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J. Biol. Chem., Vol. 277, Issue 29, 26356-26363, July 19, 2002
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From the Department of Molecular & Integrative Physiology, College
of Medicine at Urbana-Champaign, University of Illinois,
Urbana, Illinois 61801
Phenobarbital (PB) induction of
CYP2B genes is mediated by translocation of the
constitutively active androstane receptor (CAR) to the nucleus.
Interaction of CAR with p160 coactivators and enhancement of CAR
transactivation by the coactivators have been shown in cultured cells.
In the present studies, the interaction of CAR with the p160
coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) was
examined in vitro and in vivo. Binding of GRIP1
to CAR was shown by glutathione S-transferase (GST)
pull-down and affinity DNA binding. N- or C-terminal fragments of GRIP1 that contained the central receptor-interacting domain bound to GST-CAR, but the presence of ligand increased the binding to GST-CAR of
only the fragments containing the C-terminal region. In gel shift
analysis, binding to CAR was observed only with GRIP1 fragments containing the C-terminal region, and the binding was increased by a
CAR agonist and decreased by a CAR antagonist. Expression of GRIP1
enhanced CAR-mediated transactivation in cultured hepatic-derived cells
2-3-fold. In hepatocytes transfected in vivo, expression of exogenous GRIP1 alone induced transactivation of the
CYP2B1 PB-dependent enhancer 15-fold, whereas
CAR expression alone resulted in only a 3-fold enhancement in untreated
mice. Remarkably, CAR and GRIP1 together synergistically transactivated
the enhancer about 150-fold, which is approximately equal to activation
by PB treatment. In PB-treated mice, expression of exogenous CAR alone
had little effect, expression of GRIP1 increased transactivation about
2-fold, and with CAR and GRIP, a 4-fold activation was observed. In
untreated mice, expression of GRIP resulted in nuclear translocation of
green fluorescent protein-CAR. These results strongly suggest that a
p160 coactivator functions in CAR-mediated transactivation in
vivo in response to PB treatment and that the synergistic
activation of CAR by GRIP in untreated animals results from both
nuclear translocation and activation of CAR.
Glucocorticoid Receptor-interacting Protein 1 Mediates
Ligand-independent Nuclear Translocation and Activation of
Constitutive Androstane Receptor in Vivo*
§,, and
*
This work was supported by Grant GM39360 from the National
Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
§
Present address: Chilam-Dong 150, Department of
Microbiological Engineering, Jinju National University, Jinju-City
660-758, Gyeongsangnam-Do, Korea.
¶
To whom correspondence should be addressed: Dept. of
Molecular & Integrative Physiology, University of Illinois at
Urbana-Champaign, 524 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL
61801. Tel.: 217-333-1146; Fax: 217-333-1133; E-mail:
byronkem@life.uiuc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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