Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1995 Oct 25;23(20):4143–4150. doi: 10.1093/nar/23.20.4143

COUP-TF II homodimers are formed in preference to heterodimers with RXR alpha or TR beta in intact cells.

A J Butler 1, M G Parker 1
PMCID: PMC307356  PMID: 7479078

Abstract

Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) represses the transcriptional activity of a number of nuclear receptors, including that of retinoid receptors (RAR and RXR) and thyroid hormone receptors (TR). Since COUP-TF is capable of binding to DNA in vitro either as a homodimer or as a heterodimer with RXR or TR, it has not been possible to distinguish between competitive DNA binding and heterodimer formation as a mechanism to account for the repression. Using a two-hybrid system we have investigated the dimerisation properties of COUP-TF II in intact cells. In conditions where COUP-TF II homodimers and RXR alpha-RAR alpha heterodimers were formed we were unable to detect the formation of heterodimers between COUP-TF II and RXR alpha. Moreover, we were unable to detect an interaction between COUP-TF II and RXR alpha on DNA. Similarly COUP-TF II homodimers and RXR alpha-TR beta heterodimers are favoured over COUP-TF II-TR beta heterodimers. We conclude that the formation of functionally inactive heterodimers is unlikely to represent a general mechanism by which COUP-TF represses the transcriptional activity of nuclear receptors and favour a model in which repression is mediated by COUP-TF homodimers competing for binding to DNA.

Full text

PDF
4143

Images in this article

4145Image
on p.4145
4146Image
on p.4146

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersson M. L., Nordström K., Demczuk S., Harbers M., Vennström B. Thyroid hormone alters the DNA binding properties of chicken thyroid hormone receptors alpha and beta. Nucleic Acids Res. 1992 Sep 25;20(18):4803–4810. doi: 10.1093/nar/20.18.4803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bakke M., Lund J. Mutually exclusive interactions of two nuclear orphan receptors determine activity of a cyclic adenosine 3',5'-monophosphate-responsive sequence in the bovine CYP17 gene. Mol Endocrinol. 1995 Mar;9(3):327–339. doi: 10.1210/mend.9.3.7776979. [DOI] [PubMed] [Google Scholar]
  3. Baniahmad A., Köhne A. C., Renkawitz R. A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor. EMBO J. 1992 Mar;11(3):1015–1023. doi: 10.1002/j.1460-2075.1992.tb05140.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berrodin T. J., Marks M. S., Ozato K., Linney E., Lazar M. A. Heterodimerization among thyroid hormone receptor, retinoic acid receptor, retinoid X receptor, chicken ovalbumin upstream promoter transcription factor, and an endogenous liver protein. Mol Endocrinol. 1992 Sep;6(9):1468–1478. doi: 10.1210/mend.6.9.1331778. [DOI] [PubMed] [Google Scholar]
  5. Carter M. E., Gulick T., Moore D. D., Kelly D. P. A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs. Mol Cell Biol. 1994 Jul;14(7):4360–4372. doi: 10.1128/mcb.14.7.4360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Casanova J., Helmer E., Selmi-Ruby S., Qi J. S., Au-Fliegner M., Desai-Yajnik V., Koudinova N., Yarm F., Raaka B. M., Samuels H. H. Functional evidence for ligand-dependent dissociation of thyroid hormone and retinoic acid receptors from an inhibitory cellular factor. Mol Cell Biol. 1994 Sep;14(9):5756–5765. doi: 10.1128/mcb.14.9.5756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chan S. M., Xu N., Niemeyer C. C., Bone J. R., Flytzanis C. N. SpCOUP-TF: a sea urchin member of the steroid/thyroid hormone receptor family. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10568–10572. doi: 10.1073/pnas.89.22.10568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chang C., Kokontis J., Liao S. S., Chang Y. Isolation and characterization of human TR3 receptor: a member of steroid receptor superfamily. J Steroid Biochem. 1989;34(1-6):391–395. doi: 10.1016/0022-4731(89)90114-3. [DOI] [PubMed] [Google Scholar]
  9. Cooney A. J., Leng X., Tsai S. Y., O'Malley B. W., Tsai M. J. 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. 1993 Feb 25;268(6):4152–4160. [PubMed] [Google Scholar]
  10. Cooney A. J., Tsai S. Y., O'Malley B. W., Tsai M. J. 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. 1992 Sep;12(9):4153–4163. doi: 10.1128/mcb.12.9.4153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Danielian P. S., White R., Hoare S. A., Fawell S. E., Parker M. G. Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen. Mol Endocrinol. 1993 Feb;7(2):232–240. doi: 10.1210/mend.7.2.8469236. [DOI] [PubMed] [Google Scholar]
  12. Dauvois S., Danielian P. S., White R., Parker M. G. Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4037–4041. doi: 10.1073/pnas.89.9.4037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fjose A., Nornes S., Weber U., Mlodzik M. Functional conservation of vertebrate seven-up related genes in neurogenesis and eye development. EMBO J. 1993 Apr;12(4):1403–1414. doi: 10.1002/j.1460-2075.1993.tb05784.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Galson D. L., Tsuchiya T., Tendler D. S., Huang L. E., Ren Y., Ogura T., Bunn H. F. The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol. 1995 Apr;15(4):2135–2144. doi: 10.1128/mcb.15.4.2135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ge R., Rhee M., Malik S., Karathanasis S. K. Transcriptional repression of apolipoprotein AI gene expression by orphan receptor ARP-1. J Biol Chem. 1994 May 6;269(18):13185–13192. [PubMed] [Google Scholar]
  16. Kadowaki Y., Toyoshima K., Yamamoto T. Ear3/COUP-TF binds most tightly to a response element with tandem repeat separated by one nucleotide. Biochem Biophys Res Commun. 1992 Mar 16;183(2):492–498. doi: 10.1016/0006-291x(92)90509-j. [DOI] [PubMed] [Google Scholar]
  17. Kimura A., Nishiyori A., Murakami T., Tsukamoto T., Hata S., Osumi T., Okamura R., Mori M., Takiguchi M. Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) represses transcription from the promoter of the gene for ornithine transcarbamylase in a manner antagonistic to hepatocyte nuclear factor-4 (HNF-4). J Biol Chem. 1993 May 25;268(15):11125–11133. [PubMed] [Google Scholar]
  18. Kliewer S. A., Umesono K., Heyman R. A., Mangelsdorf D. J., Dyck J. A., Evans R. M. Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1448–1452. doi: 10.1073/pnas.89.4.1448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ladias J. A., Hadzopoulou-Cladaras M., Kardassis D., Cardot P., Cheng J., Zannis V., Cladaras C. Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J Biol Chem. 1992 Aug 5;267(22):15849–15860. [PubMed] [Google Scholar]
  20. Ladias J. A., Karathanasis S. K. 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. doi: 10.1126/science.1899293. [DOI] [PubMed] [Google Scholar]
  21. Laudet V., Hänni C., Coll J., Catzeflis F., Stéhelin D. Evolution of the nuclear receptor gene superfamily. EMBO J. 1992 Mar;11(3):1003–1013. doi: 10.1002/j.1460-2075.1992.tb05139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lillie J. W., Green M. R. Transcription activation by the adenovirus E1a protein. Nature. 1989 Mar 2;338(6210):39–44. doi: 10.1038/338039a0. [DOI] [PubMed] [Google Scholar]
  23. Liu Y., Yang N., Teng C. T. COUP-TF acts as a competitive repressor for estrogen receptor-mediated activation of the mouse lactoferrin gene. Mol Cell Biol. 1993 Mar;13(3):1836–1846. doi: 10.1128/mcb.13.3.1836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lu X. P., Salbert G., Pfahl M. An evolutionary conserved COUP-TF binding element in a neural-specific gene and COUP-TF expression patterns support a major role for COUP-TF in neural development. Mol Endocrinol. 1994 Dec;8(12):1774–1788. doi: 10.1210/mend.8.12.7708064. [DOI] [PubMed] [Google Scholar]
  25. Lutz B., Kuratani S., Cooney A. J., Wawersik S., Tsai S. Y., Eichele G., Tsai M. J. Developmental regulation of the orphan receptor COUP-TF II gene in spinal motor neurons. Development. 1994 Jan;120(1):25–36. doi: 10.1242/dev.120.1.25. [DOI] [PubMed] [Google Scholar]
  26. Matharu P. J., Sweeney G. E. Cloning and sequencing of a COUP transcription factor gene expressed in Xenopus embryos. Biochim Biophys Acta. 1992 Feb 11;1129(3):331–334. doi: 10.1016/0167-4781(92)90512-x. [DOI] [PubMed] [Google Scholar]
  27. Mietus-Snyder M., Sladek F. M., Ginsburg G. S., Kuo C. F., Ladias J. A., Darnell J. E., Jr, Karathanasis S. K. Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol. 1992 Apr;12(4):1708–1718. doi: 10.1128/mcb.12.4.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miyata K. S., Zhang B., Marcus S. L., Capone J. P., Rachubinski R. A. Chicken ovalbumin upstream promoter transcription factor (COUP-TF) binds to a peroxisome proliferator-responsive element and antagonizes peroxisome proliferator-mediated signaling. J Biol Chem. 1993 Sep 15;268(26):19169–19172. [PubMed] [Google Scholar]
  29. Mlodzik M., Hiromi Y., Weber U., Goodman C. S., Rubin G. M. 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. doi: 10.1016/0092-8674(90)90737-y. [DOI] [PubMed] [Google Scholar]
  30. Nagpal S., Friant S., Nakshatri H., Chambon P. RARs and RXRs: evidence for two autonomous transactivation functions (AF-1 and AF-2) and heterodimerization in vivo. EMBO J. 1993 Jun;12(6):2349–2360. doi: 10.1002/j.1460-2075.1993.tb05889.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Perlmann T., Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev. 1995 Apr 1;9(7):769–782. doi: 10.1101/gad.9.7.769. [DOI] [PubMed] [Google Scholar]
  32. Power R. F., Lydon J. P., Conneely O. M., O'Malley B. W. Dopamine activation of an orphan of the steroid receptor superfamily. Science. 1991 Jun 14;252(5012):1546–1548. doi: 10.1126/science.2047861. [DOI] [PubMed] [Google Scholar]
  33. Qiu Y., Cooney A. J., Kuratani S., DeMayo F. J., Tsai S. Y., Tsai M. J. 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 U S A. 1994 May 10;91(10):4451–4455. doi: 10.1073/pnas.91.10.4451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sadowski I., Ptashne M. A vector for expressing GAL4(1-147) fusions in mammalian cells. Nucleic Acids Res. 1989 Sep 25;17(18):7539–7539. doi: 10.1093/nar/17.18.7539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sleigh M. J. A nonchromatographic assay for expression of the chloramphenicol acetyltransferase gene in eucaryotic cells. Anal Biochem. 1986 Jul;156(1):251–256. doi: 10.1016/0003-2697(86)90180-6. [DOI] [PubMed] [Google Scholar]
  36. Tone Y., Collingwood T. N., Adams M., Chatterjee V. K. Functional analysis of a transactivation domain in the thyroid hormone beta receptor. J Biol Chem. 1994 Dec 9;269(49):31157–31161. [PubMed] [Google Scholar]
  37. Tran P., Zhang X. K., Salbert G., Hermann T., Lehmann J. M., Pfahl M. COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol Cell Biol. 1992 Oct;12(10):4666–4676. doi: 10.1128/mcb.12.10.4666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wang L. H., Ing N. H., Tsai S. Y., O'Malley B. W., Tsai M. J. The COUP-TFs compose a family of functionally related transcription factors. Gene Expr. 1991;1(3):207–216. [PMC free article] [PubMed] [Google Scholar]
  39. Wang L. H., Tsai S. Y., Cook R. G., Beattie W. G., Tsai M. J., O'Malley B. W. COUP transcription factor is a member of the steroid receptor superfamily. Nature. 1989 Jul 13;340(6229):163–166. doi: 10.1038/340163a0. [DOI] [PubMed] [Google Scholar]
  40. Wehrenberg U., Ivell R., Walther N. The COUP transcription factor (COUP-TF) is directly involved in the regulation of oxytocin gene expression in luteinizing bovine granulosa cells. Biochem Biophys Res Commun. 1992 Nov 30;189(1):496–503. doi: 10.1016/0006-291x(92)91585-e. [DOI] [PubMed] [Google Scholar]
  41. Widom R. L., Rhee M., Karathanasis S. K. Repression by ARP-1 sensitizes apolipoprotein AI gene responsiveness to RXR alpha and retinoic acid. Mol Cell Biol. 1992 Aug;12(8):3380–3389. doi: 10.1128/mcb.12.8.3380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yen P. M., Darling D. S., Carter R. L., Forgione M., Umeda P. K., Chin W. W. Triiodothyronine (T3) decreases binding to DNA by T3-receptor homodimers but not receptor-auxiliary protein heterodimers. J Biol Chem. 1992 Feb 25;267(6):3565–3568. [PubMed] [Google Scholar]
  43. Yen P. M., Sugawara A., Chin W. W. Triiodothyronine (T3) differentially affects T3-receptor/retinoic acid receptor and T3-receptor/retinoid X receptor heterodimer binding to DNA. J Biol Chem. 1992 Nov 15;267(32):23248–23252. [PubMed] [Google Scholar]
  44. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES