screening a Testis derived library.
Protein accession: 
References:  1-2
Type:  Splice variant
Species:  Human
Description:  TR2-5 isoform (nuclear receptor subfamily 2 group C member 1 isoform c):- has a shorter ligandbinding domain.This isoform was isolated by screening a Testis derived library.
Protein accession: 
References:  1-2
Type:  Splice variant
Species:  Human
Description:  TR2-7 isoform:- lacks the ligand binding domain (LBD) of TR2. This isoform was isolated by screening a Testis derived library.
References:  1-2

REFERENCES

1. Chang C, Kokontis J. (1988) Identification of a new member of the steroid receptor super-family by cloning and sequence analysis. Biochem. Biophys. Res. Commun.155 (2): 971-7. [PMID:3421977]

2. Chang C, Kokontis J, Acakpo-Satchivi L, Liao S, Takeda H, Chang Y. (1989) Molecular cloning of new human TR2 receptors: a class of steroid receptor with multiple ligand-binding domains. Biochem. Biophys. Res. Commun.165 (2): 735-41. [PMID:2597158]

3. Chang C, Lee HJ, Lee YF. (1997) Identification of the human aldolase A gene as the first induced target for the TR2 orphan receptor, a member of the steroid hormone receptor superfamily. Biochem. Biophys. Res. Commun.235 (1): 205-11. [PMID:9196064]

4. Collins LL, Lin DL, Mu XM, Chang C. (2001) Feedback regulation between orphan nuclear receptor TR2 and human papilloma virus type 16. J. Biol. Chem.276 (29): 27316-21. [PMID:11358973]

5. Hu YC, Shyr CR, Che W, Mu XM, Kim E, Chang C. (2002) Suppression of estrogen receptor-mediated transcription and cell growth by interaction with TR2 orphan receptor. J. Biol. Chem.277 (37): 33571-9. [PMID:12093804]

6. Lee CH, Chinpaisal C, Wei LN. (1998) Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol. Cell. Biol.18 (11): 6745-55. [PMID:9774688]

7. Lee HJ, Lee YF, Chang C. (1999) Identification of the histamine H1 receptor gene as a differentially repressed target of the human TR2 orphan receptor. Mol. Cell. Biochem.194 (1-2): 199-207. [PMID:10391141]

8. Lee HJ, Young WJ, Shih CY, Chang C. (1996) Suppression of the human erythropoietin gene expression by the TR2 orphan receptor, a member of the steroid receptor superfamily. J. Biol. Chem.271 (17): 10405-12. [PMID:8626614]

9. Li G, Franco PJ, Wei LN. (2003) Identification of histone deacetylase-3 domains that interact with the orphan nuclear receptor TR2. Biochem. Biophys. Res. Commun.310 (2): 384-90. [PMID:14521922]

10. Mu X, Chang C. (2003) TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3. Prostate57 (2): 129-33. [PMID:12949936]

11. Shyr CR, Collins LL, Mu XM, Platt KA, Chang C. (2002) Spermatogenesis and testis development are normal in mice lacking testicular orphan nuclear receptor 2. Mol. Cell. Biol.22 (13): 4661-6. [PMID:12052874]

12. Young WJ, Lee YF, Smith SM, Chang C. (1998) A bidirectional regulation between the TR2/TR4 orphan receptors (TR2/TR4) and the ciliary neurotrophic factor (CNTF) signaling pathway. J. Biol. Chem.273 (33): 20877-85. [PMID:9694834]

To cite this database page, please use the following:

2C. Testicular receptors: Testicular receptor 2. Last modified on 13/12/2013. Accessed on 24/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=613.

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