Human progesterone receptor complexed with the antagonist RU 486 binds to hormone response elements in a structurally altered form

Dorraya El-Ashry, S. A. Onate, S. K. Nordeen, D. P. Edwards

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Structural and functional properties of human progesterone receptor (PR) bound with the antiprogestin, RU 486, and the progestin agonist, R5020, were compared in order to identify receptor mechanisms responsible for the inability of RU 486 to activate the transcriptional capacity of receptors. RU 486 interaction with human PR did not inhibit receptor transformation as assessed by dissociation of nontransformed 8-10S oligomeric receptors (in vitro and in vivo) and by tight binding of PR to nuclei/chromatin in whole cells. Assays based on immunoprecipitation of PR-DNA complexes with an antibody to human PR and gel retardation were used to analyze the effect of RU 486 on receptor binding to the hormone response element (HRE) of the mouse mammary tumor virus (MMTV). RU 486 did not impair PR recognition of the MMTV HRE. Quantitative affinity constants and kinetic parameters of PR binding to these specific DNA sites were similar for receptors complexed with either agonist or antagonist. However, PR-RU 486 complexes exhibited an altered sedimentation rate on sucrose gradients and a faster mobility when bound to the MMTV HRE as assessed by gel retardation. These results indicate that human PR transformed by RU 486 exhibit no impairment in binding to specific DNA sites of target genes, but when bound to DNA assumes a structural form different from that of the receptor-agonist conplex. We propose that failure of PR-RU 486 complexes to activate transcription results from this structural alteration in PR, which does not permit protein-protein interactions required for receptor-mediated induction of gene transcription.

Original languageEnglish
Pages (from-to)1545-1558
Number of pages14
JournalMolecular Endocrinology
Volume3
Issue number10
StatePublished - Jan 1 1989
Externally publishedYes

Fingerprint

Mifepristone
Response Elements
Progesterone Receptors
Hormones
Mouse mammary tumor virus
DNA
Gels
Promegestone
Progestins
Immunoprecipitation
Genes
Chromatin
Sucrose
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Human progesterone receptor complexed with the antagonist RU 486 binds to hormone response elements in a structurally altered form. / El-Ashry, Dorraya; Onate, S. A.; Nordeen, S. K.; Edwards, D. P.

In: Molecular Endocrinology, Vol. 3, No. 10, 01.01.1989, p. 1545-1558.

Research output: Contribution to journalArticle

El-Ashry, Dorraya ; Onate, S. A. ; Nordeen, S. K. ; Edwards, D. P. / Human progesterone receptor complexed with the antagonist RU 486 binds to hormone response elements in a structurally altered form. In: Molecular Endocrinology. 1989 ; Vol. 3, No. 10. pp. 1545-1558.
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