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J Biol Chem, Vol. 273, Issue 45, 29291-29294, November 6, 1998
B Signaling by CREB-binding Protein and Steroid Receptor
Coactivator-1*
,,,
,
From the Vascular Research Division, Department of
Pathology, Brigham and Women's Hospital, and Harvard Medical School,
Boston, Massachusetts 02115, the § Department of
Biochemistry and Molecular Biophysics, Columbia University, New York,
New York 10032, the ¶ Department of Cellular and Molecular
Medicine, School and Department of Medicine, University of California,
San Diego, California 92093, §§ Howard Hughes Medical
Institute, University of California at San Diego, La Jolla, California
92093 and ** Genentech, Inc., South San Francisco, California 94080
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ABSTRACT |
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Top
Abstract
Introduction
Procedures
Results & Discussion
References
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The p65 (RelA) component of nuclear factor- Nuclear factor- Glucocorticoid hormones modulate the expression of a variety of genes
associated with inflammatory responses by binding to a widely expressed
intracellular receptor (GR). The GR is a member of the nuclear receptor
family of proteins, which have a conserved modular architecture
consisting of three functional domains: a DNA-binding domain,
transcriptional activating domain, and a ligand-binding domain (7, 8).
Transcriptional activation by this class of receptors requires that
part of the C-terminal ligand-binding domain (called AF2) undergo a
conformational change upon binding of ligand. This enables the
receptors to bind a series of coactivator proteins, such as SRC-1 and
CBP (9). Induction of gene expression by GR may contribute to the
effects of glucocorticoid hormones, but recent findings suggest that
DNA binding by GR is not required for some of the physiologic functions
of the receptor (10, 11).
Previous studies found that activation of NF- Cells and Transfections--
Bovine aortic endothelial cells
were obtained as described previously (17). COS-7 cells were obtained
from the American Type Culture Collection (ATCC). The COS cells were
transfected by the modified CaCl2 method as described in
Ref. 17 and in the figure legends. Whole cell extracts were prepared
from the transfected cells, and CAT activity was determined, as
described previously (17).
In studies with the GRE-NF Plasmids--
The plasmid construct p-578 E-selectin CAT was
prepared as described previously (4). CBP regions 1-100, 1-771,
706-1069, 1069-1892, and 1892-2441 were amplified by polymerase
chain reaction and inserted into pGex vectors as described previously
(4). Full-length CBP expression vector was provided by R. Goodman
(Oregon Health Science University, Portland, OR).
Three minimal promoter-reporter constructs were used in these
studies. First, a GRE-CAT construct was provided by Dr. Robert Scheinman (University of Colorado, Denver, CO) and consists
of two GRE sites in a minimal TATA box containing E1B promoter
(18). The isolated NF- GST Binding Assay--
Fragments of the CBP coding sequence were
subcloned in-frame into pGEX vectors (Amersham Pharmacia Biotech). GST
fusion proteins were expressed in Escherichia coli DH5 CBP and SRC-1 Limit NF-
SRC-1 modulates ligand-dependent transcriptional activation
of estrogen, thyroid hormone, and retinoic acid receptors (21) and
NF- GR and p65 Bind to the Same Region of the N Terminus of
CBP--
To compete effectively with p65 for CBP, GR should interact
with CBP. Previous studies indicated that binding sites for the thyroid
hormone, estrogen, and retinoic acid receptors mapped to the N-terminal
100 amino acids of CBP (19). To investigate a direct interaction
between GR and CBP, a series of fragments of the coactivator were
bacterially expressed as GST fusion proteins (4) and tested for
interaction with the GR. The receptor interacted with the N-terminal
1-771 region of CBP, as well as with the 1069-1892 region of the
coactivator (Fig. 2). Binding between the
transcriptional activators and CBP was specific because no interactions
were observed either with GST alone or with several other regions of
CBP. Further mapping of the N-terminal interaction site revealed that
GR bound to the 100-446 region of CBP (Fig. 2 and data not shown) and
not to the N-terminal 100 amino acids of CBP, similar to many of the other nuclear receptors (19).
CBP and SRC-1 Rescue GR Inhibited p65-dependent
Transactivation--
If either CBP or SRC-1 function as signal
integrators for the NF-
One possibility suggested by the preceding findings is that the
formation of complexes between either p65 or GR and the coactivators would reduce the amount of coactivator available for transcriptional activation. If competition for limiting amounts of CBP or SRC-1 account
for the inhibitory effect of GR, then increased levels of the
coactivators should restore or rescue p65-dependent gene expression. Indeed, the inhibitory effect of GR on
p65-dependent gene expression was completely abolished by
cotransfection of vectors expressing CBP, but not by a comparable
amount of empty expression vector (Fig. 3A, compare
lanes 7 and 8). The inhibitory effect of p65 on
GR-dependent gene expression was eliminated by expression
of CBP, in a dose-dependent manner (Fig. 3B,
lanes 6-9). In a similar manner, the suppression of p65 on
GR-dependent gene expression was significantly decreased by
SRC-1 (Fig. 3C, compare lane 7 with lanes
8 and 9). Control studies demonstrated that CBP or
SRC-1 overexpression did not significantly alter levels of either p65
(Fig. 3, A, B, and C,
insets) or GR (data not shown). Additionally, overexpression
of an irrelevant transcriptional activator or mutated forms of CBP did
not result in rescue, and overexpression of CBP did not modify the
amount or composition of nuclear NF- Stimulatory Interactions between the Activated GR and p65--
The
previous functional studies suggest that competition between p65 and
the GR for limiting amounts of coactivator accounts for the
antagonistic interactions between distinct signaling pathways. A
prediction of this concept is that when these activators are bound to
distinct elements in the same promoter (in cis), they should
maintain their ability to recruit coactivators and activate transcription rather than antagonize the
process. To test this prediction, a
minimal promoter-CAT construct containing a combination of an isolated
From these studies we suggest that GR-mediated repression of
p65-dependent gene expression results from competition for
the transcriptional coactivators CBP and SRC-1. This could be the result of a simple titration of a limiting amount of coactivator, as
has been described in multiple settings with a variety of other transcriptional activators (19, 23-25). This would be consistent with
recent findings that the levels of p300 are limiting relative to those
of p65 (26) and that developmental processes are sensitive to the
overall gene dosage of the CBP homolog, p300 (27). Additionally, the
dependence on coactivators may reflect more subtle mechanisms affecting
the interaction between the transcription factor and the coactivator.
Recently, evidence has been presented that hormone-activated nuclear
receptors prevent c-Jun phosphorylation and AP-1 activation by blocking
the induction of the c-Jun N-terminal kinase-signaling cascade (28).
This phosphorylation step is a prerequisite for the transcription
factor to interact with CBP. p65 interaction with CBP is also regulated
by phosphorylation. Protein kinase A stimulates p65 transcriptional
activation, in part, by promoting an interaction with CBP/p300 (29).
Additionally, the p38 and MAP kinase pathways increase p65
transactivation mediated by tumor necrosis factor (30). It is possible
that several of these phosphorylation events facilitate CBP binding and
are decreased by activated GR. Decreased phosphorylation of p65 would
constitute an additional overlapping mechanism to blunt
NF-
Because many of the large class of genes encoding inflammatory
mediators such as cytokines, chemokines, and adhesion molecules are
NF-
B
(NF-B) and the glucocorticoid receptor (GR) mutually repress each
other's ability to activate transcription. Both of these
transcriptional activators depend upon the coactivators CREB-binding
protein (CBP) and steroid receptor coactivator-1 (SRC-1) for maximal
activity. Here we show that increased levels of CBP relieves the
inhibition of glucocorticoid-mediated repression of NF-B activity
and the NF-B-mediated repression of GR activity. SRC-1 can relieve
the NF-B-mediated repression of GR activity. We propose that
cross-talk between the p65 component of NF-B and glucocorticoid
receptors is due, at least in part, to nuclear competition for limiting
amounts of the coactivators CBP and SRC-1, thus providing a novel
mechanism for decreasing expression of genes involved in the
inflammatory response.
INTRODUCTION
Top
Abstract
Introduction
Procedures
Results & Discussion
References
B
(NF-B)1 is an inducible
transcription factor that plays an essential role in the regulation of
gene expression in response to inflammatory stimuli (1-3). It is
composed of members of the Rel family (p50, p52, p65 (RelA), c-Rel, and
RelB), which share a region of homology known as the Rel homology
domain capable of directing DNA binding and mediating dimerization. In many cells, NF-B is found in an inactive form in the cytoplasm bound
to an inhibitory protein, IB. In response to many activating signals, the inhibitor is degraded by the proteasome and NF-B translocates to the nucleus where it interacts with transcription coactivator proteins to activate target genes. CREB-binding protein (CBP) and its structural homolog p300 are transcriptional coactivators of the p65 subunit (4, 5). The steroid receptor coactivator-1 (SRC-1)
also potentiates NF-B-mediated transactivation (6).
B is inhibited by
glucocorticoid-induced expression of the inhibitor, IB
, which
suggested an explanation for how these steroids suppress an
inflammatory response (12, 13). However, in endothelial cells (14, 15),
as well as some other cells, glucocorticoid-mediated repression of
NF-B activity does not involve induction of IB synthesis. In
these cells, the GR does not inhibit nuclear accumulation of
NF-B, or inhibit DNA binding, suggesting that GR blocks
NF-B-mediated transactivation. Analysis of cell lines stably
expressing a fusion protein between the DNA-binding domain of the yeast
GAL4 protein and the transactivating region of p65 revealed that
expression of the GAL4-dependent reporter gene was strongly
suppressed by the action of the dexamethasone (16). This suggests that
reduction of p65-dependent gene expression by the activated
GR involves interference with transactivation. Because transactivation
by p65 involves both CBP (4, 5) and SRC-1 (6), we investigated the role
of these coactivators in the antagonistic interaction between the
nuclear receptor and the NF-B signaling pathways. We find that
GR-mediated repression of p65-dependent gene expression results, at least in part, from competition for a limiting amount of
these versatile transcriptional coactivators.
EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results & Discussion
References
B reporter construct, bovine aortic
endothelial cells were transfected using LipofectAMINE and OptiMem
(Life Technologies, Inc.) for 5 h at 37 °C in 5%
CO2, prior to a medium exchange. Cells were harvested the
next day and lysed, and luciferase assays performed according to
the manufacturer's instructions (Promega).
B promoter-CAT reporter contains two NF-B
elements in a minimal TATA box containing promoter derived from the
vascular cell adhesion molecule-1 promoter (17). To create the
GRE-NFB reporter construct, the following oligonucleotides were
synthesized: oligonucleotide 1, 5'-GATCCTGTACAGGATGTTCTAGATGATCATGGGAAATT CCTC-3'
and oligonucleotide 2, 5'-GATCCGAGAATTTCCCATGATCATCTAGAACATCCTGTACAG-3'. The oligonucleotides
were phosphorylated, annealed, and ligated into the BglII
site of an SV40 minimal promoter-luciferase reporter vector, pGL3
Promoter (Promega).
(4). Coomassie Blue stains were done to determine equivalent protein
concentration. The mCBP GST fusion constructs were immobilized to
glutathione-Sepharose and washed, and bound proteins were incubated
with 100 µl of GR overexpressed whole cell extracts. Samples were
washed several times with 150 mM cell lysis buffer
supplemented with protease inhibitors, eluted, and subjected to
SDS-polyacrylamide gel electrophoresis. Eluted proteins were detected
by Western blot analysis using rabbit anti-GR (Santa Cruz
Biotechnology, Santa Cruz, CA).
RESULTS AND DISCUSSION
Top
Abstract
Introduction
Procedures
Results & Discussion
References
B and GR-dependent Gene
Expression--
Previous studies reported that CBP modulates
ligand-dependent transcriptional activation of the
estrogen, thyroid hormone, and retinoic acid receptors (19) and that
CBP increases p65-dependent transcription of the
E-selectin, vascular cell adhesion molecule (4), and
interferon-
-promoter-reporter constructs (20). To determine whether
CBP limits expression of GR and p65, we examined the effect of
overexpression of CBP on the expression of reporters with
isolated recognition elements in transient transfection
experiments. GRE and B promoter-reporter constructs were activated
severalfold by GR and p65, respectively (Fig.
1, A and B).
Cotransfection with CBP stimulated expression of the reporters
5-10-fold above the levels seen with the transcriptional activators
alone.
View larger version (16K):
[in a new window]
Fig. 1.
Role of CBP and SRC-1 in
p65-dependent gene expression. Overexpression of CBP
increases GR-dependent (A) and
B-dependent gene expression (B). In
A and B, COS cells were transfected with 3 µg
of an isolated GRE-CAT and 2 µg of B-CAT reporter constructs with
increasing amounts of GR (10 (lanes 2-4), 50 (lanes 5 and 6), or 100 (lanes 7 and 8) ng
of pCYGR) or p65 (0.1 (lanes 2 and 3) or 1.0 (lanes 4 and 5) µg of pcDNA-p65) expression
vectors in the presence or absence of 10 µg of a CBP expression
vector (pRc/RSV-mCBP HA). Overexpression of SRC-1 increases GR
(C) and B-dependent gene expression
(D). In C, COS cells were transfected with 2 µg
of GRE-CAT and 100 ng of GR expression vector in the presence or
absence of 5 µg of SRC-1 expression vector. Dexamethasone
(dex) was added to appropriate cultures (10 nM)
immediately after transfection. The total concentration of DNA was
adjusted to 10 µg/10-cm tissue culture dish with empty pCR3 vector.
In D, 1 µg of an E-selectin-promoter reporter (-578-CAT)
and 100 ng of p65 expression vector were transfected into COS cells in
the presence or absence of either 3.25 (lanes 3 and
4) or 6.5 µg (lanes 5 and 6) of SRC-1
expression vector. The total concentration of DNA was adjusted to 15 µg/6-cm tissue culture dish with empty pCR3 expression vector. Data
presented are representative of at least three independent
transfections.
B-dependent expression of an artificial
B-dependent reporter construct (6). Coactivator
overexpression studies were also performed to verify that SRC-1 limits
expression of GR-dependent gene expression and that SRC-1
modulates p65-dependent expression of an authentic
NF-B-dependent promoter. GRE and B promoter-reporter constructs were activated severalfold by GR and p65, respectively (Fig.
1, C and D). Cotransfection with SRC-1 stimulated
expression of the reporters 5-fold above the levels seen with the
transcriptional activators alone. Control studies demonstrate that
overexpressed CBP had no effect on minimal promoter-reporter constructs
and did not increase production of p65 or GR from the corresponding expression constructs (data not shown). These findings demonstrate that
overexpression of CBP or SRC-1 increases both p65 and
GR-dependent gene expression and suggests that the
coactivators are present in limiting amounts.
View larger version (20K):
[in a new window]
Fig. 2.
GR interacts with CBP. Regions of CBP
were tested for interaction with GR from programmed COS cell lysates.
Sepharose-resin containing GST or GST-CBP amino acids 1-100, 1-771,
706-1069, 1069-1892, or 1892-2441 were mixed with COS cell lysates
programmed by overexpression with GR.
B and GR pathways, we would expect mutual
transcriptional interference between these two
signal-dependent activators. Using transient transfection
assays, p65-mediated transcriptional activation of either
E-selectin-promoter reporter constructs (Fig.
3A) or an isolated NF-B
element-reporter (data not shown) are repressed by
dexamethasone-induced activation of GR in a dose-dependent manner (Fig. 3A, lanes 1-6). Control studies
demonstrate that overexpressed GR did not decrease production of p65
from the corresponding expression constructs (Fig. 3A,
inset). Parallel transfection studies demonstrate that
GR-dependent gene expression is repressed by p65 (Fig. 3,
B and C, lanes 3-7). Thus
p65-mediated transcriptional activation was repressed by GR, and
GR-dependent gene expression was repressed by p65,
consistent with previous reports (18, 22).
View larger version (11K):
[in a new window]
Fig. 3.
CBP rescues GR-mediated inhibition of
p65-dependent reporter gene activation (A) and
p65-mediated inhibition of GR-dependent reporter gene
expression (B), and SRC-1 rescues p65-mediated suppression
of GR-dependent reporter gene expression
(C). In A COS cells were transfected with 1 µg of an E-selectin-promoter reporter (-578-CAT), 1 µg of the p65
vector, and increasing amounts of the GR expression vector (0-0.5
µg); 10 µg of the CBP or an equivalent amount of an empty
expression vector were cotransfected as indicated. In B COS
cells were cotransfected with 3 µg of the GRE-CATreporter construct, 100 ng of GR, 500 ng of p65, and either 5 µg (lanes 6 and 7) or 10 µg (lanes 8 and 9) of the CBP expression vector. Total plasmid DNA
was kept constant at 12 µg by the addition of the respective empty
expression vector. In C, COS cells were transfected with 2 µg of GRE-CAT reporter construct, 100 ng of GR and 100 ng, 250 ng, 1 µg, 2.5 µg, and 5 µg of p65. For SRC-1 rescue, 5 µg of p65 was
used with 5 and 10 µg SRC-1 expression vector. The total DNA
concentration was adjusted to 20 µg/10-cm tissue culture dish with
the pCR3 expression plasmid. Portions of the cellular extracts from
A-C were analyzed for p65 and GR by Western blot analysis
using rabbit anti-p65 (Rockland) or rabbit anti-GR (Santa Cruz).
Dexamethasone (dex) was added to appropriate cultures (10 nM) immediately after transfection. 2-3 days after
transfection, CAT activity in cell extracts was measured as described
previously (17). Data presented are representative of at least three
independent transfections.
B complexes (data not shown).
Collectively, these functional studies demonstrate that CBP and SRC-1
are limiting for both p65- and GR-dependent transactivation
and that the coactivators can rescue the repressive interaction between
p65 and the GR.
B and a GRE site was evaluated for its responsiveness to p65 and the
activated GR. At low levels of added activators, the promoter
containing both the GR and B binding sites responded weakly to each
of the transcription factors (Fig. 4 lanes 3 and 4, respectively). Addition of both p65 and GR stimulated
expression of the reporter construct about 2-fold. The small fold
stimulation could be increased by overexpression of CBP or SRC-1 (Fig.
4, lanes 7 and 8, respectively). Notably, when
both coactivators are added, the activity of the reporter gene is
increased in a synergistic manner (Fig. 4B, lane
9), consistent with the model that the coactivators are limiting
the activity of these transcription factors. Thus simultaneous
activation of the GR and nuclear accumulation of p65 does not always
result in inhibition of reporter gene expression.
View larger version (15K):
[in a new window]
Fig. 4.
Stimulatory interactions between p65 and the
activated GR. Bovine aortic endothelial cells were co-transfected
with 1 µg of the GRE-NF B reporter construct, 1 µg of GR or 100 ng p65, in the absence or presence of either 4 µg of CBP, 4 µg of
SRC-1, or a combination of the expression vectors. The total
concentration of DNA was adjusted to 10 µg with empty pCR3 expression
vector. Dexamethasone (dex) was added to appropriate
cultures (10 nM) immediately after transfection. Data are
from four independent transfections, and the standard deviations are
shown.
B-dependent action by reducing the amount of
competent NF-B complex capable of competing for and interacting with CBP.
B-dependent (1), coactivator-mediated signal
integration could explain, at least in part, the profound effects of
glucocorticoids on suppressing immune and inflammatory responses. The
extent of the inhibition would depend upon the abundance of the
transcriptional activators, the level of the coactivator, and the
relative affinity of the transcription factor for the coactivator.
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FOOTNOTES |
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* This work was supported by National Institutes of Health research grants (to D. T., C. G., and T. C.).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.
Established Investigator of the American Heart Association.
To whom correspondence should be addressed: Dept. of Pathology,
Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02115. Tel.: 617-732-5990; Fax: 617-278-6990; E-mail: tcollins{at}bustoff.bwh.harvard.edu.
The abbreviations used are:
NF-B, nuclear
factor-B; CAT, chloramphenicol acetyltransferase; CBP, CREB-binding
protein; GR, glucocorticoid receptor; GRE, glucocorticoid response
element; GST, glutathione S-transferase; B, NF-B
binding site; IB, inhibitor B; SRC-1, steroid receptor
coactivator-1.
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REFERENCES |
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Abstract
Introduction
Procedures
Results & Discussion
References
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K. Watashi, M. Hijikata, A. Tagawa, T. Doi, H. Marusawa, and K. Shimotohno Modulation of Retinoid Signaling by a Cytoplasmic Viral Protein via Sequestration of Sp110b, a Potent Transcriptional Corepressor of Retinoic Acid Receptor, from the Nucleus Mol. Cell. Biol., November 1, 2003; 23(21): 7498 - 7509. [Abstract] [Full Text] [PDF]
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G. Li, S. Wang, and T. D. Gelehrter Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-{beta} Action J. Biol. Chem., October 24, 2003; 278(43): 41779 - 41788. [Abstract] [Full Text] [PDF]
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K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]
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G.U. Meduri, P. Carratu, and A.X. Freire Evidence of biological efficacy for prolonged glucocorticoid treatment in patients with unresolving ARDS Eur. Respir. J., August 1, 2003; 22(42_suppl): 57s - 64s. [Abstract] [Full Text] [PDF]
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F. Yan, X. Gao, D. M. Lonard, and Z. Nawaz Specific Ubiquitin-Conjugating Enzymes Promote Degradation of Specific Nuclear Receptor Coactivators Mol. Endocrinol., July 1, 2003; 17(7): 1315 - 1331. [Abstract] [Full Text] [PDF]
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M. W. Mayo, C. E. Denlinger, R. M. Broad, F. Yeung, E. T. Reilly, Y. Shi, and D. R. Jones Ineffectiveness of Histone Deacetylase Inhibitors to Induce Apoptosis Involves the Transcriptional Activation of NF-{kappa}B through the Akt Pathway J. Biol. Chem., May 23, 2003; 278(21): 18980 - 18989. [Abstract] [Full Text] [PDF]
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S. de Haij, I. M. Adcock, A. C. Bakker, S. J. P. Gobin, M. R. Daha, and C. van Kooten Steroid Responsiveness of Renal Epithelial Cells. DISSOCIATION OF TRANSREPRESSION AND TRANSACTIVATION J. Biol. Chem., February 7, 2003; 278(7): 5091 - 5098. [Abstract] [Full Text] [PDF]
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