Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Jul;16(7):3807–3813. doi: 10.1128/mcb.16.7.3807

Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and repressive states.

I G Schulman 1, H Juguilon 1, R M Evans 1
PMCID: PMC231377  PMID: 8668198

Abstract

Transactivation-defective retinoid X and thyroid hormone receptors have been used to examine mechanisms of hormonal activation. Activation and repression of transcription by retinoid X and thyroid hormone receptors are shown to be mediated by physically distinct and functionally independent regions of the hormone binding domain. Nevertheless, the ability of receptors to respond to hormone requires communication between both functional domains. Deletion of the hormone-dependent transactivation function of the retinoid X receptor, the common subunit of heterodimeric nuclear receptors, significantly impairs hormone-dependent transcription by retinoic acid, thyroid hormone, and vitamin D receptors. The results indicate that receptors do not exist in static off and on conformations but that hormone alters an equilibrium between inactive and active states.

Full Text

The Full Text of this article is available as a PDF (498.3 KB).

Selected References

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

  1. Baniahmad A., Ha I., Reinberg D., Tsai S., Tsai M. J., O'Malley B. W. Interaction of human thyroid hormone receptor beta with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8832–8836. doi: 10.1073/pnas.90.19.8832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Baniahmad A., Leng X., Burris T. P., Tsai S. Y., Tsai M. J., O'Malley B. W. The tau 4 activation domain of the thyroid hormone receptor is required for release of a putative corepressor(s) necessary for transcriptional silencing. Mol Cell Biol. 1995 Jan;15(1):76–86. doi: 10.1128/mcb.15.1.76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barettino D., Vivanco Ruiz M. M., Stunnenberg H. G. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J. 1994 Jul 1;13(13):3039–3049. doi: 10.1002/j.1460-2075.1994.tb06603.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bourguet W., Ruff M., Chambon P., Gronemeyer H., Moras D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature. 1995 Jun 1;375(6530):377–382. doi: 10.1038/375377a0. [DOI] [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. Chen J. D., Evans R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995 Oct 5;377(6548):454–457. doi: 10.1038/377454a0. [DOI] [PubMed] [Google Scholar]
  8. Damm K., Heyman R. A., Umesono K., Evans R. M. Functional inhibition of retinoic acid response by dominant negative retinoic acid receptor mutants. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2989–2993. doi: 10.1073/pnas.90.7.2989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Damm K., Thompson C. C., Evans R. M. Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist. Nature. 1989 Jun 22;339(6226):593–597. doi: 10.1038/339593a0. [DOI] [PubMed] [Google Scholar]
  10. Durand B., Saunders M., Gaudon C., Roy B., Losson R., Chambon P. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. EMBO J. 1994 Nov 15;13(22):5370–5382. doi: 10.1002/j.1460-2075.1994.tb06872.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elble R. A simple and efficient procedure for transformation of yeasts. Biotechniques. 1992 Jul;13(1):18–20. [PubMed] [Google Scholar]
  12. Flynn T. R., Hollenberg A. N., Cohen O., Menke J. B., Usala S. J., Tollin S., Hegarty M. K., Wondisford F. E. A novel C-terminal domain in the thyroid hormone receptor selectively mediates thyroid hormone inhibition. J Biol Chem. 1994 Dec 30;269(52):32713–32716. [PubMed] [Google Scholar]
  13. Fondell J. D., Brunel F., Hisatake K., Roeder R. G. Unliganded thyroid hormone receptor alpha can target TATA-binding protein for transcriptional repression. Mol Cell Biol. 1996 Jan;16(1):281–287. doi: 10.1128/mcb.16.1.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fondell J. D., Roy A. L., Roeder R. G. Unliganded thyroid hormone receptor inhibits formation of a functional preinitiation complex: implications for active repression. Genes Dev. 1993 Jul;7(7B):1400–1410. doi: 10.1101/gad.7.7b.1400. [DOI] [PubMed] [Google Scholar]
  15. Forman B. M., Umesono K., Chen J., Evans R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell. 1995 May 19;81(4):541–550. doi: 10.1016/0092-8674(95)90075-6. [DOI] [PubMed] [Google Scholar]
  16. Hall B. L., Smit-McBride Z., Privalsky M. L. Reconstitution of retinoid X receptor function and combinatorial regulation of other nuclear hormone receptors in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6929–6933. doi: 10.1073/pnas.90.15.6929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Harding H. P., Lazar M. A. The monomer-binding orphan receptor Rev-Erb represses transcription as a dimer on a novel direct repeat. Mol Cell Biol. 1995 Sep;15(9):4791–4802. doi: 10.1128/mcb.15.9.4791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heery D. M., Pierrat B., Gronemeyer H., Chambon P., Losson R. Homo- and heterodimers of the retinoid X receptor (RXR) activated transcription in yeast. Nucleic Acids Res. 1994 Mar 11;22(5):726–731. doi: 10.1093/nar/22.5.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hollenberg A. N., Monden T., Wondisford F. E. Ligand-independent and -dependent functions of thyroid hormone receptor isoforms depend upon their distinct amino termini. J Biol Chem. 1995 Jun 16;270(24):14274–14280. doi: 10.1074/jbc.270.24.14274. [DOI] [PubMed] [Google Scholar]
  20. Hörlein A. J., När A. M., Heinzel T., Torchia J., Gloss B., Kurokawa R., Ryan A., Kamei Y., Söderström M., Glass C. K. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995 Oct 5;377(6548):397–404. doi: 10.1038/377397a0. [DOI] [PubMed] [Google Scholar]
  21. Kastner P., Mark M., Chambon P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell. 1995 Dec 15;83(6):859–869. doi: 10.1016/0092-8674(95)90202-3. [DOI] [PubMed] [Google Scholar]
  22. Kurokawa R., Söderström M., Hörlein A., Halachmi S., Brown M., Rosenfeld M. G., Glass C. K. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature. 1995 Oct 5;377(6548):451–454. doi: 10.1038/377451a0. [DOI] [PubMed] [Google Scholar]
  23. Leblanc B. P., Stunnenberg H. G. 9-cis retinoic acid signaling: changing partners causes some excitement. Genes Dev. 1995 Aug 1;9(15):1811–1816. doi: 10.1101/gad.9.15.1811. [DOI] [PubMed] [Google Scholar]
  24. Lee J. W., Moore D. D., Heyman R. A. A chimeric thyroid hormone receptor constitutively bound to DNA requires retinoid X receptor for hormone-dependent transcriptional activation in yeast. Mol Endocrinol. 1994 Sep;8(9):1245–1252. doi: 10.1210/mend.8.9.7838157. [DOI] [PubMed] [Google Scholar]
  25. Lefebvre P., Gaub M. P., Tahayato A., Rochette-Egly C., Formstecher P. Protein phosphatases 1 and 2A regulate the transcriptional and DNA binding activities of retinoic acid receptors. J Biol Chem. 1995 May 5;270(18):10806–10816. doi: 10.1074/jbc.270.18.10806. [DOI] [PubMed] [Google Scholar]
  26. Leng X., Blanco J., Tsai S. Y., Ozato K., O'Malley B. W., Tsai M. J. Mouse retinoid X receptor contains a separable ligand-binding and transactivation domain in its E region. Mol Cell Biol. 1995 Jan;15(1):255–263. doi: 10.1128/mcb.15.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. MacDonald P. N., Sherman D. R., Dowd D. R., Jefcoat S. C., Jr, DeLisle R. K. The vitamin D receptor interacts with general transcription factor IIB. J Biol Chem. 1995 Mar 3;270(9):4748–4752. doi: 10.1074/jbc.270.9.4748. [DOI] [PubMed] [Google Scholar]
  28. Mak P., Fuernkranz H. A., Ge R., Karathanasis S. K. Retinoid X receptor homodimers function as transcriptional activators in yeast. Gene. 1994 Jul 22;145(1):129–133. doi: 10.1016/0378-1119(94)90335-2. [DOI] [PubMed] [Google Scholar]
  29. Mangelsdorf D. J., Evans R. M. The RXR heterodimers and orphan receptors. Cell. 1995 Dec 15;83(6):841–850. doi: 10.1016/0092-8674(95)90200-7. [DOI] [PubMed] [Google Scholar]
  30. Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., Blumberg B., Kastner P., Mark M., Chambon P. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835–839. doi: 10.1016/0092-8674(95)90199-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Matkovits T., Christakos S. Ligand occupancy is not required for vitamin D receptor and retinoid receptor-mediated transcriptional activation. Mol Endocrinol. 1995 Feb;9(2):232–242. doi: 10.1210/mend.9.2.7776973. [DOI] [PubMed] [Google Scholar]
  32. Privalsky M. L., Sharif M., Yamamoto K. R. The viral erbA oncogene protein, a constitutive repressor in animal cells, is a hormone-regulated activator in yeast. Cell. 1990 Dec 21;63(6):1277–1286. doi: 10.1016/0092-8674(90)90423-c. [DOI] [PubMed] [Google Scholar]
  33. Qi J. S., Desai-Yajnik V., Greene M. E., Raaka B. M., Samuels H. H. The ligand-binding domains of the thyroid hormone/retinoid receptor gene subfamily function in vivo to mediate heterodimerization, gene silencing, and transactivation. Mol Cell Biol. 1995 Mar;15(3):1817–1825. doi: 10.1128/mcb.15.3.1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Renaud J. P., Rochel N., Ruff M., Vivat V., Chambon P., Gronemeyer H., Moras D. Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature. 1995 Dec 14;378(6558):681–689. doi: 10.1038/378681a0. [DOI] [PubMed] [Google Scholar]
  35. Saatcioglu F., Bartunek P., Deng T., Zenke M., Karin M. A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor). Mol Cell Biol. 1993 Jun;13(6):3675–3685. doi: 10.1128/mcb.13.6.3675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schulman I. G., Chakravarti D., Juguilon H., Romo A., Evans R. M. Interactions between the retinoid X receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8288–8292. doi: 10.1073/pnas.92.18.8288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sucov H. M., Murakami K. K., Evans R. M. 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. doi: 10.1073/pnas.87.14.5392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tomura H., Lazar J., Phyillaier M., Nikodem V. M. The N-terminal region (A/B) of rat thyroid hormone receptors alpha 1, beta 1, but not beta 2 contains a strong thyroid hormone-dependent transactivation function. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5600–5604. doi: 10.1073/pnas.92.12.5600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tong G. X., Tanen M. R., Bagchi M. K. Ligand modulates the interaction of thyroid hormone receptor beta with the basal transcription machinery. J Biol Chem. 1995 May 5;270(18):10601–10611. doi: 10.1074/jbc.270.18.10601. [DOI] [PubMed] [Google Scholar]
  40. Umesono K., Murakami K. K., Thompson C. C., Evans R. M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991 Jun 28;65(7):1255–1266. doi: 10.1016/0092-8674(91)90020-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Valcárcel R., Holz H., Jiménez C. G., Barettino D., Stunnenberg H. G. Retinoid-dependent in vitro transcription mediated by the RXR/RAR heterodimer. Genes Dev. 1994 Dec 15;8(24):3068–3079. doi: 10.1101/gad.8.24.3068. [DOI] [PubMed] [Google Scholar]
  42. Wagner R. L., Apriletti J. W., McGrath M. E., West B. L., Baxter J. D., Fletterick R. J. A structural role for hormone in the thyroid hormone receptor. Nature. 1995 Dec 14;378(6558):690–697. doi: 10.1038/378690a0. [DOI] [PubMed] [Google Scholar]
  43. 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. doi: 10.1016/0092-8674(90)90068-p. [DOI] [PubMed] [Google Scholar]
  44. Zhang X. K., Salbert G., Lee M. O., Pfahl M. Mutations that alter ligand-induced switches and dimerization activities in the retinoid X receptor. Mol Cell Biol. 1994 Jun;14(6):4311–4323. doi: 10.1128/mcb.14.6.4311. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES