TABLE 14

COUP-TFI

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 PPAR4–7; HNF-4 (physical, functional): transactivation, competition for DNA binding8–10; 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
Agonists
Antagonists
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]22–25
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