Testicular receptor 4

Nomenclature: Testicular receptor 4

Systematic Nomenclature: NR2C2

Family: 2C. Testicular receptors

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

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 615 3p25 NR2C2 nuclear receptor subfamily 2, group C, member 2 1,4
Mouse 596 4q34 Nr2c2 nuclear receptor subfamily 2, group C, member 2 15
Rat 596 6D2 Nr2c2 nuclear receptor subfamily 2, group C, member 2 1
Previous and Unofficial Names
TR2R1
hTAK1
TR4
TAK1
TR4 orphan receptor
TR4-NS orphan receptor
nuclear receptor subfamily 2 group C member 2
nuclear receptor subfamily 2, group C, member 2
orphan nuclear receptor TR4
orphan receptor TR4
testicular receptor 4
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
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
tretinoin Hs Full agonist - - 17
[17]
retinol Hs Full agonist - - 17
[17]
DNA Binding
Structure:  Monomer, Homodimer, Heterodimer
HRE core sequence: 
Response element:  DR1, DR2, DR3, DR4, DR5, Other DR
DNA Binding Comments
TR4 is able to form heterodimers with TR2 on a DR5 element. TR4 interact with DR element with different spacing with the greatest activity for DR1. Transcriptional activity of TR4 can be opposite on different DR responsive elements.
Co-binding Partners
Name Interaction Effect Reference
Testicular receptor 2 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. 14
Estrogen receptor-α Physical, Functional DNA binding 12
Androgen receptor Physical, Functional DNA binding, AR heterodimerize with TR4, and function as a repressor to down-regulate TR4 target genes by preventing the binding of TR4 to the promoter region of those genes. Reciprocally, TR4 can repress AR target gene expression. 9
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
JAZF1 Co-repressor No No Yes 11
NR2C2AP Co-repressor Yes No Yes 13
Main Target Genes
Name Species Effect Technique Comments References
LHCGR Human Activated Transient transfection,EMSA ,Other LHR: TR4 binds to an imperfect DR element in the promoter of the human luteinizing hormone receptor (LHR) gene and activate LRH promoter activity in transient transfections assays in CV1 cells. Findings suggest that TR4 is able to contribute to the differential expression of the LHR gene in gonadal and non-gonadal tissues. 16
CYP21A2 Human Activated Transient transfection,EMSA ,Other Steroid 21-hydroxylase (CYP21A2): the expression of the human steroid 21-hydroxylase (21-OHase) gene is repressed by TR4 via the monomeric AGGTCA motif (−228TR4RE) in its 5 flanking region. 8
CNTFR Human Activated Transient transfection,EMSA CNTFRa: A CNTFR-DR1 was identified in the fifth intron of the alpha component of the human CNTFRα gene. Reporter gene assay demonstrated that the fifth intronof the CNTFRα gene has enhancer activity, which could be induced by TR4 in a dose-dependent manner 14
Apoplipoprotein E Human Activated Induction of apoplipoprotein E expression by TR4 orphan receptor via 5’ proximal region 7
Main Target Genes Comments
HIV1-LTR: TR4 showed high affinity to a palindromic (symmetric) element (PR9) at the 5'-end of the HIV-LTR but is not able to regulate transcription activity of the LTR on its own in transient reporter assays. TR4 may nevertheless associate with other NRs in the regulation of HIV replication [6].
Tissue Distribution
Ubiquitous (but differential expression for isoforms)
Species:  Mouse
Technique:  Northern, In situ
References:  5,15
Tissue Distribution Comments
The mouse TR4 is expressed as two mRNAs of 8 kb and 3.5 kb. The 8 kb form appears ubiquitously expressed whereas the 3.5 kb is restricted to some tissues such as brain or at much lower levels in lungs. A small 2.8 kb TR4 transcript was also observed in testis, mainly in spermatocytes and a specific 4.5 kb transcript was detected in rat spleen. The relationship between these various small transcripts (4.5, 3.5 and 2.8 kb) are still unclear. The large transcript exhibits a predominant expression in rat central nervous system, with a prominent expression in hippocampus, cerebellum and hypothalamic area as well as in adrenal gland, spleen, testis and prostate. The expression of TR4 in adult brain as well as in neuronal precursors during embryogenesis has been confirmed by in situ hybridization. It has been suggested that TR4 expression in brain is located in areas known to be involved in stress response and that TR4 expression is up-regulated by NMDA.
Physiological Consequences of Altering Gene Expression
TR4 KO mice show delayed spermatogenesis and reduce sperm counts, high rates of early postnatal mortality, growth retardation, females show defects in reproduction and maternal behaviour, impaired cerebellar function and developement.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  2-3,10
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0001588 abnormal hemoglobin PMID: 17431400 
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0008261 arrest of male meiosis PMID: 15199144 
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0001265 decreased body size PMID: 15199144 
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0004852 decreased testis weight PMID: 15199144 
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0002687 oligozoospermia PMID: 15199144 
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0001922 reduced male fertility PMID: 15199144 
Nr2c2tm1Chc Nr2c2tm1Chc/Nr2c2tm1Chc
Not Specified
MGI:1352466  MP:0001154 seminiferous tubule degeneration PMID: 15199144 
General Comments
There are still questions as to why in certain cases TR4 is a transcriptional repressor but behaves as an activator in others. Target promoter analysis seems to exclude that response element sequence is the determinant of this differential activity.

References

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1. Chang C, Da Silva SL, Ideta R, Lee Y, Yeh S, Burbach JP. (1994) Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Proc. Natl. Acad. Sci. U.S.A.91 (13): 6040-4. [PMID:8016112]

2. Chen YT, Collins LL, Uno H, Chang C. (2005) Deficits in motor coordination with aberrant cerebellar development in mice lacking testicular orphan nuclear receptor 4. Mol. Cell. Biol.25 (7): 2722-32. [PMID:15767677]

3. Collins LL, Lee YF, Heinlein CA, Liu NC, Chen YT, Shyr CR, Meshul CK, Uno H, Platt KA, Chang C. (2004) Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc. Natl. Acad. Sci. U.S.A.101 (42): 15058-63. [PMID:15477591]

4. Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM. (1994) TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol. Endocrinol.8 (12): 1667-80. [PMID:7708055]

5. Hirose T, O'Brien DA, Jetten AM. (1995) Cloning of the gene encoding the murine orphan receptor TAK1 and cell-type-specific expression in testis. Gene163 (2): 239-42. [PMID:7590273]

6. Hwang SB, Burbach JP, Chang C. (1998) TR4 orphan receptor crosstalks to chicken ovalbumin upstream protein-transcription factor and thyroid hormone receptor to induce the transcriptional activity of the human immunodeficiency virus type 1 long-terminal repeat. Endocrine8 (2): 169-75. [PMID:9704574]

7. Kim E, Yang Z, Liu NC, Chang C. (2005) Induction of apolipoprotein E expression by TR4 orphan nuclear receptor via 5' proximal promoter region. Biochem. Biophys. Res. Commun.328 (1): 85-90. [PMID:15670754]

8. Lee HJ, Lee YF, Chang C. (2001) TR4 orphan receptor represses the human steroid 21-hydroxylase gene expression through the monomeric AGGTCA motif. Biochem. Biophys. Res. Commun.285 (5): 1361-8. [PMID:11478808]

9. Lee YF, Shyr CR, Thin TH, Lin WJ, Chang C. (1999) Convergence of two repressors through heterodimer formation of androgen receptor and testicular orphan receptor-4: a unique signaling pathway in the steroid receptor superfamily. Proc. Natl. Acad. Sci. U.S.A.96 (26): 14724-9. [PMID:10611280]

10. Mu X, Lee YF, Liu NC, Chen YT, Kim E, Shyr CR, Chang C. (2004) Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis. Mol. Cell. Biol.24 (13): 5887-99. [PMID:15199144]

11. Nakajima T, Fujino S, Nakanishi G, Kim YS, Jetten AM. (2004) TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nucleic Acids Res.32 (14): 4194-204. [PMID:15302918]

12. Shyr CR, Hu YC, Kim E, Chang C. (2002) Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. J. Biol. Chem.277 (17): 14622-8. [PMID:11844790]

13. Yang Y, Wang X, Dong T, Kim E, Lin WJ, Chang C. (2003) Identification of a novel testicular orphan receptor-4 (TR4)-associated protein as repressor for the selective suppression of TR4-mediated transactivation. J. Biol. Chem.278 (9): 7709-17. [PMID:12486131]

14. 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]

15. Young WJ, Smith SM, Chang C. (1997) Induction of the intronic enhancer of the human ciliary neurotrophic factor receptor (CNTFRalpha) gene by the TR4 orphan receptor. A member of steroid receptor superfamily. J. Biol. Chem.272 (5): 3109-16. [PMID:9006963]

16. Zhang Y, Dufau ML. (2000) Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. J. Biol. Chem.275 (4): 2763-70. [PMID:10644740]

17. Zhou XE, Suino-Powell KM, Xu Y, Chan CW, Tanabe O, Kruse SW, Reynolds R, Engel JD, Xu HE. (2011) The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor. J. Biol. Chem.286 (4): 2877-85. [PMID:21068381]

How to cite this page

2C. Testicular receptors: Testicular receptor 4. Last modified on 13/12/2013. Accessed on 31/10/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=614.