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Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists

C A Sartorius1, L Tung, G S Takimoto

  • 1Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.

The Journal of Biological Chemistry
|May 5, 1993
PubMed

Insights

Elevating cAMP levels can reverse the action of progesterone antagonists, turning them into activators of transcription. This effect requires the antagonist-bound progesterone receptors (hPR) to bind DNA, offering new therapeutic insights.

Area of Science:

  • Molecular Endocrinology
  • Cancer Biology
  • Signal Transduction

Background:

  • Steroid hormone antagonists can exhibit dangerous agonist effects.
  • Progesterone antagonists interact with human progesterone receptors (hPR) isoforms, hPRB and hPRA.
  • Typically, progesterone antagonists inhibit agonist-stimulated transcription.

Purpose of the Study:

  • To investigate the functional reversal of progesterone antagonist action.
  • To explore the role of cAMP in modulating progesterone receptor activity.
  • To understand the mechanism underlying antagonist-induced transcriptional changes.

Main Methods:

  • Utilized a human breast cancer cell line and COS-1 cells.
  • Administered 8-Br-cAMP to elevate intracellular cAMP levels.
  • Assessed transcriptional activity using reporter genes with antagonist- and agonist-occupied hPR.
  • Investigated hPR binding to DNA and receptor phosphorylation.

Main Results:

  • Elevated cAMP levels reversed the action of progesterone antagonists RU486 and ZK112993, converting them into transcriptional activators.
  • This reversal was dependent on hPR binding to DNA; antagonist ZK98299, which does not bind DNA, did not show reversal.
  • cAMP synergistically increased transcriptional activity even with agonist-occupied hPR.
  • cAMP-mediated transcriptional effects occurred independently of hPR and its DNA-binding ability, and without PKA-mediated phosphorylation.

Conclusions:

  • cAMP can functionally reverse progesterone antagonist activity, contingent on receptor-DNA binding.
  • A model is proposed where cAMP-responsive factors and hPR interact to regulate gene transcription.
  • Findings suggest potential therapeutic strategies by modulating cAMP to control antagonist efficacy.

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