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. 1995 Apr 25;23(8):1311–1318. doi: 10.1093/nar/23.8.1311

Identification of a regulatory function for an orphan receptor in muscle: COUP-TF II affects the expression of the myoD gene family during myogenesis.

G E Muscat 1, S Rea 1, M Downes 1
PMCID: PMC306855  PMID: 7753622

Abstract

COUP-TF II is an 'orphan steroid receptor' that binds a wide variety of AGGTCA repeats and represses thyroid hormone (T3) and retinoid dependent trans-activation; however, very little is known of its functional and/or developmental role during mammalian cell differentiation. T3 and retinoids have been demonstrated to promote terminal muscle differentiation via activation of the muscle specific myoD gene family (myoD, myogenin, myf-5 and MRF-4). The myoD gene family can direct the fate of mesodermal cell lineages, repress proliferation, activate differentiation and the contractile phenotype. Hence, we investigated the expression and functional role of COUP-TF II during muscle differentiation. Proliferating C2C12 myoblasts expressed COUP-TF II mRNA which was repressed when cells were induced to differentiate into post-mitotic multinucleated myotubes by serum withdrawal. Concomitant with the decrease of COUP-TF II mRNA was the appearance of muscle specific mRNAs (e.g. myogenin, alpha-actin). We show that Escherichia coli expressed full length and truncated COUP-TF II bound in a sequence specific manner to the T3 response elements (TREs) in the myoD and myogenin regulatory HLH genes [Olson (1992) Dev. Biol. 154, 261-272]; and the TRE in the skeletal alpha-actin contractile protein gene. COUP-TF II diminished the homodimeric binding of the thyroid hormone receptor and the heterodimeric binding of thyroid hormone and retinoid X receptor complexes to these TREs. Constitutive over-expression of COUP-TF II cDNA in mouse C2C12 myogenic cells suppressed the levels of myoD mRNA and blocked the induction of myogenin mRNA, whereas constitutive expression of anti-sense COUP-TF II cDNA significantly increased the steady state levels of myoD mRNA and hyper-induced myogenin mRNA. These studies demonstrate for the first time (i) that COUP-TF II, functions as a physiologically relevant antagonistic regulator of myogenesis via direct effects on the myoD gene family and (ii) direct evidence for the developmental role of COUP-TF II during mammalian cell differentiation.

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Selected References

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

  1. Bains W., Ponte P., Blau H., Kedes L. Cardiac actin is the major actin gene product in skeletal muscle cell differentiation in vitro. Mol Cell Biol. 1984 Aug;4(8):1449–1453. doi: 10.1128/mcb.4.8.1449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benezra R., Davis R. L., Lockshon D., Turner D. L., Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 1990 Apr 6;61(1):49–59. doi: 10.1016/0092-8674(90)90214-y. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. 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]
  6. Davis R. L., Weintraub H., Lassar A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987 Dec 24;51(6):987–1000. doi: 10.1016/0092-8674(87)90585-x. [DOI] [PubMed] [Google Scholar]
  7. Downes M., Griggs R., Atkins A., Olson E. N., Muscat G. E. Identification of a thyroid hormone response element in the mouse myogenin gene: characterization of the thyroid hormone and retinoid X receptor heterodimeric binding site. Cell Growth Differ. 1993 Nov;4(11):901–909. [PubMed] [Google Scholar]
  8. Edmondson D. G., Olson E. N. A gene with homology to the myc similarity region of MyoD1 is expressed during myogenesis and is sufficient to activate the muscle differentiation program. Genes Dev. 1989 May;3(5):628–640. doi: 10.1101/gad.3.5.628. [DOI] [PubMed] [Google Scholar]
  9. Green S. Nuclear hormone receptors. Promiscuous liaisons. Nature. 1993 Feb 18;361(6413):590–591. doi: 10.1038/361590a0. [DOI] [PubMed] [Google Scholar]
  10. Hasty P., Bradley A., Morris J. H., Edmondson D. G., Venuti J. M., Olson E. N., Klein W. H. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature. 1993 Aug 5;364(6437):501–506. doi: 10.1038/364501a0. [DOI] [PubMed] [Google Scholar]
  11. Ing N. H., Beekman J. M., Tsai S. Y., Tsai M. J., O'Malley B. W. Members of the steroid hormone receptor superfamily interact with TFIIB (S300-II). J Biol Chem. 1992 Sep 5;267(25):17617–17623. [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. 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]
  15. Mangelsdorf D. J., Umesono K., Kliewer S. A., Borgmeyer U., Ong E. S., Evans R. M. 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. doi: 10.1016/0092-8674(81)90018-0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Muscat G. E., Gobius K., Emery J. Proliferin, a prolactin/growth hormone-like peptide represses myogenic-specific transcription by the suppression of an essential serum response factor-like DNA-binding activity. Mol Endocrinol. 1991 Jun;5(6):802–814. doi: 10.1210/mend-5-6-802. [DOI] [PubMed] [Google Scholar]
  18. Muscat G. E., Griggs R., Downes M., Emery J. Characterization of the thyroid hormone response element in the skeletal alpha-actin gene: negative regulation of T3 receptor binding by the retinoid X receptor. Cell Growth Differ. 1993 Apr;4(4):269–279. [PubMed] [Google Scholar]
  19. Muscat G. E., Kedes L. Multiple 5'-flanking regions of the human alpha-skeletal actin gene synergistically modulate muscle-specific expression. Mol Cell Biol. 1987 Nov;7(11):4089–4099. doi: 10.1128/mcb.7.11.4089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Muscat G. E., Mynett-Johnson L., Dowhan D., Downes M., Griggs R. Activation of myoD gene transcription by 3,5,3'-triiodo-L-thyronine: a direct role for the thyroid hormone and retinoid X receptors. Nucleic Acids Res. 1994 Feb 25;22(4):583–591. doi: 10.1093/nar/22.4.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. O'Malley B. W., Conneely O. M. Orphan receptors: in search of a unifying hypothesis for activation. Mol Endocrinol. 1992 Sep;6(9):1359–1361. doi: 10.1210/mend.6.9.1331771. [DOI] [PubMed] [Google Scholar]
  22. Olson E. N. Interplay between proliferation and differentiation within the myogenic lineage. Dev Biol. 1992 Dec;154(2):261–272. doi: 10.1016/0012-1606(92)90066-p. [DOI] [PubMed] [Google Scholar]
  23. Olson E. N. Signal transduction pathways that regulate skeletal muscle gene expression. Mol Endocrinol. 1993 Nov;7(11):1369–1378. doi: 10.1210/mend.7.11.8114752. [DOI] [PubMed] [Google Scholar]
  24. Power R. F., Conneely O. M., O'Malley B. W. New insights into activation of the steroid hormone receptor superfamily. Trends Pharmacol Sci. 1992 Aug;13(8):318–323. doi: 10.1016/0165-6147(92)90099-r. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Rudnicki M. A., Schnegelsberg P. N., Stead R. H., Braun T., Arnold H. H., Jaenisch R. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 1993 Dec 31;75(7):1351–1359. doi: 10.1016/0092-8674(93)90621-v. [DOI] [PubMed] [Google Scholar]
  27. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Tsai S. Y., Sagami I., Wang H., Tsai M. J., O'Malley B. W. Interactions between a DNA-binding transcription factor (COUP) and a non-DNA binding factor (S300-II). Cell. 1987 Aug 28;50(5):701–709. doi: 10.1016/0092-8674(87)90328-x. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. 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]

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