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Titolo:
SPECIFIC MUTATIONS IN THE ESTROGEN-RECEPTOR CHANGE THE PROPERTIES OF ANTIESTROGENS TO FULL AGONISTS
Autore:
MAHFOUDI A; ROULET E; DAUVOIS S; PARKER MG; WAHLI W;
Indirizzi:
UNIV LAUSANNE,INST BIOL ANIM,BATIMENT BIOL CH-1015 LAUSANNE SWITZERLAND UNIV LAUSANNE,INST BIOL ANIM CH-1015 LAUSANNE SWITZERLAND GLAXO INST MOLEC BIOL SA CH-1228 PLAN LES OUATES SWITZERLAND IMPERIAL CANC RES FUND,MOLEC ENDOCRINOL LAB LONDON WC2A 3PX ENGLAND
Titolo Testata:
Proceedings of the National Academy of Sciences of the United Statesof America
fascicolo: 10, volume: 92, anno: 1995,
pagine: 4206 - 4210
SICI:
0027-8424(1995)92:10<4206:SMITEC>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
EUKARYOTIC TRANSCRIPTIONAL ACTIVATORS; BREAST-CANCER; MAMMALIAN-CELLS; RESPONSIVE ELEMENT; SEQUENCE; EXPRESSION; IDENTIFICATION; BINDING; REGION; GENE;
Keywords:
TAMOXIFEN; ICI 164,384; ACTIVATION FUNCTION; NUCLEAR LOCALIZATION; HORMONE THERAPY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
53
Recensione:
Indirizzi per estratti:
Citazione:
A. Mahfoudi et al., "SPECIFIC MUTATIONS IN THE ESTROGEN-RECEPTOR CHANGE THE PROPERTIES OF ANTIESTROGENS TO FULL AGONISTS", Proceedings of the National Academy of Sciences of the United Statesof America, 92(10), 1995, pp. 4206-4210

Abstract

The estrogen receptor (ER) stimulates transcription of target genes by means of its two transcriptional activation domains, AF-1 in the N-terminal part of the receptor and AF-2 in its ligand-binding domain. AF-2 activity is dependent upon a putative amphipathic alpha-helix between residues 538 and 552 in the mouse ER Point mutagenesis of conservedhydrophobic residues within this region reduces estrogen-dependent transcriptional activation without affecting hormone and DNA binding significantly. Here we show that these mutations dramatically alter the pharmacology of estrogen antagonists. Both tamoxifen and ICI 164,384 behave as strong agonists in HeLa cells expressing the ER mutants. In contrast to the wild-type ER, the mutant receptors maintain nuclear localization and DNA-binding activity after ICI 164,384 treatment. Structural alterations in AF-2 caused by gene mutations such as those described herein or by estrogen-independent signaling pathways may account for the insensitivity of some breast cancers to tamoxifen treatment.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 21:36:59