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Chem Biol. 2001 May;8(5):427-36.

Differential SERM activation of the estrogen receptors (ERalpha and ERbeta) at AP-1 sites.

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  • 1Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0446, USA.

Abstract

BACKGROUND:

The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are triphenylethylene derivatives that affect transcriptional regulation by the estrogen receptors (ERalpha and ERbeta) 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 ERalpha and ERbeta and their ability to affect transcription of ERalpha and ERbeta at a consensus estrogen response element and an ER/AP-1 response element. The drugs were found to have the same affinity for ERalpha and ERbeta, although they were also found to activate transcription from an AP-1 promoter element more potently with ERbeta than with ERalpha. Derivatives of GW-5638 with alterations at the carboxylic acid still showed increased ERbeta potency compared to ERalpha, but the magnitude of the activation with ERalpha was much higher than with ERbeta.

CONCLUSIONS:

Despite similar binding affinities to isolated ERalpha and ERbeta, GW-5638 and GW-7604 show markedly lower EC(50) values with ERbeta at an AP-1-driven promoter as compared to ERalpha. 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 ERbeta than when bound to ERalpha.

PMID:
11358690
[PubMed - indexed for MEDLINE]
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