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Promoter Capture Hi-C: High-resolution, Genome-wide Profiling of Promoter Interactions
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The extreme C terminus of progesterone receptor contains a transcriptional repressor domain that functions through a

J Xu1, Z Nawaz, S Y Tsai

  • 1Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 29, 1996
PubMed

Insights

A 12-amino acid region in the human progesterone receptor (hPR) C-terminus acts as a repressor, inhibiting transcription with antagonists like RU486. Mutations or overexpression of this domain activate the receptor.

Area of Science:

  • Molecular Endocrinology
  • Steroid Receptor Signaling
  • Gene Transcription Regulation

Background:

  • Hormone agonists activate steroid receptors via conformational changes, DNA binding, and gene activation.
  • The progesterone antagonist RU486 induces most receptor activation steps but fails to trigger transcription of human progesterone receptor (hPR)-dependent genes.
  • Previous studies indicated a key conformational change, particularly in the C-terminus, differentiates hormone- and antihormone-bound receptors.

Purpose of the Study:

  • To identify the specific region within the hPR C-terminus responsible for repressing transcriptional activity in the presence of the antagonist RU486.
  • To investigate the functional role of this identified repressor domain in regulating hPR activity.

Main Methods:

  • Construction and analysis of hPR mutants lacking the C-terminus.
  • Fusion of truncated hPR or GAL4 DNA-binding domain with specific C-terminal regions.
  • Site-directed mutagenesis of the identified 12-amino acid (12AA) domain (aa 917-928).
  • Overexpression studies of the 12AA peptide in wild-type hPR.

Main Results:

  • A 12AA region (aa 917-928) in the hPR C-terminus was identified as necessary and sufficient for repressor function.
  • Mutations within this 12AA domain rendered the hPR transcriptionally active in the presence of RU486.
  • Overexpression of the 12AA peptide activated RU486-bound wild-type hPR without affecting progesterone-mediated activation.
  • These findings suggest the 12AA region may recruit corepressors to inhibit hPR activity upon RU486 binding.

Conclusions:

  • The C-terminal 12AA region of hPR functions as a potent repressor domain, specifically inhibiting transcription when the receptor is bound by antagonists like RU486.
  • This repressor domain's activity appears to be modulated by corepressor association, influencing the transcriptional outcome.
  • Understanding this repressor mechanism provides insights into differential activation by agonists versus antagonists and potential therapeutic targeting.

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