Changes in the structure of the ligand or substitutions to AF2 residues inthe estrogen receptor make independent contributions to coactivator sensitivity by SRC-1
Ja. Schwartz et Sc. Brooks, Changes in the structure of the ligand or substitutions to AF2 residues inthe estrogen receptor make independent contributions to coactivator sensitivity by SRC-1, J STEROID B, 67(3), 1998, pp. 223-232
Citations number
67
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
The estrogen receptor (ER) is a ligand-inducible transcription factor which
depends, in part, upon the C-terminal activation function (AF2) in order t
o regulate the expression of target genes. AF2 residues fold into an amphip
athic alpha-helix on helix 12 of the ER, with hydrophobic and acidic faces.
It is believed that AF2 mediates the gene regulatory activities of ligand-
activated ER by interacting with coactivator proteins. We have analyzed the
contribution of acidic AF2 residues to the process of ER coactivation by t
he steroid receptor coactivator, SRC-1. In HeLa cells, SRC-1 coexpression w
as found to restore transcriptional potency to otherwise inert complexes of
wild type ER and 4-hydroxyestratrien-17 beta-ol. SRC-1 coexpression also e
nhanced transcriptional activity of reporter genes induced by an ER mutant
with neutral replacements to acidic AF2 residues, in response to E2 or 4-hy
droxyestratrien-17 beta-ol. By contrast, ER complexes from ICI164,384-treat
ed HeLa cells were both transcriptionally inactive and coactivator insensit
ive. It is concluded that changes to the structure of the ligand or substit
utions to acidic residues in the AF2 region of the receptor contribute inde
pendently to the control of coactivator sensitivity in ER. (C) 1998 Elsevie
r Science Ltd. All rights reserved.