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Transactivation Function 1 (AF-1) and AF-2 Mediated by Steroid Receptor Coactivator Protein-1: Requirement for the AF-1 -Helical Core and for a Direct Interaction Between the N- and C-Terminal Domains
Equipe d’Endocrinologie Moléculaire de la Reproduction, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6026, Université de Rennes I, 35042 Rennes Cedex, France
Address all correspondence and requests for reprints to: Farzad Pakdel, Equipe d’Endocrinologie Moléculaire de la Reproduction, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6026, Université de Rennes I, Rennes Cedex, France. E-mail: farzad.pakdel{at}univ-rennes1.fr
The transcriptional activity of ER
(or NR3A1) after binding of
ligand is mediated through synergistic action between activation
functions (AFs) AF-1 and AF-2 and the transcriptional machinery. This
is functionally achieved by bridging coactivators such as CEBP binding
protein/p300 and members of the p160 subfamily such as steroid
receptor coactivator protein-1 (SRC-1). We previously identified a
conserved potential -helical structure within the AF-1 functional
core, and by evaluating point mutants of human ER (hER) within
this region, we show that in transfection experiments this structure is
required for synergism between SRC-1 and hER. We report that the
transcriptional synergism between AF-1 mutants and SRC-1 was abolished
in AF-1-sensitive cells such as HepG2, whereas it was reduced by 50%
in CHO-K1 cells, which have a mixed context that is sensitive to both
the AF-1 and AF-2 regions of hER.
Glutathione-S-transferase pulldown assays demonstrate
that the AF-1 core is able and sufficient for the hER N-terminal
region to interact with SRC-1. Interestingly, an enhancement of this
recruitment in the presence of the hER ligand-binding domain was
observed, which was found to be dependent on a direct interaction
between the N-terminal B domain and the ligand-binding domain. Another
functional consequence of this physical interaction, which is promoted
by both partial and full agonists of hER, was an increase in the
phosphorylation state of the N-terminal domain. Binding of
4-hydroxytamoxifen (OHT) to the hER C-terminal region induced a
functional AF-1 conformation in vitro through this N-
and C-terminal interaction. The involvement of an SRC-1-mediated
pathway in transactivation mediated by hER AF-1 was further
substantiated by transfection experiments using the OHTresponsive human
C3 promoter, which showed that OHT-induced hER AF-1 activity was
enhanced by SRC-1 and required the AF-1 -helical structure. In
conclusion, we demonstrate that the synergism between AF-1 and AF-2 is
mediated in part by a cooperative recruitment of SRC-1 by both the AF-1
-helical core and AF-2 regions and that it is stabilized by a direct
interaction between the B and C-terminal domains. This interaction of
SRC-1 with the AF-1 -helical core is essential for both
E2- and OHT-induced ER activity.
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