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. 1997 Dec;17(12):6887–6897. doi: 10.1128/mcb.17.12.6887

Differential recognition of liganded and unliganded thyroid hormone receptor by retinoid X receptor regulates transcriptional repression.

J Zhang 1, I Zamir 1, M A Lazar 1
PMCID: PMC232545  PMID: 9372920

Abstract

Thyroid hormone receptor (TR) functions as part of multiprotein complexes that also include retinoid X receptor (RXR) and transcriptional coregulators. We have found that both the TR CoR box and ninth heptad are required for RXR interaction and in turn for interaction with corepressor proteins N-CoR and SMRT. Remarkably, the recruitment of RXR to repression-defective CoR box and ninth-heptad mutants via a heterologous dimerization interface restores both corepressor interaction and repression. The addition of thyroid hormone obviates the CoR box requirement for RXR interaction, provided that the AF2 activation helix at the C terminus of TR is intact. These results indicate that RXR differentially recognizes the unliganded and liganded conformations of TR and that these differences appear to play a major role in the recruitment of corepressors to TR-RXR heterodimers.

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Selected References

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  1. Au-Fliegner M., Helmer E., Casanova J., Raaka B. M., Samuels H. H. The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation. Mol Cell Biol. 1993 Sep;13(9):5725–5737. doi: 10.1128/mcb.13.9.5725. [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., Bugge T. H., Bartunek P., Vivanco Ruiz M. D., Sonntag-Buck V., Beug H., Zenke M., Stunnenberg H. G. Unliganded T3R, but not its oncogenic variant, v-erbA, suppresses RAR-dependent transactivation by titrating out RXR. EMBO J. 1993 Apr;12(4):1343–1354. doi: 10.1002/j.1460-2075.1993.tb05779.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. Bugge T. H., Pohl J., Lonnoy O., Stunnenberg H. G. RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors. EMBO J. 1992 Apr;11(4):1409–1418. doi: 10.1002/j.1460-2075.1992.tb05186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carey M., Kakidani H., Leatherwood J., Mostashari F., Ptashne M. An amino-terminal fragment of GAL4 binds DNA as a dimer. J Mol Biol. 1989 Oct 5;209(3):423–432. doi: 10.1016/0022-2836(89)90007-7. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Chen H. W., Privalsky M. L. The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms. Mol Cell Biol. 1993 Oct;13(10):5970–5980. doi: 10.1128/mcb.13.10.5970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Collingwood T. N., Butler A., Tone Y., Clifton-Bligh R. J., Parker M. G., Chatterjee V. K. Thyroid hormone-mediated enhancement of heterodimer formation between thyroid hormone receptor beta and retinoid X receptor. J Biol Chem. 1997 May 16;272(20):13060–13065. doi: 10.1074/jbc.272.20.13060. [DOI] [PubMed] [Google Scholar]
  12. Collingwood T. N., Rajanayagam O., Adams M., Wagner R., Cavaillès V., Kalkhoven E., Matthews C., Nystrom E., Stenlof K., Lindstedt G. A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):248–253. doi: 10.1073/pnas.94.1.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. Hasumura S., Kitagawa S., Pastan I., Cheng S. Y. Solubilization and characterization of a membrane 3, 3', 5-triiodo-L-thyronine binding protein from rat pituitary tumor GH3 cells. Biochem Biophys Res Commun. 1985 Dec 31;133(3):837–843. doi: 10.1016/0006-291x(85)91210-0. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Katz D., Lazar M. A. Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes. J Biol Chem. 1993 Oct 5;268(28):20904–20910. [PubMed] [Google Scholar]
  19. Kliewer S. A., Umesono K., Mangelsdorf D. J., Evans R. M. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature. 1992 Jan 30;355(6359):446–449. doi: 10.1038/355446a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Kurokawa R., Yu V. C., När A., Kyakumoto S., Han Z., Silverman S., Rosenfeld M. G., Glass C. K. Differential orientations of the DNA-binding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers. Genes Dev. 1993 Jul;7(7B):1423–1435. doi: 10.1101/gad.7.7b.1423. [DOI] [PubMed] [Google Scholar]
  22. Lazar M. A., Berrodin T. J., Harding H. P. Differential DNA binding by monomeric, homodimeric, and potentially heteromeric forms of the thyroid hormone receptor. Mol Cell Biol. 1991 Oct;11(10):5005–5015. doi: 10.1128/mcb.11.10.5005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leid M., Kastner P., Lyons R., Nakshatri H., Saunders M., Zacharewski T., Chen J. Y., Staub A., Garnier J. M., Mader S. 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. doi: 10.1016/0092-8674(92)90478-u. [DOI] [PubMed] [Google Scholar]
  24. Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
  25. Marks M. S., Hallenbeck P. L., Nagata T., Segars J. H., Appella E., Nikodem V. M., Ozato K. H-2RIIBP (RXR beta) heterodimerization provides a mechanism for combinatorial diversity in the regulation of retinoic acid and thyroid hormone responsive genes. EMBO J. 1992 Apr;11(4):1419–1435. doi: 10.1002/j.1460-2075.1992.tb05187.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Martin B., Renkawitz R., Muller M. Two silencing sub-domains of v-erbA synergize with each other, but not with RXR. Nucleic Acids Res. 1994 Nov 25;22(23):4898–4905. doi: 10.1093/nar/22.23.4898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McDonnell D. P., Dana S. L., Hoener P. A., Lieberman B. A., Imhof M. O., Stein R. B. Cellular mechanisms which distinguish between hormone- and antihormone-activated estrogen receptor. Ann N Y Acad Sci. 1995 Jun 12;761:121–137. doi: 10.1111/j.1749-6632.1995.tb31374.x. [DOI] [PubMed] [Google Scholar]
  28. Nagaya T., Jameson J. L. Thyroid hormone receptor dimerization is required for dominant negative inhibition by mutations that cause thyroid hormone resistance. J Biol Chem. 1993 Jul 25;268(21):15766–15771. [PubMed] [Google Scholar]
  29. Perlmann T., Rangarajan P. N., Umesono K., Evans R. M. Determinants for selective RAR and TR recognition of direct repeat HREs. Genes Dev. 1993 Jul;7(7B):1411–1422. doi: 10.1101/gad.7.7b.1411. [DOI] [PubMed] [Google Scholar]
  30. Rastinejad F., Perlmann T., Evans R. M., Sigler P. B. Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature. 1995 May 18;375(6528):203–211. doi: 10.1038/375203a0. [DOI] [PubMed] [Google Scholar]
  31. Reginato M. J., Zhang J., Lazar M. A. DNA-independent and DNA-dependent mechanisms regulate the differential heterodimerization of the isoforms of the thyroid hormone receptor with retinoid X receptor. J Biol Chem. 1996 Nov 8;271(45):28199–28205. doi: 10.1074/jbc.271.45.28199. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Rentoumis A., Chatterjee V. K., Madison L. D., Datta S., Gallagher G. D., Degroot L. J., Jameson J. L. Negative and positive transcriptional regulation by thyroid hormone receptor isoforms. Mol Endocrinol. 1990 Oct;4(10):1522–1531. doi: 10.1210/mend-4-10-1522. [DOI] [PubMed] [Google Scholar]
  34. Sande S., Privalsky M. L. Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors. Mol Endocrinol. 1996 Jul;10(7):813–825. doi: 10.1210/mend.10.7.8813722. [DOI] [PubMed] [Google Scholar]
  35. Schulman I. G., Juguilon H., Evans R. M. Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and repressive states. Mol Cell Biol. 1996 Jul;16(7):3807–3813. doi: 10.1128/mcb.16.7.3807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schulman I. G., Li C., Schwabe J. W., Evans R. M. The phantom ligand effect: allosteric control of transcription by the retinoid X receptor. Genes Dev. 1997 Feb 1;11(3):299–308. doi: 10.1101/gad.11.3.299. [DOI] [PubMed] [Google Scholar]
  37. Seol W., Mahon M. J., Lee Y. K., Moore D. D. Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR. Mol Endocrinol. 1996 Dec;10(12):1646–1655. doi: 10.1210/mend.10.12.8961273. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. 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]
  40. 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]
  41. Willy P. J., Mangelsdorf D. J. Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR. Genes Dev. 1997 Feb 1;11(3):289–298. doi: 10.1101/gad.11.3.289. [DOI] [PubMed] [Google Scholar]
  42. Yang Y. Z., Burgos-Trinidad M., Wu Y., Koenig R. J. Thyroid hormone receptor variant alpha2. Role of the ninth heptad in dna binding, heterodimerization with retinoid X receptors, and dominant negative activity. J Biol Chem. 1996 Nov 8;271(45):28235–28242. doi: 10.1074/jbc.271.45.28235. [DOI] [PubMed] [Google Scholar]
  43. Yoh S. M., Chatterjee V. K., Privalsky M. L. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol Endocrinol. 1997 Apr;11(4):470–480. doi: 10.1210/mend.11.4.9914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yu V. C., Delsert C., Andersen B., Holloway J. M., Devary O. V., När A. M., Kim S. Y., Boutin J. M., Glass C. K., Rosenfeld M. G. 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. doi: 10.1016/0092-8674(91)90301-e. [DOI] [PubMed] [Google Scholar]
  45. Zamir I., Harding H. P., Atkins G. B., Hörlein A., Glass C. K., Rosenfeld M. G., Lazar M. A. A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. Mol Cell Biol. 1996 Oct;16(10):5458–5465. doi: 10.1128/mcb.16.10.5458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zamir I., Zhang J., Lazar M. A. Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes Dev. 1997 Apr 1;11(7):835–846. doi: 10.1101/gad.11.7.835. [DOI] [PubMed] [Google Scholar]
  47. Zhang X. K., Hoffmann B., Tran P. B., 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. doi: 10.1038/355441a0. [DOI] [PubMed] [Google Scholar]

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