Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1991 Aug;11(8):4097–4103. doi: 10.1128/mcb.11.8.4097

Antagonism between retinoic acid receptors.

M Husmann 1, J Lehmann 1, B Hoffmann 1, T Hermann 1, M Tzukerman 1, M Pfahl 1
PMCID: PMC361221  PMID: 1649387

Abstract

In the developing mouse, retinoic acid receptors (RARs) beta and gamma 1 are expressed in characteristic spatiotemporal patterns which are correlated with different developmental fates of the respective tissues. Understanding the cues that regulate the expression of the various RARs may therefore provide insights into the process of tissue diversification. Transcription of RAR beta is rapidly upregulated through a retinoic acid-responsive element (here referred to as the beta RARE) in its promoter. Like RAR alpha and RAR beta, RAR gamma 1 has been implicated in the activation of the beta RARE. Therefore, it is puzzling that RAR beta and RAR gamma 1 appear to be expressed in reciprocal patterns. In the present report, we show that RAR gamma 1, one of the two predominant RAR gamma isoforms, can inhibit the activity of RAR gamma 2, RAR beta, and endogenous RAR on the beta RARE. In contrast, the three RAR gamma isoforms tested and RAR beta activated a palindromic thyroid hormone response element with similar levels of efficiency. The differential activity of RAR gamma 1 compared with that of RAR beta appears to reside in both the N-terminal and the C-terminal halves of RAR gamma 1. RAR gamma 1-mediated inhibition of other RARs may involve competition for the response element as well as direct interaction with other receptors and might be part of a regulatory system contributing to the characteristic tissue distribution of the various RARs.

Full text

PDF
4097

Selected References

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

  1. Benbrook D., Lernhardt E., Pfahl M. A new retinoic acid receptor identified from a hepatocellular carcinoma. Nature. 1988 Jun 16;333(6174):669–672. doi: 10.1038/333669a0. [DOI] [PubMed] [Google Scholar]
  2. Brand N., Petkovich M., Krust A., Chambon P., de Thé H., Marchio A., Tiollais P., Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. doi: 10.1038/332850a0. [DOI] [PubMed] [Google Scholar]
  3. Dollé P., Ruberte E., Kastner P., Petkovich M., Stoner C. M., Gudas L. J., Chambon P. Differential expression of genes encoding alpha, beta and gamma retinoic acid receptors and CRABP in the developing limbs of the mouse. Nature. 1989 Dec 7;342(6250):702–705. doi: 10.1038/342702a0. [DOI] [PubMed] [Google Scholar]
  4. Dollé P., Ruberte E., Leroy P., Morriss-Kay G., Chambon P. Retinoic acid receptors and cellular retinoid binding proteins. I. A systematic study of their differential pattern of transcription during mouse organogenesis. Development. 1990 Dec;110(4):1133–1151. doi: 10.1242/dev.110.4.1133. [DOI] [PubMed] [Google Scholar]
  5. Eichele G., Tickle C., Alberts B. M. Studies on the mechanism of retinoid-induced pattern duplications in the early chick limb bud: temporal and spatial aspects. J Cell Biol. 1985 Nov;101(5 Pt 1):1913–1920. doi: 10.1083/jcb.101.5.1913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Forman B. M., Samuels H. H. Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol. 1990 Sep;4(9):1293–1301. doi: 10.1210/mend-4-9-1293. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Giguère V., Shago M., Zirngibl R., Tate P., Rossant J., Varmuza S. Identification of a novel isoform of the retinoic acid receptor gamma expressed in the mouse embryo. Mol Cell Biol. 1990 May;10(5):2335–2340. doi: 10.1128/mcb.10.5.2335. [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. 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]
  11. Hoffmann B., Lehmann J. M., Zhang X. K., Hermann T., Husmann M., Graupner G., Pfahl M. A retinoic acid receptor-specific element controls the retinoic acid receptor-beta promoter. Mol Endocrinol. 1990 Nov;4(11):1727–1736. doi: 10.1210/mend-4-11-1727. [DOI] [PubMed] [Google Scholar]
  12. Kastner P., Krust A., Mendelsohn C., Garnier J. M., Zelent A., Leroy P., Staub A., Chambon P. Murine isoforms of retinoic acid receptor gamma with specific patterns of expression. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2700–2704. doi: 10.1073/pnas.87.7.2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Krust A., Kastner P., Petkovich M., Zelent A., Chambon P. A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5310–5314. doi: 10.1073/pnas.86.14.5310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kumar V., Green S., Stack G., Berry M., Jin J. R., Chambon P. Functional domains of the human estrogen receptor. Cell. 1987 Dec 24;51(6):941–951. doi: 10.1016/0092-8674(87)90581-2. [DOI] [PubMed] [Google Scholar]
  15. Lammer E. J., Chen D. T., Hoar R. M., Agnish N. D., Benke P. J., Braun J. T., Curry C. J., Fernhoff P. M., Grix A. W., Jr, Lott I. T. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3;313(14):837–841. doi: 10.1056/NEJM198510033131401. [DOI] [PubMed] [Google Scholar]
  16. Lehmann J. M., Hoffmann B., Pfahl M. Genomic organization of the retinoic acid receptor gamma gene. Nucleic Acids Res. 1991 Feb 11;19(3):573–578. doi: 10.1093/nar/19.3.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Leroy P., Krust A., Zelent A., Mendelsohn C., Garnier J. M., Kastner P., Dierich A., Chambon P. Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J. 1991 Jan;10(1):59–69. doi: 10.1002/j.1460-2075.1991.tb07921.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maden M. Vitamin A and pattern formation in the regenerating limb. Nature. 1982 Feb 25;295(5851):672–675. doi: 10.1038/295672a0. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. Niazi I. A., Saxena S. Abnormal hind limb regeneration in tadpoles of the toad, Bufo andersoni, exposed to excess vitamin A. Folia Biol (Krakow) 1978;26(1):3–8. [PubMed] [Google Scholar]
  24. Osumi-Yamashita N., Noji S., Nohno T., Koyama E., Doi H., Eto K., Taniguchi S. Expression of retinoic acid receptor genes in neural crest-derived cells during mouse facial development. FEBS Lett. 1990 May 7;264(1):71–74. doi: 10.1016/0014-5793(90)80767-d. [DOI] [PubMed] [Google Scholar]
  25. Pfahl M., Tzukerman M., Zhang X. K., Lehmann J. M., Hermann T., Wills K. N., Graupner G. Nuclear retinoic acid receptors: cloning, analysis, and function. Methods Enzymol. 1990;189:256–270. doi: 10.1016/0076-6879(90)89297-u. [DOI] [PubMed] [Google Scholar]
  26. Ragsdale C. W., Jr, Petkovich M., Gates P. B., Chambon P., Brockes J. P. Identification of a novel retinoic acid receptor in regenerative tissues of the newt. Nature. 1989 Oct 19;341(6243):654–657. doi: 10.1038/341654a0. [DOI] [PubMed] [Google Scholar]
  27. Rosa F. W., Wilk A. L., Kelsey F. O. Teratogen update: vitamin A congeners. Teratology. 1986 Jun;33(3):355–364. doi: 10.1002/tera.1420330315. [DOI] [PubMed] [Google Scholar]
  28. Ruberte E., Dolle P., Krust A., Zelent A., Morriss-Kay G., Chambon P. Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. Development. 1990 Feb;108(2):213–222. doi: 10.1242/dev.108.2.213. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Summerbell D. The effect of local application of retinoic acid to the anterior margin of the developing chick limb. J Embryol Exp Morphol. 1983 Dec;78:269–289. [PubMed] [Google Scholar]
  31. Thaller C., Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 1987 Jun 18;327(6123):625–628. doi: 10.1038/327625a0. [DOI] [PubMed] [Google Scholar]
  32. Tickle C., Alberts B., Wolpert L., Lee J. Local application of retinoic acid to the limb bond mimics the action of the polarizing region. Nature. 1982 Apr 8;296(5857):564–566. doi: 10.1038/296564a0. [DOI] [PubMed] [Google Scholar]
  33. Tickle C., Lee J., Eichele G. A quantitative analysis of the effect of all-trans-retinoic acid on the pattern of chick wing development. Dev Biol. 1985 May;109(1):82–95. doi: 10.1016/0012-1606(85)90348-3. [DOI] [PubMed] [Google Scholar]
  34. Tora L., Gronemeyer H., Turcotte B., Gaub M. P., Chambon P. The N-terminal region of the chicken progesterone receptor specifies target gene activation. Nature. 1988 May 12;333(6169):185–188. doi: 10.1038/333185a0. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Zelent A., Krust A., Petkovich M., Kastner P., Chambon P. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature. 1989 Jun 29;339(6227):714–717. doi: 10.1038/339714a0. [DOI] [PubMed] [Google Scholar]
  37. Zelent A., Mendelsohn C., Kastner P., Krust A., Garnier J. M., Ruffenach F., Leroy P., Chambon P. Differentially expressed isoforms of the mouse retinoic acid receptor beta generated by usage of two promoters and alternative splicing. EMBO J. 1991 Jan;10(1):71–81. doi: 10.1002/j.1460-2075.1991.tb07922.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. de Thé H., Vivanco-Ruiz M. M., Tiollais P., Stunnenberg H., Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature. 1990 Jan 11;343(6254):177–180. doi: 10.1038/343177a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES