TABLE 11

TR4

Receptor nomenclature NR2C2
Receptor code 4.10.1:OR:2:C2
Other names TAK1
Molecular information Hs: 596aa, P49116, chr. 3p251,2
Rn: 596aa, P55094, chr. 4q341
Mm: 596aa, P49117, chr. 6 D23
DNA binding
   Structure Monomer, homodimer, heterodimer
   HRE core sequence AGGTCA n AGGTCA (DR-1, DR-2, DR-3, DR-4, DR-5, half-site)
Partners TR2 (physical, functional): DNA binding, exerts a stronger repressive activity than expressing either receptor alone4; ER (physical, functional): DNA binding5; AR (physical, functional): DNA binding, repression of TR4 target genes6
Agonists
Antagonists
Coactivators
Corepressors TRA16, TIP277,8
Biologically important isoforms TAk1 {Hs}; TR4a1 {Hs, Rn}: differs in the A/B domain—present in brain, ovary, and placenta; TR4a2 {Hs, Rn}: differs in the A/B domain—present in brain, ovary, and placenta
Tissue distribution Developmental: neuronal precursors
Adult: brain (hippocampus, cerebellum, hypothalamic area), CNS, adrenal gland, spleen, testis (spermatocytes), prostate, lungs {Mm, Rn} [Northern blot, in situ hybridization]3,9
Functional assays
Main target genes Activated: HIV1-LTR {Hs},10 LHcgR {Hs},11 steroid 21-hydoxylase {Hs},12 CNTFRα {Hs},4 ApoE {Hs}13
Mutant phenotype Knockout mice exhibit delayed spermatogenesis and reduced sperm production {Mm} [knockout]14; knockout mice have a significantly reduced number of offspring; they demonstrate high rates of early postnatal mortality, as well as significant growth retardation; in addition, female mutants show defects in reproduction and maternal behavior, with pups dying soon after birth with no indication of milk intake {Mm} [knockout]15; knockout mice exhibit behavior deficits in motor coordination, suggesting impaired cerebellar function {Mm} [knockout]16
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; CNS, central nervous system; CNTFR, ciliary neurotrophic factor receptor; LTR, long terminal repeat; LHR, luteinizing hormone receptor

  • ↵1. Chang C, Da Silva SL, Ideta R, Lee Y, Yeh S, and Burbach JP (1994) Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. Proc Natl Acad Sci USA 91: 6040-6044

  • ↵2. Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, and Jetten AM (1994) TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol 8: 1667-1680

  • ↵3. Young WJ, Smith SM, and Chang C (1997) Induction of the intronic enhancer of the human ciliary neurotrophic factor receptor (CNTFRα) gene by the TR4 orphan receptor: a member of steroid receptor superfamily. J Biol Chem 272: 3109-3116

  • ↵4. Young WJ, Lee YF, Smith SM, and Chang CA (1998) bidirectional regulation between the TR2/TR4 orphan receptors (TR2/TR4) and the ciliary neurotrophic factor (CNTF) signaling pathway. J Biol Chem 273: 20877-20885

  • ↵5. Shyr CR, Hu YC, Kim E, and Chang C (2002) Modulation of estrogen receptor-mediated transactivation by orphan receptor TR4 in MCF-7 cells. J Biol Chem 277: 14622-14628

  • ↵6. Lee YF, Shyr CR, Thin TH, Lin WJ, and 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 USA 96: 14724-14729

  • ↵7. Yang Y, Wang X, Dong T, Kim E, Lin WJ, and 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: 7709-7717

  • ↵8. Nakajima T, Fujino S, Nakanishi G, Kim YS, and Jetten AM (2004) TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4. Nucleic Acids Res 32: 4194-4204

  • ↵9. Hirose T, O'Brien DA, and Jetten AM (1995) Cloning of the gene encoding the murine orphan receptor TAK1 and cell-type-specific expression in testis. Gene 163: 239-242

  • ↵10. Hwang SB, Burbach JP, and 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. Endocrine 8: 169-175

  • ↵11. Zhang Y and Dufau ML (2000) Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. J Biol Chem 275: 2763-2770

  • ↵12. Lee HJ, Lee YF, and Chang C (2001) TR4 orphan receptor represses the human steroid 21-hydroxylase gene expression through the monomeric AGGTCA motif. Biochem Biophys Res Commun 285: 1361-1368

  • ↵13. Kim E, Yang Z, Liu NC, and Chang C (2005) Induction of apolipoprotein E expression by TR4 orphan nuclear receptor via 5′ proximal promoter region. Biochem Biophys Res Commun 328: 85-90

  • ↵14. Mu X, Lee YF, Liu NC, Chen YT, Kim E, Shyr CR, and 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: 5887-5899

  • ↵15. Collins LL, Lee YF, Heinlein CA, Liu NC, Chen YT, Shyr CR, Meshul CK, Uno H, Platt KA, and Chang C (2004) Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc Natl Acad Sci USA 101: 15058-15063

  • ↵16. Chen YT, Collins LL, Uno H, and Chang C (2005) Deficits in motor coordination with aberrant cerebellar development in mice lacking testicular orphan nuclear receptor 4. Mol Cell Biol 25: 2722-2732