Differential SERM activation of the estrogen receptors (ERα and ERβ) at AP-1 sites

Ross V. Weatherman, Nicola J. Clegg, Thomas S. Scanlan

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Background: The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are triphenylethylene derivatives that affect transcriptional regulation by the estrogen receptors (ERα and ERβ) but show different effects in different tissues. A third triphenylethylene derivative, GW-5638, displays tissue selectivity in rats identical to that of raloxifene, suggesting that GW-5638 and raloxifene share a mechanism of action that is different from that of tamoxifen. Results: Both GW-5638 and its hydroxylated analog GW-7604 were tested for their ability to bind to ERα and ERβ and their ability to affect transcription of ERα and ERβ at a consensus estrogen response element and an ER/AP-1 response element. The drugs were found to have the same affinity for ERα and ERβ, although they were also found to activate transcription from an AP-1 promoter element more potently with ERβ than with ERα. Derivatives of GW-5638 with alterations at the carboxylic acid still showed increased ERβ potency compared to ERα, but the magnitude of the activation with ERα was much higher than with ERβ. Conclusions: Despite similar binding affinities to isolated ERα and ERβ, GW-5638 and GW-7604 show markedly lower EC50 values with ERβ at an AP-1-driven promoter as compared to ERα. This suggests that the two compounds produce a more active ER/AP-1 conformation of the ER/AP-1 transcription factor complex when bound to ERβ than when bound to ERα.

Original languageEnglish (US)
Pages (from-to)427-436
Number of pages10
JournalChemistry and Biology
Volume8
Issue number5
DOIs
StatePublished - May 1 2001

Keywords

  • AP-1
  • Estrogen receptor
  • GW-5638
  • Raloxifene
  • SERM
  • Tamoxifen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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