Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1992 Mar;11(3):1015–1023. doi: 10.1002/j.1460-2075.1992.tb05140.x

A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor.

A Baniahmad 1, A C Köhne 1, R Renkawitz 1
PMCID: PMC556542  PMID: 1347744

Abstract

Inhibition of gene transcription is brought about by several mechanisms. The least understood mechanism is probably silencing, the analogue to transcriptional enhancing. We provide evidence that the silencing function of the oncogene product v-ERBA or the cellular counterpart, the thyroid hormone receptor (TR, c-erbA) is located in the C-terminal part and is transferable to a heterologous DNA binding domain. Deletion analyses suggest an important role for a basic and hydrophilic amino acid stretch on both ends of the domain. In addition we show that the related retinoic acid receptor (RAR) also contains a functional silencing domain similar in size and amino acid sequence. However, the activity of this domain can be neutralized by an additional domain in the C-terminus which functions cell specifically.

Full text

PDF
1015

Images in this article

1016Image
on p.1016
1016Image
on p.1016
1017Image
on p.1017
1018Image
on p.1018
1019Image
on p.1019

Selected References

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

  1. Baniahmad A., Muller M., Steiner C., Renkawitz R. Activity of two different silencer elements of the chicken lysozyme gene can be compensated by enhancer elements. EMBO J. 1987 Aug;6(8):2297–2303. doi: 10.1002/j.1460-2075.1987.tb02504.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baniahmad A., Steiner C., Köhne A. C., Renkawitz R. Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. Cell. 1990 May 4;61(3):505–514. doi: 10.1016/0092-8674(90)90532-j. [DOI] [PubMed] [Google Scholar]
  3. Bigler J., Eisenman R. N. c-erbA encodes multiple proteins in chicken erythroid cells. Mol Cell Biol. 1988 Oct;8(10):4155–4161. doi: 10.1128/mcb.8.10.4155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brent G. A., Dunn M. K., Harney J. W., Gulick T., Larsen P. R., Moore D. D. Thyroid hormone aporeceptor represses T3-inducible promoters and blocks activity of the retinoic acid receptor. New Biol. 1989 Dec;1(3):329–336. [PubMed] [Google Scholar]
  5. 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]
  6. Carey M., Lin Y. S., Green M. R., Ptashne M. A mechanism for synergistic activation of a mammalian gene by GAL4 derivatives. Nature. 1990 May 24;345(6273):361–364. doi: 10.1038/345361a0. [DOI] [PubMed] [Google Scholar]
  7. Choi O. R., Engel J. D. Developmental regulation of beta-globin gene switching. Cell. 1988 Oct 7;55(1):17–26. doi: 10.1016/0092-8674(88)90005-0. [DOI] [PubMed] [Google Scholar]
  8. Damm K., Beug H., Graf T., Vennström B. A single point mutation in erbA restores the erythroid transforming potential of a mutant avian erythroblastosis virus (AEV) defective in both erbA and erbB oncogenes. EMBO J. 1987 Feb;6(2):375–382. doi: 10.1002/j.1460-2075.1987.tb04765.x. [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. Denner L. A., Weigel N. L., Maxwell B. L., Schrader W. T., O'Malley B. W. Regulation of progesterone receptor-mediated transcription by phosphorylation. Science. 1990 Dec 21;250(4988):1740–1743. doi: 10.1126/science.2176746. [DOI] [PubMed] [Google Scholar]
  11. Dobens L., Rudolph K., Berger E. M. Ecdysterone regulatory elements function as both transcriptional activators and repressors. Mol Cell Biol. 1991 Apr;11(4):1846–1853. doi: 10.1128/mcb.11.4.1846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ernsberger U., Sendtner M., Rohrer H. Proliferation and differentiation of embryonic chick sympathetic neurons: effects of ciliary neurotrophic factor. Neuron. 1989 Mar;2(3):1275–1284. doi: 10.1016/0896-6273(89)90312-7. [DOI] [PubMed] [Google Scholar]
  13. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fawell S. E., Lees J. A., White R., Parker M. G. Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor. Cell. 1990 Mar 23;60(6):953–962. doi: 10.1016/0092-8674(90)90343-d. [DOI] [PubMed] [Google Scholar]
  15. Forman B. M., Yang C. R., Au M., Casanova J., Ghysdael J., Samuels H. H. A domain containing leucine-zipper-like motifs mediate novel in vivo interactions between the thyroid hormone and retinoic acid receptors. Mol Endocrinol. 1989 Oct;3(10):1610–1626. doi: 10.1210/mend-3-10-1610. [DOI] [PubMed] [Google Scholar]
  16. Forrest D., Muñoz A., Raynoschek C., Vennström B., Beug H. Requirement for the C-terminal domain of the v-erbA oncogene protein for biological function and transcriptional repression. Oncogene. 1990 Mar;5(3):309–316. [PubMed] [Google Scholar]
  17. Giguere V., Ong E. S., Segui P., Evans R. M. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. doi: 10.1038/330624a0. [DOI] [PubMed] [Google Scholar]
  18. Glass C. K., Devary O. V., Rosenfeld M. G. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor. Cell. 1990 Nov 16;63(4):729–738. doi: 10.1016/0092-8674(90)90139-6. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Glass C. K., Lipkin S. M., Devary O. V., Rosenfeld M. G. Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer. Cell. 1989 Nov 17;59(4):697–708. doi: 10.1016/0092-8674(89)90016-0. [DOI] [PubMed] [Google Scholar]
  21. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Graf T., Beug H. Role of the v-erbA and v-erbB oncogenes of avian erythroblastosis virus in erythroid cell transformation. Cell. 1983 Aug;34(1):7–9. doi: 10.1016/0092-8674(83)90130-7. [DOI] [PubMed] [Google Scholar]
  23. Graupner G., Wills K. N., Tzukerman M., Zhang X. K., Pfahl M. Dual regulatory role for thyroid-hormone receptors allows control of retinoic-acid receptor activity. Nature. 1989 Aug 24;340(6235):653–656. doi: 10.1038/340653a0. [DOI] [PubMed] [Google Scholar]
  24. Green S., Chambon P. Nuclear receptors enhance our understanding of transcription regulation. Trends Genet. 1988 Nov;4(11):309–314. doi: 10.1016/0168-9525(88)90108-4. [DOI] [PubMed] [Google Scholar]
  25. Hudson L. G., Santon J. B., Glass C. K., Gill G. N. Ligand-activated thyroid hormone and retinoic acid receptors inhibit growth factor receptor promoter expression. Cell. 1990 Sep 21;62(6):1165–1175. doi: 10.1016/0092-8674(90)90393-s. [DOI] [PubMed] [Google Scholar]
  26. Jaynes J. B., O'Farrell P. H. Active repression of transcription by the engrailed homeodomain protein. EMBO J. 1991 Jun;10(6):1427–1433. doi: 10.1002/j.1460-2075.1991.tb07663.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kawai S., Nishizawa M. New procedure for DNA transfection with polycation and dimethyl sulfoxide. Mol Cell Biol. 1984 Jun;4(6):1172–1174. doi: 10.1128/mcb.4.6.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Levine M., Manley J. L. Transcriptional repression of eukaryotic promoters. Cell. 1989 Nov 3;59(3):405–408. doi: 10.1016/0092-8674(89)90024-x. [DOI] [PubMed] [Google Scholar]
  29. Licht J. D., Grossel M. J., Figge J., Hansen U. M. Drosophila Krüppel protein is a transcriptional repressor. Nature. 1990 Jul 5;346(6279):76–79. doi: 10.1038/346076a0. [DOI] [PubMed] [Google Scholar]
  30. Muñoz A., Zenke M., Gehring U., Sap J., Beug H., Vennström B. Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein. EMBO J. 1988 Jan;7(1):155–159. doi: 10.1002/j.1460-2075.1988.tb02795.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. När A. M., Boutin J. M., Lipkin S. M., Yu V. C., Holloway J. M., Glass C. K., Rosenfeld M. G. The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell. 1991 Jun 28;65(7):1267–1279. doi: 10.1016/0092-8674(91)90021-p. [DOI] [PubMed] [Google Scholar]
  33. Peterson C. L., Kruger W., Herskowitz I. A functional interaction between the C-terminal domain of RNA polymerase II and the negative regulator SIN1. Cell. 1991 Mar 22;64(6):1135–1143. doi: 10.1016/0092-8674(91)90268-4. [DOI] [PubMed] [Google Scholar]
  34. Privalsky M. L., Boucher P., Koning A., Judelson C. Genetic dissection of functional domains within the avian erythroblastosis virus v-erbA oncogene. Mol Cell Biol. 1988 Oct;8(10):4510–4517. doi: 10.1128/mcb.8.10.4510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988 Oct 20;335(6192):683–689. doi: 10.1038/335683a0. [DOI] [PubMed] [Google Scholar]
  36. Renkawitz R. Transcriptional repression in eukaryotes. Trends Genet. 1990 Jun;6(6):192–197. doi: 10.1016/0168-9525(90)90176-7. [DOI] [PubMed] [Google Scholar]
  37. Robbins J., Dilworth S. M., Laskey R. A., Dingwall C. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell. 1991 Feb 8;64(3):615–623. doi: 10.1016/0092-8674(91)90245-t. [DOI] [PubMed] [Google Scholar]
  38. Samuels H. H., Stanley F., Casanova J. Depletion of L-3,5,3'-triiodothyronine and L-thyroxine in euthyroid calf serum for use in cell culture studies of the action of thyroid hormone. Endocrinology. 1979 Jul;105(1):80–85. doi: 10.1210/endo-105-1-80. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Sap J., Muñoz A., Schmitt J., Stunnenberg H., Vennström B. Repression of transcription mediated at a thyroid hormone response element by the v-erb-A oncogene product. Nature. 1989 Jul 20;340(6230):242–244. doi: 10.1038/340242a0. [DOI] [PubMed] [Google Scholar]
  41. Silver P. A., Chiang A., Sadler I. Mutations that alter both localization and production of a yeast nuclear protein. Genes Dev. 1988 Jun;2(6):707–717. doi: 10.1101/gad.2.6.707. [DOI] [PubMed] [Google Scholar]
  42. Thompson C. C., Weinberger C., Lebo R., Evans R. M. Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science. 1987 Sep 25;237(4822):1610–1614. doi: 10.1126/science.3629259. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. Zenke M., Kahn P., Disela C., Vennström B., Leutz A., Keegan K., Hayman M. J., Choi H. R., Yew N., Engel J. D. v-erbA specifically suppresses transcription of the avian erythrocyte anion transporter (band 3) gene. Cell. 1988 Jan 15;52(1):107–119. doi: 10.1016/0092-8674(88)90535-1. [DOI] [PubMed] [Google Scholar]
  46. 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]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES