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. 2001 Dec 1;360(Pt 2):387–393. doi: 10.1042/0264-6021:3600387

Single thyroid hormone receptor monomers are competent for co-activator-mediated transactivation.

M Quack 1, C Carlberg 1
PMCID: PMC1222239  PMID: 11716767

Abstract

Thyroid hormone receptor (T(3)R) belongs to the superfamily of nuclear receptors containing highly related transcription factors that transform an incoming signal in the form of a lipophilic hormone into an activation of the basal transcriptional machinery. Like many other nuclear receptors, T(3)R acts preferentially as a heterodimer with retinoid X receptor (RXR) but it also has the unique property of binding as a monomer to DNA. This study demonstrates that T(3)R monomers bind preferentially to AGGTCA binding motifs and are able to co-exist with T(3)R-RXR heterodimers in the presence of limiting amounts of RXR. DNA-bound T(3)R monomers efficiently contact all three members of the p160 co-activator family, which in turn boost T(3)R monomer-mediated transactivation. In solution T(3)R monomers take only one agonistic conformation (c2(LPD)), whereas bound to DNA they also stabilize, like T(3)R-RXR heterodimers, a second agonistic conformation (c1(LPD)). Conformation c2(LPD) seems to be of lower ligand sensitivity (10 nM), whereas, both in T(3)R-RXR heterodimers and in DNA-bound T(3)R monomers, c1(LPD) is already activated at a ligand concentration of 1 nM. Taken together, these results suggest that single T(3)R monomers are fully competent for ligand-induced transactivation and that their role in gene regulation by thyroid hormone might have been underestimated.

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Selected References

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  1. Blumberg B., Evans R. M. Orphan nuclear receptors--new ligands and new possibilities. Genes Dev. 1998 Oct 15;12(20):3149–3155. doi: 10.1101/gad.12.20.3149. [DOI] [PubMed] [Google Scholar]
  2. Carlberg C. Mechanisms of nuclear signalling by vitamin D3. Interplay with retinoid and thyroid hormone signalling. Eur J Biochem. 1995 Aug 1;231(3):517–527. [PubMed] [Google Scholar]
  3. Carlberg C., Quack M., Herdick M., Bury Y., Polly P., Toell A. Central role of VDR conformations for understanding selective actions of vitamin D(3) analogues. Steroids. 2001 Mar-May;66(3-5):213–221. doi: 10.1016/s0039-128x(00)00150-1. [DOI] [PubMed] [Google Scholar]
  4. Feng W., Ribeiro R. C., Wagner R. L., Nguyen H., Apriletti J. W., Fletterick R. J., Baxter J. D., Kushner P. J., West B. L. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science. 1998 Jun 12;280(5370):1747–1749. doi: 10.1126/science.280.5370.1747. [DOI] [PubMed] [Google Scholar]
  5. Freedman L. P. Increasing the complexity of coactivation in nuclear receptor signaling. Cell. 1999 Apr 2;97(1):5–8. doi: 10.1016/s0092-8674(00)80708-4. [DOI] [PubMed] [Google Scholar]
  6. Giguère V. Orphan nuclear receptors: from gene to function. Endocr Rev. 1999 Oct;20(5):689–725. doi: 10.1210/edrv.20.5.0378. [DOI] [PubMed] [Google Scholar]
  7. Glass C. K. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocr Rev. 1994 Jun;15(3):391–407. doi: 10.1210/edrv-15-3-391. [DOI] [PubMed] [Google Scholar]
  8. Herdick M., Bury Y., Quack M., Uskokovic M. R., Polly P., Carlberg C. Response element and coactivator-mediated conformational change of the vitamin D(3) receptor permits sensitive interaction with agonists. Mol Pharmacol. 2000 Jun;57(6):1206–1217. [PubMed] [Google Scholar]
  9. 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]
  10. Lehmann J. M., Zhang X. K., Graupner G., Lee M. O., Hermann T., Hoffmann B., Pfahl M. Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching. Mol Cell Biol. 1993 Dec;13(12):7698–7707. doi: 10.1128/mcb.13.12.7698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Levin A. A., Sturzenbecker L. J., Kazmer S., Bosakowski T., Huselton C., Allenby G., Speck J., Kratzeisen C., Rosenberger M., Lovey A. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992 Jan 23;355(6358):359–361. doi: 10.1038/355359a0. [DOI] [PubMed] [Google Scholar]
  12. Li H., Gomes P. J., Chen J. D. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8479–8484. doi: 10.1073/pnas.94.16.8479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Moras D., Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol. 1998 Jun;10(3):384–391. doi: 10.1016/s0955-0674(98)80015-x. [DOI] [PubMed] [Google Scholar]
  16. Oñate S. A., Tsai S. Y., Tsai M. J., O'Malley B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354–1357. doi: 10.1126/science.270.5240.1354. [DOI] [PubMed] [Google Scholar]
  17. Quack M., Carlberg C. Ligand-triggered stabilization of vitamin D receptor/retinoid X receptor heterodimer conformations on DR4-type response elements. J Mol Biol. 2000 Feb 25;296(3):743–756. doi: 10.1006/jmbi.2000.3499. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Sap J., Muñoz A., Damm K., Goldberg Y., Ghysdael J., Leutz A., Beug H., Vennström B. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature. 1986 Dec 18;324(6098):635–640. doi: 10.1038/324635a0. [DOI] [PubMed] [Google Scholar]
  20. Schräder M., Becker-André M., Carlberg C. Thyroid hormone receptor functions as monomeric ligand-induced transcription factor on octameric half-sites. Consequences also for dimerization. J Biol Chem. 1994 Mar 4;269(9):6444–6449. [PubMed] [Google Scholar]
  21. Schräder M., Nayeri S., Kahlen J. P., Müller K. M., Carlberg C. Natural vitamin D3 response elements formed by inverted palindromes: polarity-directed ligand sensitivity of vitamin D3 receptor-retinoid X receptor heterodimer-mediated transactivation. Mol Cell Biol. 1995 Mar;15(3):1154–1161. doi: 10.1128/mcb.15.3.1154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Voegel J. J., Heine M. J., Zechel C., Chambon P., Gronemeyer H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996 Jul 15;15(14):3667–3675. [PMC free article] [PubMed] [Google Scholar]
  24. Wu Y., Koenig R. J. Gene regulation by thyroid hormone. Trends Endocrinol Metab. 2000 Aug;11(6):207–211. doi: 10.1016/s1043-2760(00)00263-0. [DOI] [PubMed] [Google Scholar]
  25. Yoh S. M., Privalsky M. L. Transcriptional repression by thyroid hormone receptors. A role for receptor homodimers in the recruitment of SMRT corepressor. J Biol Chem. 2001 Feb 21;276(20):16857–16867. doi: 10.1074/jbc.M010022200. [DOI] [PubMed] [Google Scholar]
  26. Zhang J., Lazar M. A. The mechanism of action of thyroid hormones. Annu Rev Physiol. 2000;62:439–466. doi: 10.1146/annurev.physiol.62.1.439. [DOI] [PubMed] [Google Scholar]
  27. Zhao Q., Khorasanizadeh S., Miyoshi Y., Lazar M. A., Rastinejad F. Structural elements of an orphan nuclear receptor-DNA complex. Mol Cell. 1998 May;1(6):849–861. doi: 10.1016/s1097-2765(00)80084-2. [DOI] [PubMed] [Google Scholar]

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