Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1990 Dec 1;272(2):391–397. doi: 10.1042/bj2720391

Ligand specificities of recombinant retinoic acid receptors RAR alpha and RAR beta.

M Crettaz 1, A Baron 1, G Siegenthaler 1, W Hunziker 1
PMCID: PMC1149712  PMID: 2176462

Abstract

Binding of retinoic acid (RA) to specific RA receptors alpha and beta (RAR alpha and RAR beta) was studied. Receptors were obtained in two ways: (1) full-length receptors were produced by transient expression of the respective human cDNAs in COS 1 cells; and (2) the ligand-binding domains of RAR alpha and RAR beta were produced in Escherichia coli. RA binding to the wild-type and truncated forms of the receptor was identical for both RAR alpha and RAR beta, indicating that the ligand-binding domains have retained the binding characteristics of the intact receptors. Furthermore, RA bound with the same affinity to both RAR alpha and RAR beta. Only retinoid analogues with an acidic end-group were able to actively bind to both receptors. On measuring the binding of various retinoids, we have found that the properties of the ligand-binding sites of RAR alpha and RAR beta were rather similar. Two retinoid analogues were capable of binding preferentially to either RAR alpha or RAR beta, suggesting that it may be possible to synthesize specific ligands for RAR alpha and RAR beta.

Full text

PDF
396

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. Bollag W. Retinoids and cancer. Cancer Chemother Pharmacol. 1979;3(4):207–215. doi: 10.1007/BF00254733. [DOI] [PubMed] [Google Scholar]
  3. Bollag W. Vitamin A and retinoids: from nutrition to pharmacotherapy in dermatology and oncology. Lancet. 1983 Apr 16;1(8329):860–863. doi: 10.1016/s0140-6736(83)91394-6. [DOI] [PubMed] [Google Scholar]
  4. Bolmer S. D., Wolf G. Retinoids and phorbol esters alter release of fibronectin from enucleated cells. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6541–6545. doi: 10.1073/pnas.79.21.6541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  7. Felgner P. L., Gadek T. R., Holm M., Roman R., Chan H. W., Wenz M., Northrop J. P., Ringold G. M., Danielsen M. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7413–7417. doi: 10.1073/pnas.84.21.7413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Frolik C. A., Roberts A. B., Tavela T. E., Roller P. P., Newton D. L., Sporn M. B. Isolation and identification of 4-hydroxy- and 4-oxoretinoic acid. In vitro metabolites of all-trans-retinoic acid in hamster trachea and liver. Biochemistry. 1979 May 15;18(10):2092–2097. doi: 10.1021/bi00577a039. [DOI] [PubMed] [Google Scholar]
  9. Frolik C. A., Roller P. P., Roberts A. B., Sporn M. B. In vitro and in vivo metabolism of all-trans- and 13-cis-retinoic acid in hamsters. Identification of 13-cis-4-oxoretinoic acid. J Biol Chem. 1980 Sep 10;255(17):8057–8062. [PubMed] [Google Scholar]
  10. 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]
  11. Giguère V., Hollenberg S. M., Rosenfeld M. G., Evans R. M. Functional domains of the human glucocorticoid receptor. Cell. 1986 Aug 29;46(5):645–652. doi: 10.1016/0092-8674(86)90339-9. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Hashimoto Y., Kagechika H., Shudo K. Expression of retinoic acid receptor genes and the ligand-binding selectivity of retinoic acid receptors (RAR's). Biochem Biophys Res Commun. 1990 Feb 14;166(3):1300–1307. doi: 10.1016/0006-291x(90)91007-f. [DOI] [PubMed] [Google Scholar]
  14. Hashimoto Y., Petkovich M., Gaub M. P., Kagechika H., Shudo K., Chambon P. The retinoic acid receptors alpha and beta are expressed in the human promyelocytic leukemia cell line HL-60. Mol Endocrinol. 1989 Jul;3(7):1046–1052. doi: 10.1210/mend-3-7-1046. [DOI] [PubMed] [Google Scholar]
  15. Jetten A. M., Anderson K., Deas M. A., Kagechika H., Lotan R., Rearick J. I., Shudo K. New benzoic acid derivatives with retinoid activity: lack of direct correlation between biological activity and binding to cellular retinoic acid binding protein. Cancer Res. 1987 Jul 1;47(13):3523–3527. [PubMed] [Google Scholar]
  16. Johnson J. D., Davies P. J. Pertussis toxin inhibits retinoic acid-induced expression of tissue transglutaminase in macrophages. J Biol Chem. 1986 Nov 15;261(32):14982–14986. [PubMed] [Google Scholar]
  17. Kistler A. Limb bud cell cultures for estimating the teratogenic potential of compounds. Validation of the test system with retinoids. Arch Toxicol. 1987 Aug;60(6):403–414. doi: 10.1007/BF00302382. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Lippman S. M., Kessler J. F., Meyskens F. L., Jr Retinoids as preventive and therapeutic anticancer agents (Part I). Cancer Treat Rep. 1987 Apr;71(4):391–405. [PubMed] [Google Scholar]
  20. Lochner J. E., Badwey J. A., Horn W., Karnovsky M. L. all-trans-Retinal stimulates superoxide release and phospholipase C activity in neutrophils without significantly blocking protein kinase C. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7673–7677. doi: 10.1073/pnas.83.20.7673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  22. Nervi C., Grippo J. F., Sherman M. I., George M. D., Jetten A. M. Identification and characterization of nuclear retinoic acid-binding activity in human myeloblastic leukemia HL-60 cells. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5854–5858. doi: 10.1073/pnas.86.15.5854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Orfanos C. E., Ehlert R., Gollnick H. The retinoids. A review of their clinical pharmacology and therapeutic use. Drugs. 1987 Oct;34(4):459–503. doi: 10.2165/00003495-198734040-00003. [DOI] [PubMed] [Google Scholar]
  24. Petkovich M., Brand N. J., Krust A., Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. doi: 10.1038/330444a0. [DOI] [PubMed] [Google Scholar]
  25. Rees J. L., Redfern C. P. Expression of the alpha and beta retinoic acid receptors in skin. J Invest Dermatol. 1989 Dec;93(6):818–820. doi: 10.1111/1523-1747.ep12284435. [DOI] [PubMed] [Google Scholar]
  26. Smith T. J., Davis F. B., Davis P. J. Retinoic acid is a modulator of thyroid hormone activation of Ca2+-ATPase in the human erythrocyte membrane. J Biol Chem. 1989 Jan 15;264(2):687–689. [PubMed] [Google Scholar]
  27. Teelmann K. Retinoids: toxicology and teratogenicity to date. Pharmacol Ther. 1989;40(1):29–43. doi: 10.1016/0163-7258(89)90072-7. [DOI] [PubMed] [Google Scholar]
  28. Teelmann K. Testing of retinoids for systemic and topical use in human psoriasis and other disorders of keratinization: mouse papilloma test. Methods Enzymol. 1990;190:382–395. doi: 10.1016/0076-6879(90)90044-2. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. 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 Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES