Receptor nomenclature NR2F1
Receptor code 4.10.1:OR:2:F1
Other names COUPα, COUP-TFA, EAR3, SVP44
Molecular information Hs: 423aa, P10589, chr. 5q151
Rn: 419aa, Q62681, chr. 2q112
Mm: 422aa, Q60632, chr. 13 C23
DNA binding
   Structure Homodimer, heterodimer
   HRE core sequence AGGTCA n AGGTCA (DR-0, DR-1, DR-3, DR-4, DR-5, DR-6, DR-8, DR-11, palindrome)
Partners RXR (physical, functional): sequesters RXR partners, thereby reducing its availability for use by TR, VDR, RAR, and PPAR47; HNF-4 (physical, functional): transactivation, competition for DNA binding810; TR (physical, functional): heterodimerization interferes with TR-dependent transcriptional regulation7,11; RAR (physical, functional): heterodimerization interferes with RAR-dependent transcriptional regulation7,11; ERα (physical, functional): formation of a ERα complex results in an increased recruitment of ERK2/p42 MAPK, phosphorylation of the human ERα on Ser118, and enhanced transcriptional activity; COUP-TF has also been shown to antagonize ER activation of the lactoferrin and oxytocin promoters12,13
Coactivators BCL11B1, NCOA1, CREBBP10,14, 15
Corepressors NCOR1, NCOR2, BCL11A14,16
Biologically important isoforms
Tissue distribution Developmental: rostral brain, presumptive hindbrain, anterior somites, CNS (neural tubes, motor neurons), tongue, follicles of the vibrissae, the cochlea, and nasal septum stroma; in organs that require mesenchymal and epithelial interactions, COUP-TFI is expressed in the mesenchymal cells but not in the terminally differentiated epithelium; adult: rostral and caudal part of brain, supraoptic nucleus {Mm} [Northern blot, in situ hybridization, immunohistology]3,7,17
Functional assays
Main target genes Activated: NGFI-A {Rn},15 PEPCK {Hs, Mm, Rn},18,19 TF {Hs}8; repressed: CYP3A1 {Hs, Mm, Rn},20 MHC class I {Mm}21
Mutant phenotype Animals die at birth from starvation and dehydration; these animals exhibit defects in morphogenesis of the ninth cranial ganglion and nerve resulting from an excess cell death in the ganglionic precursor cells {Mm} [knockout]2225
Human disease
  • aa, amino acids; chr., chromosome; HRE, hormone response element; VDR, vitamin D receptor; CNS, central nervous system; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; CREBBP, cAMP response element-binding protein binding protein; MHC, major histocompatibility class

  • 1. Wang LH, Tsai SY, Cook RG, Beattie WG, Tsai MJ, and O'Malley BW (1989) COUP transcription factor is a member of the steroid receptor superfamily. Nature (Lond) 340: 163-166

  • 2. Connor H, Nornes H, and Neuman T (1995) Expression screening reveals an orphan receptor chick ovalbumin upstream promoter transcription factor I as a regulator of neurite/substrate-cell contacts and cell aggregation. J Biol Chem 270: 15066-15070

  • 3. Qiu Y, Cooney AJ, Kuratani S, DeMayo FJ, Tsai SY, and Tsai MJ (1994) Spatiotemporal expression patterns of chicken ovalbumin upstream promoter-transcription factors in the developing mouse central nervous system: evidence for a role in segmental patterning of the diencephalon. Proc Natl Acad Sci USA 91: 4451-4455

  • 4. Kliewer SA, Umesono K, Heyman RA, Mangelsdorf DJ, Dyck JA, and Evans RM (1992) Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci USA 89: 1448-1452

  • 5. Cooney J, Tsai SY, O'Malley BW, and Tsai MJ (1992) Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors. Mol Cell Biol 12: 4153-4163

  • 6. Tran P, Zhang XK, Salbert G, Hermann T, Lehmann JM, and Pfahl M (1992) COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol Cell Biol 12: 4666-4676

  • 7. Cooney J, Leng X, Tsai SY, O'Malley BW, and Tsai MJ (1993) Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors. J Biol Chem 268: 4152-4160

  • 8. Schaeffer E, Guillou F, Part D, and Zakin MM (1993) A different combination of transcription factors modulates the expression of the human transferrin promoter in liver and Sertoli cells. J Biol Chem 268: 23399-23408

  • 9. Ktistaki E and Talianidis I (1997) Chicken ovalbumin upstream promoter transcription factors act as auxiliary cofactors for hepatocyte nuclear factor 4 and enhance hepatic gene expression. Mol Cell Biol 17: 2790-2797

  • 10. Sugiyama T, Wang JC, Scott DK, and Granner DK (2000) Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI): definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene. J Biol Chem 275: 3446-3454

  • 11. Leng X, Cooney AJ, Tsai SY, and Tsai MJ (1996) Molecular mechanisms of COUP-TF-mediated transcriptional repression: evidence for transrepression and active repression. Mol Cell Biol 16: 2332-2340

  • 12. Liu Y, Yang N, and Teng CT (1993) COUP-TF acts as a competitive repressor for estrogen receptor-mediated activation of the mouse lactoferrin gene. Mol Cell Biol 13: 1836-1846

  • 13. Metivier R, Gay FA, Hubner MR, Flouriot G, Salbert G, Gannon F, Kah O, and Pakdel F (2002) Formation of an hERα -COUP-TFI complex enhances hERα AF-1 through Ser118 phosphorylation by MAPK. EMBO (Eur Mol Biol Organ) J 21: 3443-3453

  • 14. Avram D, Fields A, Pretty On Top K, Nevrivy DJ, Ishmael JE, and Leid M (2000) Isolation of a novel family of C2H2 zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors. J Biol Chem 275: 10315-10322

  • 15. Pipaon C, Tsai SY, and Tsai MJ (1999) COUP-TF upregulates NGFI-A gene expression through an Sp1 binding site. Mol Cell Biol 19: 2734-2745

  • 16. Shibata H, Nawaz Z, Tsai SY, O'Malley BW, and Tsai MJ (1997) Gene silencing by chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is mediated by transcriptional corepressors, nuclear receptor-corepressor (N-CoR) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT). Mol Endocrinol 11: 714-724

  • 17. Tsai SY and Tsai MJ (1997) Chick ovalbumin upstream promoter-transcription factors (COUP-TFs): coming of age. Endocr Rev 18: 229-240

  • 18. Scott DK, Mitchell JA, and Granner DK (1996) The orphan receptor COUP-TF binds to a third glucocorticoid accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem 271: 31909-31914

  • 19. Hall RK, Sladek FM, and Granner DK (1995) The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Proc Natl Acad Sci USA 92: 412-416

  • 20. Ogino M, Nagata K, Miyata M, and Yamazoe Y (1999) Hepatocyte nuclear factor 4-mediated activation of rat CYP3A1 gene and its modes of modulation by apolipoprotein AI regulatory protein I and v-ErbA-related protein 3. Arch Biochem Biophys 362: 32-37

  • 21. Liu X, Ge R, Westmoreland S, Cooney AJ, Tsai SY, Tsai MJ, and Ricciardi RP (1994) Negative regulation by the R2 element of the MHC class I enhancer in adenovirus-12 transformed cells correlates with high levels of COUP-TF binding. Oncogene 9: 2183-2190

  • 22. Qiu Y, Pereira FA, DeMayo FJ, Lydon JP, Tsai SY, and Tsai MJ (1997) Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization. Genes Dev 11: 1925-1937

  • 23. Zhou C, Tsai SY, and Tsai MJ (2001) COUP-TFI: an intrinsic factor for early regionalization of the neocortex. Genes Dev 15: 2054-2059

  • 24. Zhou C, Qiu Y, Pereira FA, Crair MC, Tsai SY, and Tsai MJ (1999) The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons. Neuron 24: 847-859

  • 25. Yamaguchi H, Zhou C, Lin SC, Durand B, Tsai SY, and Tsai MJ (2004) The nuclear orphan receptor COUP-TFI is important for differentiation of oligodendrocytes. Dev Biol 266: 238-251