Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists.

Details

Serval ID
serval:BIB_2E2C994779D3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Mahfoudi A., Roulet E., Dauvois S., Parker M.G., Wahli W.
ISSN
0027-8424 (Print)
ISSN-L
0027-8424
Publication state
Published
Issued date
05/1995
Volume
92
Number
10
Pages
4206-4210
Language
english
Notes
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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 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.
Keywords
Amino Acid Sequence, Animals, Binding Sites, Cell Line, Chickens, Conserved Sequence, DNA-Binding Proteins/chemistry, DNA-Binding Proteins/metabolism, Estradiol/analogs & derivatives, Estradiol/pharmacology, Estrogen Antagonists/pharmacology, Gene Expression/drug effects, Gene Expression/physiology, HeLa Cells, Humans, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Oncorhynchus mykiss, Point Mutation, Polyunsaturated Alkamides, Protein Structure, Secondary, Rats, Receptors, Estrogen/agonists, Receptors, Estrogen/chemistry, Recombinant Proteins/agonists, Recombinant Proteins/chemistry, Sequence Homology, Amino Acid, Tamoxifen/analogs & derivatives, Tamoxifen/pharmacology, Transcription, Genetic/drug effects, Transfection, Xenopus
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 16:04
Last modification date
20/08/2019 13:12
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