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Proc Natl Acad Sci U S A
1995 May 09;9210:4206-10.
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Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists.
Mahfoudi A
,
Roulet E
,
Dauvois S
,
Parker MG
,
Wahli W
.
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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 conserved hydrophobic 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.
Beato,
Gene regulation by steroid hormones.
1989, Pubmed
Beato,
Gene regulation by steroid hormones.
1989,
Pubmed
Berry,
Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen.
1990,
Pubmed
Borgna,
High-affinity binding to the estrogen receptor of [3H]4-hydroxytamoxifen, an active antiestrogen metabolite.
1980,
Pubmed
Bowler,
Novel steroidal pure antiestrogens.
1989,
Pubmed
Cavaillès,
Interaction of proteins with transcriptionally active estrogen receptors.
1994,
Pubmed
Danielian,
Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors.
1992,
Pubmed
Danielian,
Identification of residues in the estrogen receptor that confer differential sensitivity to estrogen and hydroxytamoxifen.
1993,
Pubmed
Dauvois,
Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover.
1992,
Pubmed
Dauvois,
The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling.
1993,
Pubmed
Evans,
The steroid and thyroid hormone receptor superfamily.
1988,
Pubmed
Fuqua,
Estrogen receptor mutations in breast cancer.
1993,
Pubmed
Gibson,
The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of estrogen receptor in uterine tissue.
1991,
Pubmed
Goodrich,
Drosophila TAFII40 interacts with both a VP16 activation domain and the basal transcription factor TFIIB.
1993,
Pubmed
Gorman,
Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells.
1982,
Pubmed
Green,
Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A.
,
Pubmed
Greene,
Immunochemical studies of estrogen receptors.
1984,
Pubmed
Halachmi,
Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription.
1994,
Pubmed
Ham,
Regulation of gene expression by nuclear hormone receptors.
1989,
Pubmed
Hoey,
Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators.
1993,
Pubmed
Ing,
Members of the steroid hormone receptor superfamily interact with TFIIB (S300-II).
1992,
Pubmed
Jacq,
Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor.
1994,
Pubmed
Jordan,
Endocrine pharmacology of antiestrogens as antitumor agents.
1990,
Pubmed
Karnik,
Estrogen receptor mutations in tamoxifen-resistant breast cancer.
1994,
Pubmed
Klein-Hitpass,
An estrogen-responsive element derived from the 5' flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells.
1986,
Pubmed
,
Xenbase
Koike,
Molecular cloning and characterization of rat estrogen receptor cDNA.
1987,
Pubmed
Krust,
The chicken oestrogen receptor sequence: homology with v-erbA and the human oestrogen and glucocorticoid receptors.
1986,
Pubmed
Kumar,
The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer.
1988,
Pubmed
Lees,
Identification of two transactivation domains in the mouse oestrogen receptor.
1989,
Pubmed
Martin,
Evidence for interaction of different eukaryotic transcriptional activators with distinct cellular targets.
1990,
Pubmed
Martinez,
Cooperative binding of estrogen receptor to imperfect estrogen-responsive DNA elements correlates with their synergistic hormone-dependent enhancer activity.
1989,
Pubmed
,
Xenbase
Mitchell,
Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins.
1989,
Pubmed
Morrow,
Molecular mechanisms of resistance to tamoxifen therapy in breast cancer.
1993,
Pubmed
NULL,
Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by Nolvadex Adjuvant Trial Organisation.
1983,
Pubmed
Pakdel,
Human estrogen receptor mutants with altered estrogen and antiestrogen ligand discrimination.
1992,
Pubmed
Pakdel,
Full-length sequence and in vitro expression of rainbow trout estrogen receptor cDNA.
1990,
Pubmed
Powles,
The case for clinical trials of tamoxifen for prevention of breast cancer.
1992,
Pubmed
Ptashne,
How eukaryotic transcriptional activators work.
1988,
Pubmed
Pugh,
Mechanism of transcriptional activation by Sp1: evidence for coactivators.
1990,
Pubmed
Sadovsky,
Transcriptional activators differ in their responses to overexpression of TATA-box-binding protein.
1995,
Pubmed
Sporn,
Chemoprevention of cancer.
1993,
Pubmed
Tasset,
Distinct classes of transcriptional activating domains function by different mechanisms.
1990,
Pubmed
Tora,
The human estrogen receptor has two independent nonacidic transcriptional activation functions.
1989,
Pubmed
Wahli,
Superfamily of steroid nuclear receptors: positive and negative regulators of gene expression.
1991,
Pubmed
Wakeling,
Biology and mode of action of pure antioestrogens.
1988,
Pubmed
Wakeling,
A potent specific pure antiestrogen with clinical potential.
1991,
Pubmed
Walker,
Sequence homologies in the region preceding the transcription initiation site of the liver estrogen-responsive vitellogenin and apo-VLDLII genes.
1984,
Pubmed
,
Xenbase
Weiler,
The Xenopus laevis estrogen receptor: sequence homology with human and avian receptors and identification of multiple estrogen receptor messenger ribonucleic acids.
1987,
Pubmed
,
Xenbase
White,
Structural organization and expression of the mouse estrogen receptor.
1987,
Pubmed
Wolf,
The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain.
1994,
Pubmed
Wrenn,
Structure-function analysis of the hormone binding domain of the human estrogen receptor by region-specific mutagenesis and phenotypic screening in yeast.
1993,
Pubmed
Zawel,
Advances in RNA polymerase II transcription.
1992,
Pubmed
de Wet,
Firefly luciferase gene: structure and expression in mammalian cells.
1987,
Pubmed