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Mol Cell Biol. Oct 1992; 12(10): 4666–4676.
PMCID: PMC360393

COUP orphan receptors are negative regulators of retinoic acid response pathways.

Abstract

The vitamin hormone retinoic acid (RA) regulates many complex biological programs. The hormonal signals are mediated at the level of transcription by multiple nuclear receptors. These receptors belong to the steroid/thyroid hormone receptor superfamily that also includes a large number of orphan receptors whose biological roles have not yet been determined. Although much has been learned in recent years about RA receptor (RAR) functions, little is known about how specific RA response programs are restricted to certain tissues and cell types during development and in the adult. It has been recently shown that RAR activities are regulated by retinoid X receptors (RXR) through heterodimer formation. In an effort to isolate and further characterize nuclear receptors that modulate RAR and/or RXR activities, we have screened cDNA libraries by using a RXR alpha cDNA probe. Two clones, COUP alpha and COUP beta, identical and closely related to the orphan receptor COUP-TF, were obtained. We show that COUP proteins dramatically inhibit retinoid receptor activities on certain response elements that are activated by RAR/RXR heterodimers or RXR homodimers. COUP alpha and -beta bind strongly to these response elements, including a palindromic thyroid hormone response element and a direct repeat RA response element as well as an RXR-specific response element. In addition, we found that the previously identified COUP-TF binding site in the ovalbumin gene functions in vitro as an RA response element that is repressed in the presence of COUP. Our data suggest that the COUP receptors are a novel class of RAR and RXR regulators that can restrict RA signaling to certain elements. The COUP orphan receptors may thus play an important role in cell- or tissue-specific repression of subsets of RA-sensitive programs during development and in the adult.

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Selected References

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  • Benbrook D, Lernhardt E, Pfahl M. A new retinoic acid receptor identified from a hepatocellular carcinoma. Nature. 1988 Jun 16;333(6174):669–672. [PubMed]
  • Brand N, Petkovich M, Krust A, Chambon P, de Thé H, Marchio A, Tiollais P, Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. [PubMed]
  • de Thé H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature. 1990 Jan 11;343(6254):177–180. [PubMed]
  • Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. [PubMed]
  • Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG. Inhibition of estrogen receptor-DNA binding by the "pure" antiestrogen ICI 164,384 appears to be mediated by impaired receptor dimerization. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6883–6887. [PMC free article] [PubMed]
  • Forman BM, Yang CR, Au M, Casanova J, Ghysdael J, Samuels HH. A domain containing leucine-zipper-like motifs mediate novel in vivo interactions between the thyroid hormone and retinoic acid receptors. Mol Endocrinol. 1989 Oct;3(10):1610–1626. [PubMed]
  • Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. [PubMed]
  • Giguère V, Shago M, Zirngibl R, Tate P, Rossant J, Varmuza S. Identification of a novel isoform of the retinoic acid receptor gamma expressed in the mouse embryo. Mol Cell Biol. 1990 May;10(5):2335–2340. [PMC free article] [PubMed]
  • Glass CK, Holloway JM, Devary OV, Rosenfeld MG. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell. 1988 Jul 29;54(3):313–323. [PubMed]
  • Graupner G, Wills KN, Tzukerman M, Zhang XK, Pfahl M. Dual regulatory role for thyroid-hormone receptors allows control of retinoic-acid receptor activity. Nature. 1989 Aug 24;340(6235):653–656. [PubMed]
  • Green S, Chambon P. Nuclear receptors enhance our understanding of transcription regulation. Trends Genet. 1988 Nov;4(11):309–314. [PubMed]
  • Hamada K, Gleason SL, Levi BZ, Hirschfeld S, Appella E, Ozato K. H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8289–8293. [PMC free article] [PubMed]
  • Hermann T, Hoffmann B, Zhang XK, Tran P, Pfahl M. Heterodimeric receptor complexes determine 3,5,3'-triiodothyronine and retinoid signaling specificities. Mol Endocrinol. 1992 Jul;6(7):1153–1162. [PubMed]
  • Hermann T, Zhang XK, Tzukerman M, Wills KN, Graupner G, Pfahl M. Regulatory functions of a non-ligand-binding thyroid hormone receptor isoform. Cell Regul. 1991 Jul;2(7):565–574. [PMC free article] [PubMed]
  • Husmann M, Lehmann J, Hoffmann B, Hermann T, Tzukerman M, Pfahl M. Antagonism between retinoic acid receptors. Mol Cell Biol. 1991 Aug;11(8):4097–4103. [PMC free article] [PubMed]
  • Kastner P, Krust A, Mendelsohn C, Garnier JM, Zelent A, Leroy P, Staub A, Chambon P. Murine isoforms of retinoic acid receptor gamma with specific patterns of expression. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2700–2704. [PMC free article] [PubMed]
  • Kliewer SA, Umesono K, Heyman RA, Mangelsdorf DJ, Dyck JA, Evans RM. Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1448–1452. [PMC free article] [PubMed]
  • Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature. 1992 Jan 30;355(6359):446–449. [PubMed]
  • Krust A, Kastner P, Petkovich M, Zelent A, Chambon P. A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5310–5314. [PMC free article] [PubMed]
  • Ladias JA, Karathanasis SK. Regulation of the apolipoprotein AI gene by ARP-1, a novel member of the steroid receptor superfamily. Science. 1991 Feb 1;251(4993):561–565. [PubMed]
  • Lehmann JM, Hoffmann B, Pfahl M. Genomic organization of the retinoic acid receptor gamma gene. Nucleic Acids Res. 1991 Feb 11;19(3):573–578. [PMC free article] [PubMed]
  • Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377–395. [PubMed]
  • Leroy P, Krust A, Zelent A, Mendelsohn C, Garnier JM, Kastner P, Dierich A, Chambon P. Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J. 1991 Jan;10(1):59–69. [PMC free article] [PubMed]
  • Luckow B, Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. [PMC free article] [PubMed]
  • Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature. 1991 Aug 8;352(6335):497–505. [PubMed]
  • Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. [PubMed]
  • Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer U, Ong ES, Evans RM. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell. 1991 Aug 9;66(3):555–561. [PubMed]
  • Mendelsohn C, Ruberte E, LeMeur M, Morriss-Kay G, Chambon P. Developmental analysis of the retinoic acid-inducible RAR-beta 2 promoter in transgenic animals. Development. 1991 Nov;113(3):723–734. [PubMed]
  • Miyajima N, Kadowaki Y, Fukushige S, Shimizu S, Semba K, Yamanashi Y, Matsubara K, Toyoshima K, Yamamoto T. Identification of two novel members of erbA superfamily by molecular cloning: the gene products of the two are highly related to each other. Nucleic Acids Res. 1988 Dec 9;16(23):11057–11074. [PMC free article] [PubMed]
  • Mlodzik M, Hiromi Y, Weber U, Goodman CS, Rubin GM. The Drosophila seven-up gene, a member of the steroid receptor gene superfamily, controls photoreceptor cell fates. Cell. 1990 Jan 26;60(2):211–224. [PubMed]
  • Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. [PubMed]
  • Pfahl M, Tzukerman M, Zhang XK, Lehmann JM, Hermann T, Wills KN, Graupner G. Nuclear retinoic acid receptors: cloning, analysis, and function. Methods Enzymol. 1990;189:256–270. [PubMed]
  • Power RF, Lydon JP, Conneely OM, O'Malley BW. Dopamine activation of an orphan of the steroid receptor superfamily. Science. 1991 Jun 14;252(5012):1546–1548. [PubMed]
  • Power RF, Mani SK, Codina J, Conneely OM, O'Malley BW. Dopaminergic and ligand-independent activation of steroid hormone receptors. Science. 1991 Dec 13;254(5038):1636–1639. [PubMed]
  • Rosen ED, O'Donnell AL, Koenig RJ. Protein-protein interactions involving erbA superfamily receptors: through the TRAPdoor. Mol Cell Endocrinol. 1991 Jun;78(1-2):C83–C88. [PubMed]
  • Rottman JN, Widom RL, Nadal-Ginard B, Mahdavi V, Karathanasis SK. A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways. Mol Cell Biol. 1991 Jul;11(7):3814–3820. [PMC free article] [PubMed]
  • Smith WC, Nakshatri H, Leroy P, Rees J, Chambon P. A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. EMBO J. 1991 Aug;10(8):2223–2230. [PMC free article] [PubMed]
  • Sucov HM, Murakami KK, Evans RM. Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5392–5396. [PMC free article] [PubMed]
  • Tsai SY, Sagami I, Wang H, Tsai MJ, O'Malley BW. Interactions between a DNA-binding transcription factor (COUP) and a non-DNA binding factor (S300-II). Cell. 1987 Aug 28;50(5):701–709. [PubMed]
  • Tzukerman M, Zhang XK, Pfahl M. Inhibition of estrogen receptor activity by the tumor promoter 12-O-tetradeconylphorbol-13-acetate: a molecular analysis. Mol Endocrinol. 1991 Dec;5(12):1983–1992. [PubMed]
  • Umesono K, Evans RM. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell. 1989 Jun 30;57(7):1139–1146. [PubMed]
  • Umesono K, Giguere V, Glass CK, Rosenfeld MG, Evans RM. Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature. 1988 Nov 17;336(6196):262–265. [PubMed]
  • Umesono K, Murakami KK, Thompson CC, Evans RM. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991 Jun 28;65(7):1255–1266. [PubMed]
  • Wang LH, Tsai SY, Cook RG, Beattie WG, Tsai MJ, O'Malley BW. COUP transcription factor is a member of the steroid receptor superfamily. Nature. 1989 Jul 13;340(6229):163–166. [PubMed]
  • Widom RL, Rhee M, Karathanasis SK. Repression by ARP-1 sensitizes apolipoprotein AI gene responsiveness to RXR alpha and retinoic acid. Mol Cell Biol. 1992 Aug;12(8):3380–3389. [PMC free article] [PubMed]
  • Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, När AM, Kim SY, Boutin JM, Glass CK, Rosenfeld MG. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell. 1991 Dec 20;67(6):1251–1266. [PubMed]
  • Zelent A, Mendelsohn C, Kastner P, Krust A, Garnier JM, Ruffenach F, Leroy P, Chambon P. Differentially expressed isoforms of the mouse retinoic acid receptor beta generated by usage of two promoters and alternative splicing. EMBO J. 1991 Jan;10(1):71–81. [PMC free article] [PubMed]
  • Zenke M, Muñoz A, Sap J, Vennström B, Beug H. v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA. Cell. 1990 Jun 15;61(6):1035–1049. [PubMed]
  • Zhang XK, Hoffmann B, Tran PB, Graupner G, Pfahl M. Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors. Nature. 1992 Jan 30;355(6359):441–446. [PubMed]
  • Zhang XK, Lehmann J, Hoffmann B, Dawson MI, Cameron J, Graupner G, Hermann T, Tran P, Pfahl M. Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature. 1992 Aug 13;358(6387):587–591. [PubMed]
  • Zhang XK, Tran PB, Pfahl M. DNA binding and dimerization determinants for thyroid hormone receptor alpha and its interaction with a nuclear protein. Mol Endocrinol. 1991 Dec;5(12):1909–1920. [PubMed]
  • Arluke A. The ethical thinking of animal researchers: problems and prospects. New Biol. 1991 Jan;3(1):1–2. [PubMed]

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