Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Aug 1;89(15):6731–6735. doi: 10.1073/pnas.89.15.6731

At least three promoters direct expression of the mouse glucocorticoid receptor gene.

U Strähle 1, A Schmidt 1, G Kelsey 1, A F Stewart 1, T J Cole 1, W Schmid 1, G Schütz 1
PMCID: PMC49577  PMID: 1495961

Abstract

We have characterized the gene for the mouse glucocorticoid receptor. The gene spans approximately 110 kilobases, and glucocorticoid receptor transcripts are assembled from nine exons. Expression of the gene is controlled by at least three promoters, resulting in glucocorticoid receptor transcripts with different 5' nontranslated exons. One promoter is cell-specific, found to be active only in T lymphocytes. The other two promoters are active to various degrees in all cell lines and tissues so far analyzed and are located in a CpG island. The promoter activities are accompanied by DNase I hypersensitivity sites in chromatin. In contrast to a conservation of exon-intron structure, differences in promoter organization suggest a divergence between the evolution of regulatory and coding regions among members of the steroid receptor super-family.

Full text

PDF
6732

Images in this article

Selected References

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

  1. Anderson D. J., Axel R. A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids. Cell. 1986 Dec 26;47(6):1079–1090. doi: 10.1016/0092-8674(86)90823-8. [DOI] [PubMed] [Google Scholar]
  2. Ballard P. L., Baxter J. D., Higgins S. J., Rousseau G. G., Tomkins G. M. General presence of glucocorticoid receptors in mammalian tissues. Endocrinology. 1974 Apr;94(4):998–1002. doi: 10.1210/endo-94-4-998. [DOI] [PubMed] [Google Scholar]
  3. Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. doi: 10.1016/0092-8674(89)90237-7. [DOI] [PubMed] [Google Scholar]
  4. Brand N. J., Petkovich M., Chambon P. Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha). Nucleic Acids Res. 1990 Dec 11;18(23):6799–6806. doi: 10.1093/nar/18.23.6799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  6. Danielsen M., Northrop J. P., Ringold G. M. The mouse glucocorticoid receptor: mapping of functional domains by cloning, sequencing and expression of wild-type and mutant receptor proteins. EMBO J. 1986 Oct;5(10):2513–2522. doi: 10.1002/j.1460-2075.1986.tb04529.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dieken E. S., Meese E. U., Miesfeld R. L. nti glucocorticoid receptor transcripts lack sequences encoding the amino-terminal transcriptional modulatory domain. Mol Cell Biol. 1990 Sep;10(9):4574–4581. doi: 10.1128/mcb.10.9.4574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eisen L. P., Elsasser M. S., Harmon J. M. Positive regulation of the glucocorticoid receptor in human T-cells sensitive to the cytolytic effects of glucocorticoids. J Biol Chem. 1988 Aug 25;263(24):12044–12048. [PubMed] [Google Scholar]
  9. Encío I. J., Detera-Wadleigh S. D. The genomic structure of the human glucocorticoid receptor. J Biol Chem. 1991 Apr 15;266(11):7182–7188. [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Green S., Walter P., Kumar V., Krust A., Bornert J. M., Argos P., Chambon P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986 Mar 13;320(6058):134–139. doi: 10.1038/320134a0. [DOI] [PubMed] [Google Scholar]
  13. Gross D. S., Garrard W. T. Nuclease hypersensitive sites in chromatin. Annu Rev Biochem. 1988;57:159–197. doi: 10.1146/annurev.bi.57.070188.001111. [DOI] [PubMed] [Google Scholar]
  14. Ham J., Thomson A., Needham M., Webb P., Parker M. Characterization of response elements for androgens, glucocorticoids and progestins in mouse mammary tumour virus. Nucleic Acids Res. 1988 Jun 24;16(12):5263–5276. doi: 10.1093/nar/16.12.5263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Herman J. P., Patel P. D., Akil H., Watson S. J. Localization and regulation of glucocorticoid and mineralocorticoid receptor messenger RNAs in the hippocampal formation of the rat. Mol Endocrinol. 1989 Nov;3(11):1886–1894. doi: 10.1210/mend-3-11-1886. [DOI] [PubMed] [Google Scholar]
  16. Hoeck W., Rusconi S., Groner B. Down-regulation and phosphorylation of glucocorticoid receptors in cultured cells. Investigations with a monospecific antiserum against a bacterially expressed receptor fragment. J Biol Chem. 1989 Aug 25;264(24):14396–14402. [PubMed] [Google Scholar]
  17. Hollenberg S. M., Weinberger C., Ong E. S., Cerelli G., Oro A., Lebo R., Thompson E. B., Rosenfeld M. G., Evans R. M. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985 Dec 19;318(6047):635–641. doi: 10.1038/318635a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huckaby C. S., Conneely O. M., Beattie W. G., Dobson A. D., Tsai M. J., O'Malley B. W. Structure of the chromosomal chicken progesterone receptor gene. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8380–8384. doi: 10.1073/pnas.84.23.8380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jeltsch J. M., Turcotte B., Garnier J. M., Lerouge T., Krozowski Z., Gronemeyer H., Chambon P. Characterization of multiple mRNAs originating from the chicken progesterone receptor gene. Evidence for a specific transcript encoding form A. J Biol Chem. 1990 Mar 5;265(7):3967–3974. [PubMed] [Google Scholar]
  20. Kastner P., Krust A., Turcotte B., Stropp U., Tora L., Gronemeyer H., Chambon P. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 1990 May;9(5):1603–1614. doi: 10.1002/j.1460-2075.1990.tb08280.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Laudet V., Begue A., Henry-Duthoit C., Joubel A., Martin P., Stehelin D., Saule S. Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene. Nucleic Acids Res. 1991 Mar 11;19(5):1105–1112. doi: 10.1093/nar/19.5.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Lubahn D. B., Brown T. R., Simental J. A., Higgs H. N., Migeon C. J., Wilson E. M., French F. S. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9534–9538. doi: 10.1073/pnas.86.23.9534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Miesfeld R. L. The structure and function of steroid receptor proteins. Crit Rev Biochem Mol Biol. 1989;24(2):101–117. doi: 10.3109/10409238909086395. [DOI] [PubMed] [Google Scholar]
  26. Miesfeld R., Okret S., Wikström A. C., Wrange O., Gustafsson J. A., Yamamoto K. R. Characterization of a steroid hormone receptor gene and mRNA in wild-type and mutant cells. Nature. 1984 Dec 20;312(5996):779–781. doi: 10.1038/312779a0. [DOI] [PubMed] [Google Scholar]
  27. Ponglikitmongkol M., Green S., Chambon P. Genomic organization of the human oestrogen receptor gene. EMBO J. 1988 Nov;7(11):3385–3388. doi: 10.1002/j.1460-2075.1988.tb03211.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rackwitz H. R., Zehetner G., Frischauf A. M., Lehrach H. Rapid restriction mapping of DNA cloned in lambda phage vectors. Gene. 1984 Oct;30(1-3):195–200. doi: 10.1016/0378-1119(84)90120-3. [DOI] [PubMed] [Google Scholar]
  29. Reik A., Schütz G., Stewart A. F. Glucocorticoids are required for establishment and maintenance of an alteration in chromatin structure: induction leads to a reversible disruption of nucleosomes over an enhancer. EMBO J. 1991 Sep;10(9):2569–2576. doi: 10.1002/j.1460-2075.1991.tb07797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rosewicz S., McDonald A. R., Maddux B. A., Goldfine I. D., Miesfeld R. L., Logsdon C. D. Mechanism of glucocorticoid receptor down-regulation by glucocorticoids. J Biol Chem. 1988 Feb 25;263(6):2581–2584. [PubMed] [Google Scholar]
  31. Strähle U., Klock G., Schütz G. A DNA sequence of 15 base pairs is sufficient to mediate both glucocorticoid and progesterone induction of gene expression. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7871–7875. doi: 10.1073/pnas.84.22.7871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Strähle U., Schmid W., Schütz G. Synergistic action of the glucocorticoid receptor with transcription factors. EMBO J. 1988 Nov;7(11):3389–3395. doi: 10.1002/j.1460-2075.1988.tb03212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yamamoto K. R. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–252. doi: 10.1146/annurev.ge.19.120185.001233. [DOI] [PubMed] [Google Scholar]
  34. Zong J., Ashraf J., Thompson E. B. The promoter and first, untranslated exon of the human glucocorticoid receptor gene are GC rich but lack consensus glucocorticoid receptor element sites. Mol Cell Biol. 1990 Oct;10(10):5580–5585. doi: 10.1128/mcb.10.10.5580. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES