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Titolo:
Paradoxical interactions among estrogen receptors, estrogens and SERMS: mutual annihilation and synergy
Autore:
Kaye, AM; Spatz, M; Waisman, A; Sasson, S; Tamir, S; Vaya, J; Somjen, D;
Indirizzi:
Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel Weizmann Inst Sci Rehovot Israel IL-76100 enet, IL-76100 Rehovot, Israel Pharmos Ltd, IL-76326 Rehovot, Israel Pharmos Ltd Rehovot Israel IL-76326 harmos Ltd, IL-76326 Rehovot, Israel Hebrew Univ Jerusalem, Dept Pharmacol, Sch Pharm, Fac Med, IL-91120 Jerusalem, Israel Hebrew Univ Jerusalem Jerusalem Israel IL-91120 -91120 Jerusalem, Israel Migal Galilee Technol Inst, Kiryat Shmona, Israel Migal Galilee Technol Inst Kiryat Shmona Israel , Kiryat Shmona, Israel Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel Tel Aviv Univ Tel Aviv Israel IL-69978 ac Med, IL-69978 Tel Aviv, Israel Tel Aviv Sourasky Med Ctr, Inst Endocrinol, Tel Aviv, Israel Tel Aviv Sourasky Med Ctr Tel Aviv Israel Endocrinol, Tel Aviv, Israel
Titolo Testata:
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
fascicolo: 1-5, volume: 76, anno: 2001,
pagine: 85 - 93
SICI:
0960-0760(200101/03)76:1-5<85:PIAERE>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
CREATINE-KINASE ACTIVITY; PARATHYROID-HORMONE; CELL-LINES; B ACTIVITY; IN-VITRO; BINDING; TAMOXIFEN; GENE; ANTIESTROGENS; STIMULATION;
Keywords:
17 beta-estradiol; estrogens; SERMS; creatine kinase B; antagonism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Kaye, AM Weizmann Inst Sci, Dept Mol Genet, POB 26, IL-76100 Rehovot, Israel Weizmann Inst Sci POB 26 Rehovot Israel IL-76100 Rehovot, Israel
Citazione:
A.M. Kaye et al., "Paradoxical interactions among estrogen receptors, estrogens and SERMS: mutual annihilation and synergy", J STEROID B, 76(1-5), 2001, pp. 85-93

Abstract

The phenomenon of mutual annihilation of action between 17 beta estradiol (E-2) and a selective estrogen receptor modulator (SERM), previously described in prepubertal rat diaphysis, epiphysis and uterus, has been investigated in ROS 17/2.8 rat osteoblastic cells and in transiently co-transfected cells in culture. In ROS 17/2.8 cells, the estrogen-induced marker enzyme creatine kinase B (CKB) was stimulated by raloxifene, tamoxifen and tamoxifenmethiodide to a specific activity equal to or greater than that induced by10 nM E-2. However, when a fully inhibitory dose of any of these SERMS wasgiven simultaneously with E-2, no Stimulation of CK activity resulted. Therefore, SERMS can be full agonists when acting alone, but complete antagonists to a super-physiological dose of estrogen. It is expected that excess tamoxifen would prevent the action of a SERM, but that the agonist activity of a SERM is abolished by 1000-fold less estrogen is a phenomenon without obvious explanation by classical pharmacology of competitive inhibition. To probe the mechanism of this interaction further, a ckb-CAT reporter plasmid, plus the human receptor expression plasmid, HEO, was transfected transiently into several cell types. In MCF-7 cells, a 1:10 ratio of E-2 to tamoxifen produced mutual annihilation, but the same ratio in ROS 17/2.8 or HeLa cells led to synergistic stimulation. In HeLa cells, co-transfected with themore efficient wild-type estrogen receptor plasmid, HEGO, synergy was demonstrated only at sub-saturation levels of HEGO. We speculate that, in the presence of estradiol and a SERM, not only active homodimers would be formed, but also hetero-dimers of estrogen-liganded and tamoxifen-liganded receptor monomers, depending on the molar ratio of their ligands and their relative affinities. The resulting hetero-dimer conformation would change the specific receptor surface for interactions with the growing number of co-activators and co-repressors, structural changes which could help to explain themutual annihilation and synergy phenomena and their cell selectivity. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 14/07/20 alle ore 19:23:14