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Titolo:
Differential SERM activation of the estrogen receptors (ER alpha and ER beta) at AP-1 sites
Autore:
Weatherman, RV; Clegg, NJ; Scanlon, TS;
Indirizzi:
Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA Univ Calif San Francisco San Francisco CA USA 94143 ancisco, CA 94143 USA Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA94143 USA Univ Calif San Francisco San Francisco CA USA 94143 rancisco, CA94143 USA
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 5, volume: 8, anno: 2001,
pagine: 427 - 436
SICI:
1074-5521(200105)8:5<427:DSAOTE>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
LIGAND; ANTIESTROGENS; VITELLOGENIN; COACTIVATOR; TAMOXIFEN; REGION; BONE;
Keywords:
estrogen receptor; GW-5638; raloxifene; SERM; tamoxifen; AP-1;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
21
Recensione:
Indirizzi per estratti:
Indirizzo: Scanlon, TS Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco,CA 94143 USA Univ Calif San Francisco San Francisco CA USA 94143 94143 USA
Citazione:
R.V. Weatherman et al., "Differential SERM activation of the estrogen receptors (ER alpha and ER beta) at AP-1 sites", CHEM BIOL, 8(5), 2001, pp. 427-436

Abstract

Background: The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are triphenylethylene derivatives that affect transcriptionalregulation by the estrogen receptors (ER alpha and ER beta) 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 isdifferent From that of tamoxifen. Results: Both GW-5638 and its hydroxylated analog GW-7604 were tested for their ability to bind to ER alpha and ER beta and their ability to affect transcription of ER alpha and ER beta at a consensus estrogen response element and an ER/AP-1 response element. The drugs were found to have the same affinity for ER alpha and ER beta. although they were also found to activatetranscription from an AP-1 promoter element more potently with ER beta than with ER alpha. Derivatives of GW-5638 with alterations at the carboxylic acid still showed increased ER beta potency compared to ER alpha, but the magnitude of the activation with ER alpha was much higher than with ER beta. Conclusions: Despite similar binding affinities to isolated ER alpha and ER beta, GW-5638 and GW-7604 show markedly lower EC50 values with ER beta atan AP-1-driven promoter as compared to ER alpha. 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 ER beta than when bound to ER alpha. (C) 2001 Elsevier Science Ltd. All rights reserved.

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Documento generato il 20/01/21 alle ore 02:55:03