Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1993 Oct;13(10):6509–6519. doi: 10.1128/mcb.13.10.6509

DNA bending by retinoid X receptor-containing retinoid and thyroid hormone receptor complexes.

X P Lu 1, N L Eberhardt 1, M Pfahl 1
PMCID: PMC364710  PMID: 8413250

Abstract

Retinoid X receptors (RXR) have been identified as common subunits in the regulation of multiple hormonal signaling pathways. Using circular permutation and phasing analysis of specific response elements, we present evidence that RXR-retinoic acid receptor and RXR-thyroid hormone receptor heterodimer or RXR-RXR homodimer complexes induce directed DNA bends when bound to their cognate response elements. The extent of DNA bending induced by the RXR alpha-containing complexes varied and depended on the structure of the DNA-binding sites and the RXR partners. The overall bending orientation for RXR-containing complexes is directed toward the major groove of the DNA helix at the center of hormone response elements. Our observation implicates DNA bending as a possible mechanism underlying transcriptional regulation of distinct retinoid and thyroid hormone responsive genes.

Full text

PDF
6509

Images in this article

6511Image
on p.6511
6512Image
on p.6512
6513Image
on p.6513
6514Image
on p.6514
6516Image
on p.6516

Selected References

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

  1. Baur C. P., Knippers R. Protein-induced bending of the simian virus 40 origin of replication. J Mol Biol. 1988 Oct 20;203(4):1009–1019. doi: 10.1016/0022-2836(88)90125-8. [DOI] [PubMed] [Google Scholar]
  2. Berkenstam A., Vivanco Ruiz M. M., Barettino D., Horikoshi M., Stunnenberg H. G. Cooperativity in transactivation between retinoic acid receptor and TFIID requires an activity analogous to E1A. Cell. 1992 May 1;69(3):401–412. doi: 10.1016/0092-8674(92)90443-g. [DOI] [PubMed] [Google Scholar]
  3. Bracco L., Kotlarz D., Kolb A., Diekmann S., Buc H. Synthetic curved DNA sequences can act as transcriptional activators in Escherichia coli. EMBO J. 1989 Dec 20;8(13):4289–4296. doi: 10.1002/j.1460-2075.1989.tb08615.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Calladine C. R., Drew H. R., McCall M. J. The intrinsic curvature of DNA in solution. J Mol Biol. 1988 May 5;201(1):127–137. doi: 10.1016/0022-2836(88)90444-5. [DOI] [PubMed] [Google Scholar]
  5. De Luca L. M. Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J. 1991 Nov;5(14):2924–2933. [PubMed] [Google Scholar]
  6. Desvergne B., Petty K. J., Nikodem V. M. Functional characterization and receptor binding studies of the malic enzyme thyroid hormone response element. J Biol Chem. 1991 Jan 15;266(2):1008–1013. [PubMed] [Google Scholar]
  7. Duester G., Shean M. L., McBride M. S., Stewart M. J. Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis. Mol Cell Biol. 1991 Mar;11(3):1638–1646. doi: 10.1128/mcb.11.3.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gartenberg M. R., Ampe C., Steitz T. A., Crothers D. M. Molecular characterization of the GCN4-DNA complex. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6034–6038. doi: 10.1073/pnas.87.16.6034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Glass C. K., Holloway J. M., Devary O. V., Rosenfeld M. G. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell. 1988 Jul 29;54(3):313–323. doi: 10.1016/0092-8674(88)90194-8. [DOI] [PubMed] [Google Scholar]
  10. Gober J. W., Shapiro L. Integration host factor is required for the activation of developmentally regulated genes in Caulobacter. Genes Dev. 1990 Sep;4(9):1494–1504. doi: 10.1101/gad.4.9.1494. [DOI] [PubMed] [Google Scholar]
  11. Goodsell D. S., Kopka M. L., Cascio D., Dickerson R. E. Crystal structure of CATGGCCATG and its implications for A-tract bending models. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2930–2934. doi: 10.1073/pnas.90.7.2930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hermann T., Hoffmann B., Zhang X. K., Tran P., Pfahl M. Heterodimeric receptor complexes determine 3,5,3'-triiodothyronine and retinoid signaling specificities. Mol Endocrinol. 1992 Jul;6(7):1153–1162. doi: 10.1210/mend.6.7.1324421. [DOI] [PubMed] [Google Scholar]
  13. Heyman R. A., Mangelsdorf D. J., Dyck J. A., Stein R. B., Eichele G., Evans R. M., Thaller C. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992 Jan 24;68(2):397–406. doi: 10.1016/0092-8674(92)90479-v. [DOI] [PubMed] [Google Scholar]
  14. Hoover T. R., Santero E., Porter S., Kustu S. The integration host factor stimulates interaction of RNA polymerase with NIFA, the transcriptional activator for nitrogen fixation operons. Cell. 1990 Oct 5;63(1):11–22. doi: 10.1016/0092-8674(90)90284-l. [DOI] [PubMed] [Google Scholar]
  15. Horikoshi M., Bertuccioli C., Takada R., Wang J., Yamamoto T., Roeder R. G. Transcription factor TFIID induces DNA bending upon binding to the TATA element. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1060–1064. doi: 10.1073/pnas.89.3.1060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Husmann M., Lehmann J., Hoffmann B., Hermann T., Tzukerman M., Pfahl M. Antagonism between retinoic acid receptors. Mol Cell Biol. 1991 Aug;11(8):4097–4103. doi: 10.1128/mcb.11.8.4097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kerppola T. K., Curran T. DNA bending by Fos and Jun: the flexible hinge model. Science. 1991 Nov 22;254(5035):1210–1214. doi: 10.1126/science.1957173. [DOI] [PubMed] [Google Scholar]
  18. Kerppola T. K., Curran T. Fos-Jun heterodimers and Jun homodimers bend DNA in opposite orientations: implications for transcription factor cooperativity. Cell. 1991 Jul 26;66(2):317–326. doi: 10.1016/0092-8674(91)90621-5. [DOI] [PubMed] [Google Scholar]
  19. Kim J., Zwieb C., Wu C., Adhya S. Bending of DNA by gene-regulatory proteins: construction and use of a DNA bending vector. Gene. 1989 Dec 21;85(1):15–23. doi: 10.1016/0378-1119(89)90459-9. [DOI] [PubMed] [Google Scholar]
  20. Kim S., Landy A. Lambda Int protein bridges between higher order complexes at two distant chromosomal loci attL and attR. Science. 1992 Apr 10;256(5054):198–203. doi: 10.1126/science.1533056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. King I. N., de Soyza T., Catanzaro D. F., Lavin T. N. Thyroid hormone receptor-induced bending of specific DNA sequences is modified by an accessory factor. J Biol Chem. 1993 Jan 5;268(1):495–501. [PubMed] [Google Scholar]
  22. 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]
  23. Lehmann J. M., Zhang X. K., Pfahl M. RAR gamma 2 expression is regulated through a retinoic acid response element embedded in Sp1 sites. Mol Cell Biol. 1992 Jul;12(7):2976–2985. doi: 10.1128/mcb.12.7.2976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Leidig F., Shepard A. R., Zhang W. G., Stelter A., Cattini P. A., Baxter J. D., Eberhardt N. L. Thyroid hormone responsiveness in human growth hormone-related genes. Possible correlation with receptor-induced DNA conformational changes. J Biol Chem. 1992 Jan 15;267(2):913–921. [PubMed] [Google Scholar]
  26. Lerman L. S., Frisch H. L. Why does the electrophoretic mobility of DNA in gels vary with the length of the molecule? Biopolymers. 1982 May;21(5):995–997. doi: 10.1002/bip.360210511. [DOI] [PubMed] [Google Scholar]
  27. Leroy P., Nakshatri H., Chambon P. Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10138–10142. doi: 10.1073/pnas.88.22.10138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Luisi B. F., Xu W. X., Otwinowski Z., Freedman L. P., Yamamoto K. R., Sigler P. B. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature. 1991 Aug 8;352(6335):497–505. doi: 10.1038/352497a0. [DOI] [PubMed] [Google Scholar]
  30. Lumpkin O. J., Déjardin P., Zimm B. H. Theory of gel electrophoresis of DNA. Biopolymers. 1985 Aug;24(8):1573–1593. doi: 10.1002/bip.360240812. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. Maroun R. C., Olson W. K. Base sequence effects in double-helical DNA. III. Average properties of curved DNA. Biopolymers. 1988 Apr;27(4):585–603. doi: 10.1002/bip.360270404. [DOI] [PubMed] [Google Scholar]
  34. McAllister C. F., Achberger E. C. Rotational orientation of upstream curved DNA affects promoter function in Bacillus subtilis. J Biol Chem. 1989 Jun 25;264(18):10451–10456. [PubMed] [Google Scholar]
  35. Mitchell P. J., Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. doi: 10.1126/science.2667136. [DOI] [PubMed] [Google Scholar]
  36. Moitoso de Vargas L., Kim S., Landy A. DNA looping generated by DNA bending protein IHF and the two domains of lambda integrase. Science. 1989 Jun 23;244(4911):1457–1461. doi: 10.1126/science.2544029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Muñoz-Cánoves P., Vik D. P., Tack B. F. Mapping of a retinoic acid-responsive element in the promoter region of the complement factor H gene. J Biol Chem. 1990 Nov 25;265(33):20065–20068. [PubMed] [Google Scholar]
  38. Nagpal S., Saunders M., Kastner P., Durand B., Nakshatri H., Chambon P. Promoter context- and response element-dependent specificity of the transcriptional activation and modulating functions of retinoic acid receptors. Cell. 1992 Sep 18;70(6):1007–1019. doi: 10.1016/0092-8674(92)90250-g. [DOI] [PubMed] [Google Scholar]
  39. Nardulli A. M., Shapiro D. J. Binding of the estrogen receptor DNA-binding domain to the estrogen response element induces DNA bending. Mol Cell Biol. 1992 May;12(5):2037–2042. doi: 10.1128/mcb.12.5.2037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Petty K. J., Desvergne B., Mitsuhashi T., Nikodem V. M. Identification of a thyroid hormone response element in the malic enzyme gene. J Biol Chem. 1990 May 5;265(13):7395–7400. [PubMed] [Google Scholar]
  41. Ptashne M., Gann A. A. Activators and targets. Nature. 1990 Jul 26;346(6282):329–331. doi: 10.1038/346329a0. [DOI] [PubMed] [Google Scholar]
  42. Pérez-Martín J., Espinosa M. The RepA repressor can act as a transcriptional activator by inducing DNA bends. EMBO J. 1991 Jun;10(6):1375–1382. doi: 10.1002/j.1460-2075.1991.tb07657.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rojo F., Zaballos A., Salas M. Bend induced by the phage phi 29 transcriptional activator in the viral late promoter is required for activation. J Mol Biol. 1990 Feb 20;211(4):713–725. doi: 10.1016/0022-2836(90)90072-t. [DOI] [PubMed] [Google Scholar]
  44. Salvo J. J., Grindley N. D. Helical phasing between DNA bends and the determination of bend direction. Nucleic Acids Res. 1987 Dec 10;15(23):9771–9779. doi: 10.1093/nar/15.23.9771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Salvo J. J., Grindley N. D. The gamma delta resolvase bends the res site into a recombinogenic complex. EMBO J. 1988 Nov;7(11):3609–3616. doi: 10.1002/j.1460-2075.1988.tb03239.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schinkel A. H., Groot Koerkamp M. J., Teunissen A. W., Tabak H. F. RNA polymerase induces DNA bending at yeast mitochondrial promoters. Nucleic Acids Res. 1988 Oct 11;16(19):9147–9163. doi: 10.1093/nar/16.19.9147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schultz S. C., Shields G. C., Steitz T. A. Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees. Science. 1991 Aug 30;253(5023):1001–1007. doi: 10.1126/science.1653449. [DOI] [PubMed] [Google Scholar]
  48. Schwabe J. W., Neuhaus D., Rhodes D. Solution structure of the DNA-binding domain of the oestrogen receptor. Nature. 1990 Nov 29;348(6300):458–461. doi: 10.1038/348458a0. [DOI] [PubMed] [Google Scholar]
  49. Shuey D. J., Parker C. S. Bending of promoter DNA on binding of heat shock transcription factor. Nature. 1986 Oct 2;323(6087):459–461. doi: 10.1038/323459a0. [DOI] [PubMed] [Google Scholar]
  50. Smith W. C., Nakshatri H., Leroy P., Rees J., Chambon P. A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. EMBO J. 1991 Aug;10(8):2223–2230. doi: 10.1002/j.1460-2075.1991.tb07758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Thompson J. F., Landy A. Empirical estimation of protein-induced DNA bending angles: applications to lambda site-specific recombination complexes. Nucleic Acids Res. 1988 Oct 25;16(20):9687–9705. doi: 10.1093/nar/16.20.9687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Umesono K., Giguere V., Glass C. K., Rosenfeld M. G., Evans R. M. Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature. 1988 Nov 17;336(6196):262–265. doi: 10.1038/336262a0. [DOI] [PubMed] [Google Scholar]
  53. Vasios G. W., Gold J. D., Petkovich M., Chambon P., Gudas L. J. A retinoic acid-responsive element is present in the 5' flanking region of the laminin B1 gene. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9099–9103. doi: 10.1073/pnas.86.23.9099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Vasios G., Mader S., Gold J. D., Leid M., Lutz Y., Gaub M. P., Chambon P., Gudas L. The late retinoic acid induction of laminin B1 gene transcription involves RAR binding to the responsive element. EMBO J. 1991 May;10(5):1149–1158. doi: 10.1002/j.1460-2075.1991.tb08055.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Verrijzer C. P., van Oosterhout J. A., van Weperen W. W., van der Vliet P. C. POU proteins bend DNA via the POU-specific domain. EMBO J. 1991 Oct;10(10):3007–3014. doi: 10.1002/j.1460-2075.1991.tb07851.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wang L., Helmann J. D., Winans S. C. The A. tumefaciens transcriptional activator OccR causes a bend at a target promoter, which is partially relaxed by a plant tumor metabolite. Cell. 1992 May 15;69(4):659–667. doi: 10.1016/0092-8674(92)90229-6. [DOI] [PubMed] [Google Scholar]
  57. Wechsler D. S., Dang C. V. Opposite orientations of DNA bending by c-Myc and Max. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7635–7639. doi: 10.1073/pnas.89.16.7635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Williams J. S., Eckdahl T. T., Anderson J. N. Bent DNA functions as a replication enhancer in Saccharomyces cerevisiae. Mol Cell Biol. 1988 Jul;8(7):2763–2769. doi: 10.1128/mcb.8.7.2763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wu H. M., Crothers D. M. The locus of sequence-directed and protein-induced DNA bending. Nature. 1984 Apr 5;308(5959):509–513. doi: 10.1038/308509a0. [DOI] [PubMed] [Google Scholar]
  60. 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]
  61. Zahn K., Blattner F. R. Direct evidence for DNA bending at the lambda replication origin. Science. 1987 Apr 24;236(4800):416–422. doi: 10.1126/science.2951850. [DOI] [PubMed] [Google Scholar]
  62. 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]
  63. Zhang X. K., Lehmann J., Hoffmann B., Dawson M. I., Cameron J., Graupner G., Hermann T., Tran P., Pfahl M. Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature. 1992 Aug 13;358(6387):587–591. doi: 10.1038/358587a0. [DOI] [PubMed] [Google Scholar]
  64. Zhang X. K., Wills K. N., Graupner G., Tzukerman M., Hermann T., Pfahl M. Ligand-binding domain of thyroid hormone receptors modulates DNA binding and determines their bifunctional roles. New Biol. 1991 Feb;3(2):169–181. [PubMed] [Google Scholar]
  65. Zhang X. K., Wills K. N., Husmann M., Hermann T., Pfahl M. Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities. Mol Cell Biol. 1991 Dec;11(12):6016–6025. doi: 10.1128/mcb.11.12.6016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Zinkel S. S., Crothers D. M. DNA bend direction by phase sensitive detection. Nature. 1987 Jul 9;328(6126):178–181. doi: 10.1038/328178a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES