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PMID: 7972059 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Antiprogestins prevent progesterone receptor binding to hormone responsive elements in vivo.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 91 ·No. 24 ·1994-11-22 ·Pages 11333-7

Truss M, Bartsch J, Beato M

Abstract

Antiprogestins inhibit progesterone action by competing for binding to the progesterone receptor and are potentially important pharmaceuticals in fertility control and cancer therapy. Why the complex of antiprogestins and progesterone receptor is functionally inactive is unclear. Present models are based on indirect evidence, such as transfection competition assays and in vitro DNA binding studies, partly because of difficulties in visualizing the receptor bound to DNA in vivo. Here we used genomic footprinting analysis to show ligand-dependent binding of endogenous progesterone receptor to the hormone responsive elements (HREs) of a chromosomally integrated mouse mammary tumor virus long terminal repeat in a human mammary carcinoma cell line. The antiprogestins RU 486 and ZK 98299 do not promote binding of the progesterone receptor to this natural HRE in vivo, even at concentrations that completely inhibit the agonistic effects of potent synthetic progestins. Moreover, antiprogestins cause a rapid disappearance of the agonist-induced progesterone receptor footprint. We conclude that antiprogestins interfere with receptor function by preventing its specific DNA binding.

MeSH Terms
Base Sequence Cell Line DNA-Binding Proteins/metabolism Gene Expression Regulation Gonanes/pharmacology Humans In Vitro Techniques Mammary Tumor Virus, Mouse/genetics Mifepristone/pharmacology Molecular Sequence Data Oligodeoxyribonucleotides/chemistry Progestins/antagonists & inhibitors Promegestone/pharmacology Promoter Regions, Genetic RNA, Messenger/genetics Receptors, Progesterone/metabolism Transcription, Genetic
Chemicals
DNA-Binding Proteins Gonanes Oligodeoxyribonucleotides Progestins RNA, Messenger Receptors, Progesterone Mifepristone Promegestone onapristone
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Truss M
Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Germany.
Bartsch J
Beato M
References (37)
37 references, click to expand
  1. In vivo footprinting of rat TAT gene: dynamic interplay between the glucocorticoid receptor and a liver-specific factor.
    Cell. 1991 Nov 29;67(5):977-86 PMID: 1683601
  2. Progestin receptors: isoforms and antihormone action.
    J Steroid Biochem Mol Biol. 1991;40(1-3):271-8 PMID: 1958531
  3. In vitro activity of the transcription activation functions of the progesterone receptor. Evidence for intermediary factors.
    J Biol Chem. 1992 Jan 25;267(3):1834-9 PMID: 1730721
  4. Effects of hormone and cellular modulators of protein phosphorylation on transcriptional activity, DNA binding, and phosphorylation of human progesterone receptors.
    Mol Endocrinol. 1992 Apr;6(4):607-20 PMID: 1316549
  5. The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor.
    Cell. 1992 May 15;69(4):703-13 PMID: 1586949
  6. Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation.
    J Biol Chem. 1992 Sep 25;267(27):19513-20 PMID: 1326555
  7. Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor.
    Biochemistry. 1992 Nov 3;31(43):10491-501 PMID: 1420166
  8. Ligands induce conformational changes in the carboxyl-terminus of progesterone receptors which are detected by a site-directed antipeptide monoclonal antibody.
    Mol Endocrinol. 1992 Oct;6(10):1585-97 PMID: 1448113
  9. Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP.
    J Biol Chem. 1993 May 5;268(13):9262-6 PMID: 8387487
  10. In vivo evidence against the existence of antiprogestins disrupting receptor binding to DNA.
    Proc Natl Acad Sci U S A. 1993 May 15;90(10):4421-5 PMID: 8506282
  11. The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.
    Proc Natl Acad Sci U S A. 1993 May 15;90(10):4441-5 PMID: 8389450
  12. Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone.
    Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6120-4 PMID: 8327492
  13. Latent agonist activity of the steroid antagonist, RU486, is unmasked in cells treated with activators of protein kinase A.
    Mol Endocrinol. 1993 Jun;7(6):731-42 PMID: 8395651
  14. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors.
    Endocr Rev. 1993 Aug;14(4):459-79 PMID: 8223341
  15. Newly expressed progesterone receptor cannot activate stable, replicated mouse mammary tumor virus templates but acquires transactivation potential upon continuous expression.
    Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11202-6 PMID: 8248228
  16. Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function.
    Mol Endocrinol. 1993 Oct;7(10):1244-55 PMID: 8264658
  17. Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors.
    Mol Endocrinol. 1993 Oct;7(10):1256-65 PMID: 8123133
  18. Steroid receptor analyses of nine human breast cancer cell lines.
    Cancer Res. 1978 Aug;38(8):2434-7 PMID: 667841
  19. A chimaeric receptor allows insulin to stimulate tyrosine kinase activity of epidermal growth factor receptor.
    Nature. 1986 Nov 6-12;324(6092):68-70 PMID: 3024008
  20. Steroid-free glucocorticoid receptor binds specifically to mouse mammary tumour virus DNA.
    Nature. 1986 Dec 18-31;324(6098):688-91 PMID: 3025742
  21. Steroid-dependent interaction of transcription factors with the inducible promoter of mouse mammary tumor virus in vivo.
    Cell. 1987 Jan 30;48(2):261-70 PMID: 3026639
  22. Antiglucocorticosteroid effects suggest why steroid hormone is required for receptors to bind DNA in vivo but not in vitro.
    Nature. 1987 Aug 13-19;328(6131):624-6 PMID: 3614365
  23. Differential gene activation by glucocorticoids and progestins through the hormone regulatory element of mouse mammary tumor virus.
    Cell. 1988 May 6;53(3):371-82 PMID: 2835167
  24. Unspecific and sequence-specific deoxyribonucleic acid binding of the partially purified human progesterone receptor.
    Mol Endocrinol. 1988 Jun;2(6):571-8 PMID: 2843763
  25. Receptors bound to antiprogestin from abortive complexes with hormone responsive elements.
    Nature. 1988 Dec 15;336(6200):695-8 PMID: 3200320
  26. Steroid hormone-dependent interaction of human progesterone receptor with its target enhancer element.
    Mol Endocrinol. 1988 Dec;2(12):1221-9 PMID: 3216861
  27. Gene regulation by steroid hormones.
    Cell. 1989 Feb 10;56(3):335-44 PMID: 2644044
  28. Binding of hormone accelerates the kinetics of glucocorticoid and progesterone receptor binding to DNA.
    Proc Natl Acad Sci U S A. 1989 Feb;86(4):1123-7 PMID: 2919163
  29. Human progesterone receptor binding to mouse mammary tumor virus deoxyribonucleic acid: dependence on hormone and nonreceptor nuclear factor(s).
    Mol Endocrinol. 1989 Feb;3(2):381-91 PMID: 2540430
  30. Genomic sequencing and methylation analysis by ligation mediated PCR.
    Science. 1989 Nov 10;246(4931):810-3 PMID: 2814502
  31. Human progesterone receptor complexed with the antagonist RU 486 binds to hormone response elements in a structurally altered form.
    Mol Endocrinol. 1989 Oct;3(10):1545-58 PMID: 2608048
  32. Nuclear factor I acts as a transcription factor on the MMTV promoter but competes with steroid hormone receptors for DNA binding.
    EMBO J. 1990 Jul;9(7):2233-9 PMID: 2162764
  33. Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor.
    EMBO J. 1990 Dec;9(12):3923-32 PMID: 2249658
  34. Scaffold-attached regions from the human interferon beta domain can be used to enhance the stable expression of genes under the control of various promoters.
    Biochemistry. 1991 Feb 5;30(5):1264-70 PMID: 1991107
  35. Ubiquitous transcription factor OTF-1 mediates induction of the MMTV promoter through synergistic interaction with hormone receptors.
    Cell. 1991 Feb 8;64(3):565-72 PMID: 1846780
  36. Two types of antiprogestins identified by their differential action in transcriptionally active extracts from T47D cells.
    Nucleic Acids Res. 1991 Mar 25;19(6):1227-34 PMID: 2030942
  37. Dopaminergic and ligand-independent activation of steroid hormone receptors.
    Science. 1991 Dec 13;254(5038):1636-9 PMID: 1749936
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.91.24.11333
Published
1994-11-22
Pages
11333-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC45225
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.91.24.11333 PMC Full Text View journal details
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