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Department of Molecular Biology University of Gent-VIB 9000 Gent, Belgium
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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B
(NF-B) and AP-1. Both factors make use of the coactivator cAMP
response element-binding protein (CREB)-binding protein (CBP) to
enhance their transcriptional activities, which led to the hypothesis
that a mutual antagonism between p65 or c-Jun and activated
glucocorticoid receptor (GR) results from a limited amount of
CBP. Recently, we showed that glucocorticoid repression of
NF-B-driven gene expression occurs irrespective of the amount of
coactivator levels in the cell. In the current study, we extend this
observation and demonstrate that also AP-1-targeted gene repression by
glucocorticoids is refractory to increased amounts of nuclear
coactivators. From results with Gal4 chimeric proteins we conclude that
glucocorticoid repression occurs by a promoter-independent mechanism
involving a nuclear interplay between activated GR and AP-1,
independently of CBP levels in the cell. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Interleukin-6 (IL-6) is a pleiotropic cytokine that is implicated in endocrine and metabolic actions, as well as in immune regulation and aging. IL-6 is thought to play a key role in a number of inflammatory processes, such as rheumatoid arthritis, trauma, and stress, and is also involved in the pathogenesis of osteoporosis, HIV infection, sepsis, and progression of cancer (12, 13). Understanding the regulation of this gene may therefore lead to a controlled and tissue-restricted modulation of its pleiotropic actions.
Glucocorticoids not only inhibit proliferation by suppressing AP-1 activity of genes involved in proliferation, such as c-Jun (14), but they can also mediate a strong suppression of AP-1-driven genes involved in inflammation and immune dysregulation, including IL-6. Glucocorticoid action is mediated by binding to the glucocorticoid receptor (GR), which belongs to the family of nuclear hormone receptors. These ligand-regulated sequence-specific transcription factors may activate or repress gene expression. Whereas gene activation is generally mediated by binding of homodimeric GR subunits to their cognate DNA elements, experiments with mice expressing a dimerization-defective GR demonstrated that gene repression is mainly conducted by interference of the GR monomer with the activities of other transcription factors, including AP-1 (15). Recently, the negative interference between GR and AP-1 was demonstrated in an in vivo model system of TPA-induced expression of collagenase and stromelysin in skin, and GC repression of these genes was also shown to involve the DNA-binding independent function of GR (16).
As CBP can enhance transcriptional activation of AP-1 as well as of nuclear receptors (reviewed in Ref. 17), it was proposed that mutual antagonism between these different signal transduction pathways could be explained by the mutual competition for limiting amounts of CBP within the cell (11). Recent reports also showed that SRC-1 can functionally interact and enhance AP-1-mediated gene expression (18). SRC-1 was originally identified as a coactivator for the nuclear receptor superfamily (19), prompting a role for SRC-1 also in mediating nuclear receptor-dependent gene repression of AP-1-driven genes and vice versa (18). The idea behind a limitation in the amount of coactivator protein such as CBP arose from the observation that a single mutated CBP allele, leading to a heterozygous phenotype, already results in severe developmental defects. This mutation correlates with a disorder called the Rubinstein-Taybi syndrome and includes facial distortions, broadening of thumbs and toes, and mental retardation (20).
In a previous study we demonstrated that glucocorticoid repression of
various nuclear factor (NF)-B-driven genes occurs independently of
coactivator levels in the cell (21). In the present study we
demonstrate that glucocorticoids can mediate suppression of the
AP-1-driven IL-6 promoter, independently of the levels of coexpressed
coactivators. Our data further rule out a direct involvement of CBP in
transrepression of GR on other AP-1-driven genes as well.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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B, AP-1, CREB, and
C/EBP transcription factors. However, depending on the stimulus, the
signaling pathways leading to the two most important players, NF-B
and AP-1, are clearly distinguishable. Indeed, tumor necrosis factor
(TNF) induction of the IL-6 promoter almost exclusively triggers
NF-B activity, while induction of the IL-6 promoter by staurosporine
(STS), a protein kinase inhibitor, is predominantly mediated by
activation of AP-1, CREB, and C/EBP (22).
We were interested to determine whether activated GR was able to
repress TNF-
- or STS-dependent pathways to a similar extent. Figure 1A
shows the regulation by TNF, STS, and
dexamethasone (DEX) of the wild-type IL-6 promoter and two crucial
point-mutated variants, stably transfected in L929sA cells. With the
construction p1168hu.IL6P-luc+, glucocorticoids can repress the
TNF-induced as well as the STS-induced IL-6-promoter activity (lanes 3
vs. 4 and lanes 5 vs. 6, respectively). The
synergism between TNF and STS is also efficiently inhibited by DEX
(lane 7 vs. 8). A point-mutated variant of the NF-B
response element abrogates inducibility by TNF (lane 11), but retains
STS-induced IL-6 promoter activity, which is also clearly repressed by
DEX to background levels (lanes 13 vs. 14 and 15
vs. 16).
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that
mutation of the AP-1 or the CRE site greatly abolishes inducibility by
STS, whereas mutation of the C/EBP site was only marginally effective.
Moreover, a double mutant AP-1/CRE is even no longer responsive at all
to STS, demonstrating a more prominent role for both AP-1 and CREB as
compared with C/EBP for induction by STS and repression by DEX. This is
also evidenced by the fact that the synergism between STS and TNF is
less outspoken in the AP-1 response element-mutated promoter construct
(Fig. 1A, lane 7 vs. lane 23). Consequently, the AP-1
activity may represent an as likely target for glucocorticoid action,
almost as effective for IL-6 gene repression as NF-B.
Figure 1C demonstrates that repression is also apparent on an
STS-induced recombinant AP-1-driven promoter construct pTRE-Luc+. TNF
cannot stimulate this promoter variant, which is in agreement with the
results obtained with the NF-B response element-mutated variant of
the IL-6 promoter (Fig. 1A, lane 11). Background levels of pTRE-luc+
promoter activity can also be repressed by DEX, most probably by
antagonizing endogenously activated, DNA-bound AP-1.
Glucocorticoid Repression Acts on AP-1-Driven IL-6 Gene Expression,
Irrespective of Coactivator Levels in the Cell
We set out to explore how glucocorticoids suppress the AP-1-driven
IL-6 gene. The IL-6 promoter construct p1168hu.IL6P-luc+ can be
activated through its NF-B element, as well as via its AP-1-element,
and this promoter activity can be effectively inhibited by
glucocorticoids. Both transcription factors have been reported to
enhance their transcriptional activities via recruitment of the
coactivator CBP (4, 24, 25, 26). Within the IL-6 promoter context,
activation of NF-B is necessary and sufficient to engage this
coactivator for transcriptional stimulation (22). Here, we demonstrate
a significant cooperative enhancement of coexpressed CBP with
c-Jun-driven IL-6 promoter activity, indicating that CBP also mediates
amplification of the AP-1 response. Furthermore, we investigated
whether glucocorticoid repression of c-Jun-induced IL-6 promoter
activity still occurs in the presence of increasing amounts of CBP.
Figure 2A shows that CBP alone is able to
slightly enhance background promoter activity (lane 3), most probably
via endogenous transcription factors that are constitutively bound to
the DNA (i.e. AP-1, CREB, NF-IL6). Consistent herewith, DEX
can suppress the background level as well as the activity of the
promoter induced by CBP alone (lanes 2 and 4). Furthermore and as
expected, activated GR also represses c-Jun transactivation to
background levels (lanes 6 and 7 vs. lane 5).
Additional CBP stimulates the c-Jun-induced promoter activity 2-
to almost 4-fold (lanes 8 and 11 vs. lane 5). Most
importantly, we observe that the synergistic activation by CBP and
c-Jun is also inhibited by glucocorticoids to almost background levels
(lanes 10 and 13) irrespective of the amounts added of CBP. Moreover,
cotransfection of the coactivators SRC-1 and p/CAF further contributes
to c-Jun transactivation, but does not relieve glucocorticoid-mediated
repression (Fig. 2B). This extends our observations beyond CBP and
indicates that glucocorticoid repression works independently of
coactivator complexes present in the cell.
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B has previously been designated to be the most important
transcription factor for IL-6 promoter regulation, at least in response
to TNF. Nevertheless, we also tested the point-mutated variant
1168(Bmut).IL6P-luc+, in which the B site is abolished, leaving
an almost exclusive c-Jun-driven regulation by the AP-1 site. Figure 2C
shows that, although the level of c-Jun activation is similar as
compared with the wild-type promoter, the cooperation with CBP is less.
Because stress is one of the inducing agents of NF-B, it may well be
that the activity of the c-Jun-induced wild-type IL-6 promoter is a
combination of the activity of transfected c-Jun and of endogenous
NF-B, which is synergistically enhanced by administering extra
amounts of CBP. Since glucocorticoids strongly repress NF-B
activity, this hypothesis could also explain why the relative
repression of the B-mutated IL-6 promoter variant is also less than
repression of the wild-type promoter (lanes 7 and 9 of Fig. 2C
vs. lanes 11 and 13 of Fig. 2A). Nevertheless, the relative
repression level by glucocorticoids of the combined activity by c-Jun
and CBP is comparable to that exerted by c-Jun alone (Fig. 2C, lanes 4
and 6 vs. lanes 7 and 9), ruling out competition for CBP as
a way to mediate glucocorticoid repression.
We conclude that glucocorticoids effectively repress AP-1-driven gene
expression of the IL-6 wild-type promoter, as well as of the variant
with the NF-B site abolished, irrespective of the amount of CBP
present in the cell.
Glucocorticoid Repression Is Maintained on a Recombinant
AP-1-Driven Promoter Construct, Irrespective of CBP Levels in the
Cell
To investigate the general applicability of these findings, we
tested the regulation by glucocorticoids on a c-Jun-induced recombinant
promoter construct pAP-1-luc+, containing three AP-1 sites followed by
a viral E1B TATA box. Figure 3 shows that
CBP stimulates this promoter by means of endogenously present AP-1
(lane 2 vs. lane 1) and that glucocorticoids repress this
activity even below background levels (lane 3). As expected, c-Jun
activity is abolished by treatment with glucocorticoids (lane 4
vs. lanes 5 and 6). CBP costimulates the c-Jun-activated
recombinant construct, similarly as observed for the B-mutated IL-6
promoter construct (lane 4 vs. lane 7). Most importantly,
activated GR efficiently transrepresses the cooperative potential of
c-Jun with CBP, regardless of the presence of extra CBP in the
cells (lane 7 vs. lane 8).
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Gal4 alone or Gal4 combined with CBP do not activate the
reporter (Fig. 4A, lanes 1 and 2).
Gal4-c-Jun induces a slight but significant activation (lane 3). We
further demonstrate that glucocorticoids repress the Gal4-c-Jun
activity to background levels, suggesting that glucocorticoid
repression of AP-1 is mediated by a direct interference between
activated GR and the transactivation function of c-Jun (lane 3
vs. lane 4). Increasing amounts of CBP stepwise increase
Gal4-c-Jun-dependent transcription from the Gal4-driven reporter (lanes
5 and 6), but transrepression still occurs under conditions of maximal
cooperation between c-Jun and CBP (lanes 7 and 8).
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shows
that CBP can also stimulate this strong viral transactivator by a
factor 2 in agreement with data from Utley and co-workers (27),
demonstrating that the enzymatic HAT activity of CBP cooperates with
the neighboring acidic transactivation domains of VP16. Interestingly,
specific glucocorticoid repression, as observed for Gal4-c-Jun-driven
Gal4-dependent reporter gene expression (Fig. 4A), does not occur with
reporter stimulation by Gal4-VP16 (Fig. 4B, lanes 4, 6, and 7), whether
or not in the presence of CBP. This result provides additional proof
that GC repression of Gal4-c-Jun, after overexpression and subsequent
activation of GR, is not caused by nonspecific squelching effects or by
affecting CBP activity in a transcriptionally active promoter complex,
but is highly specific for Gal4-c-Jun-driven transactivation,
irrespective of the amount of CBP present in the cell.
Inhibition of JNK Activation by Glucocorticoids May Contribute to
Their Repressive Effects on AP-1-Driven Genes
We tested the effect of DEX on different phosphorylated, activated
mitogen-activated protein kinases (MAPKs), since the antagonism between
c-Jun and the glucocorticoid receptor in HeLa cells was reported to
result from an inhibition of the JNK pathway (28). Figure 5A demonstrates that this is also the
case in L929sA cells, which contain endogenous GR. The amount of
phosphorylated p46/p54 protein is reduced upon cotreatment of TNF and
DEX (Fig. 5A, compare lane 7 to lane 8). In contrast, in untransfected
HEK293T cells, the amount of GR is negligible, which may explain the
lack of effect of DEX on the amount of TNF-activated JNK kinases (Fig. 5A, compare lane 3 to lane 4). In comparison, the amount of
phosphorylated ERK and p38 MAPK (Fig. 5, B and C) is unaffected by DEX
treatment in both cell lines. Similar results were obtained in L929sA
cells for the synthetic glucocorticoids RU24782 and RU24858, which
dissociate transactivation from AP-1 transrepression (Fig. 5D).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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B-driven proinflammatory genes. Even before the actual target was
known at the molecular level, glucocorticoids were widely acknowledged
as powerful antiinflammatory and immunosuppressive agents on a purely
empirical basis. Studies aimed at elucidating their mechanism of action
could therefore contribute to the design of antiinflammatory compounds
devoid of side effects.
We demonstrated earlier that the signaling pathways induced by TNF and
STS, which lead to activation of the IL-6 promoter, could be
discriminated at the transcription factor level. TNF almost exclusively
leads to NF-B activity, while STS focuses on activation of AP-1,
CREB, and C/EBP (22). Thus, in the IL-6 promoter context, NF-B and
other functional elements, such as AP-1, do not compete with each other
for limiting amounts of CBP, but instead cooperate to establish a
functional enhanceosome-like structure, comparable to a model that has
been reported earlier for the interferon-ß promoter (29). Previous
work from our hands focused on the mechanism of GC-mediated repression
of various NF-B-driven genes (21). We could clearly demonstrate that
cofactor squelching is not a general mechanism by which activated GR
inhibits NF-B activity and vice versa. This finding urged
us to also closely investigate the mechanism of GC-mediated suppression
of AP-1-driven gene expression. Depending on the investigated cell type
or promoter, different results are apparent, making the mechanism by
which glucocorticoids repress AP-1-driven genes a controversial
issue (reviewed in Refs. 30, 31). One hypothesis proposes that
competition between nuclear factors for limited amounts of coactivator
molecule accounts for the observed inhibition of AP-1 activity by
glucocorticoids (11, 18). Our data present conclusive evidence that
glucocorticoid repression of c-Jun-mediated activation of the IL-6
promoter is not relieved by overexpression of coactivator molecules in
the cell. These results are in contradiction with conclusions made by
Kamei et al. (11), and Lee et al. (18), which
suggest that glucocorticoid repression of AP-1 activity can be
abolished by adding extra amounts of CBP or SRC-1. We noticed that both
reports failed to demonstrate the necessary controls showing the
induction level of CBP or SRC-1 together with c-Jun or c-fos
in the absence of repression, and therefore do not allow to compare the
repression of AP-1 alone vs. the repression of AP-1 with CBP
or SRC-1 together. In contrast, our data show that repression is
maintained under conditions of cooperativity of c-Jun with CBP. From
these results we conclude that repression does not result from limiting
the amount of CBP, which would favor a competition model as a means to
explain transrepression. A competition model has also been proposed for
androgen receptor-mediated repression (32, 33), although Aarnisalo
et al. (32) did not find evidence to support this
model for glucocorticoid repression of AP-1-activity, which is in
agreement with the data presented here.
A valid alternative mechanism concerns a direct interaction between AP-1 and GR. Direct interference was proposed to mediate GC repression of the AP-1-driven collagenase gene (3, 34, 35). However, for some genes containing a composite element, such as the proliferin gene, the transcriptional outcome of glucocorticoid treatment highly depends on the composition of AP-1 and can be inhibitory for the Jun/Fos pair, but stimulatory for the Jun homodimer (36, 37, 38). Inversely, transactivation by nuclear receptors is either negatively or positively influenced by AP-1 and appears to be a cell-specific phenomenon (39). The findings that describe the conditional occurrence of costimulatory effects between AP-1 and GR cannot be reconciled with a general competition model. Moreover, as various transcription factors converge at the level of CBP/p300 for their transcriptional activity, pure competition for cofactors cannot account for the strict specificity of repression phenomena.
Furthermore, the existence of dissociating ligands and of various receptor point-mutants of GR (40, 41, 42, 43), which separate transactivation and transrepression, disfavors a competition model as well. According to this model GR is supposed to attract equally well coactivators in its repressive state, while a separation of transactivation and transrepression functions indirectly implies that GR in its repressive state might no longer be able to attract coactivators and perhaps only recruits corepressor molecules. This idea is supported, although indirectly, by the observation that retinoids that are only involved in transrepression (44) no longer recruit coactivators (Dr. H. Gronemeyer, personal communication).
In further contradiction to the coactivator competition model is the fact that Gal4-VP16 activity, although enhanced by overexpressed CBP, cannot be repressed by activated GR, whereas the Gal4-c-Jun activity distinctly is. This rules out that the mechanism of gene repression relies on a general and aspecific squelching of and competition for common cofactors.
Displacement of an NF-B- or AP-1-specific coactivating complex by a
so-far-unidentified GR-specific silencing corepressor complex, as
identified for unliganded retinoic acid receptor/retinoid X receptor
(RAR/RXR) and thyroid hormone receptor (TR) (45, 46), might also be
hypothesized, but is not supported by any experimental evidence.
Alternatively, glucocorticoid transrepression might also be achieved by
a GR-mediated posttranslational modification of coactivators or
associated transcription factors (17). In this respect, glucocorticoids
have been shown to inhibit AP-1 transactivation by interference with
the upstream JNK pathway (28). Our data can indeed substantiate an
inhibitory effect of DEX pretreatment on TNF-induced activation of JNK
kinases, but not of phosphorylated p38 or ERK kinases. Moreover, the
dissociated compounds RU24782 and RU24858, which only exhibit
transrepressive capacities, are also able to inhibit JNK activation.
The inhibitory role of GR on the upstream JNK kinases and the direct
link with transrepression by inactivating transcriptional complexes
therefore represent plausible alternative mechanisms that may partially
help to explain transrepression by nuclear receptors of AP-1, but not
of NF-B.
In conclusion, our data do not support the involvement of competition as a mechanism of transrepression of AP-1-driven genes by glucocorticoids. Rather, a recently described allosteric model, a variant of the direct interaction model, which links differential actions of GR in transactivation and transrepression to a different conformational state of the DNA-binding domain, together with the inhibition of incoming signals from the JNK pathway, may provide answers to many observations, previously considered bottlenecks. This model is currently the only one that also provides an explanation for the differential interplay between GR and AP-1 and is, finally, in agreement with our results (47).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Bmut).IL6P-luc+, p1168(AP-1 mut).IL6P-luc+,
p1168(CREmut).IL6P-luc+, p1168(AP-1-CREmut).IL6P-luc+, and
p1168(C/EBPmut).IL6P-luc+ were described previously (22, 48). The
reporter gene plasmid pAP1-luc+ was purchased from
Stratagene Cloning Systems (La Jolla, CA) and the
TK-promoter containing TRE-driven reporter gene, pTRE-luc+, was kindly
donated by Dr. Resche-Rigon (Marion Hoechst Roussel-Uclaf, Paris).
Construction of the pRSV-c-Jun expression vector was described
previously (22). The expression plasmids pCMV-CBP, pRSV and pRSV-p65,
and pSVhGR were kind gifts from Dr. R. Eckner (Institute for
Molecular Biology, Zurich, Switzerland), Dr. G. Manfioletti (University
of Trieste, Trieste, Italy), and Dr. W. Rombauts (University of Leuven,
Leuven, Belgium), respectively. The pcDNA3 vector, used as an empty
control vector for the CBP-expressing plasmid, was purchased from
Invitrogen (San Diego, CA). The expression plasmids coding
for SRC-1 (PCR3.1 SCR-1a) and p/CAF (pCX-p/CAF) were kind gifts from
Dr. M. Tsai (Department of Cell Biology, Baylor College of Medicine,
Houston, TX) and Dr. Nakatani (Laboratory of Molecular Growth
Regulation, Bethesda, MD), respectively. The plasmids pGal4, pGal4-p65,
and pGal4-VP16 were generously provided by Dr. M. L. Schmitz
(German Cancer Research Center, Heidelberg, Germany).
p(Gal)2–50 hu.IL6P-luc+ and pGal4-c-Jun were previously described (49, 50).
Cytokines and Reagents
DEX was purchased from Sigma-Aldrich Corp. (Irvine,
UK). The dissociated glucocorticoids RU24782 and RU24858 were kindly
donated by Dr. M. Resche-Rigon and previously described (40, 41). The
origin and activity of TNF, as well as the preparation of luciferase
(luc) reagent, were described previously (48). STS was purchased from
Calbiochem-Novabiochem International (San Diego, CA) and
was stored as a 2 mM solution in dimethyl sulfoxide at –20
C. Luciferase (luc) assays were carried out according to the
manufacturer’s instructions (Promega Corp., Madison, WI).
Control experiments showed that the final quantities of organic solvent
used did not interfere with any of the assays. Normalization of luc
activity, expressed as arbitrary light units, was performed by
measurement of ß-galactosidase (ß-gal) levels in a chemiluminescent
reporter assay Galacto-Light kit (Tropix, Inc., Bedford, MA) or
according to Bradford’s protein determination (51). Light emission was
measured in a luminescence microplate counter (Topcount; Packard
Instruments, Meriden, CT).
The phospho-specific p38 (Thr-180/Tyr-182), p42/p44 (Thr-202/Tyr-204) and SAPK/JNK (Thr-183/Tyr-185) MAPK polyclonal rabbit antibodies detect only the dual phosphorylated form of MAPK. They were purchased from New England Biolabs, Inc. (Beverly, MA) as part of a kit, which also includes antirabbit IgG coupled to horseradish peroxidase, used as a second antibody for Western blotting.
Transfections
Stable transfections of L929sA cells were described previously
(48). HEK293T cells were transiently transfected by the calcium
phosphate coprecipitation protocol (52). Briefly,
105 actively growing cells were seeded in a
24-well plate 24 h before transfection and either 400 or 600 ng of
total DNA were transfected. Sixteen hours post-transfection the medium
was replaced with fresh medium, containing 10-6
M DEX where appropriate for another 24 h. Cells were
lysed with lysis buffer (Tropix, Inc.), and samples were assayed for
their protein or ß-gal content and luciferase activity.
MAPK Activation Assay
The assay was performed essentially as described by Boone
et al. (53). Briefly, HEK293T or L929sA cells were seeded at
250,000 cells per well in six-well plates. After 24 h, cells were
either left untreated, or treated with 1 µM DEX
or with dissociated compounds (RU24858 or RU24782) for 2 h and/or
2,000 IU/ml TNF for 15 min. At the end of the incubation period, cells
were washed in PBS. Cell extracts were essentially prepared as
described in the protocol of a PhosphoPlus p38 MAPK antibody kit
(New England Biolabs, Inc.). One fifth of the total cell
lysate (20 µl) was separated by 12% SDS-PAGE and blotted onto a
nitrocellulose membrane. Western blot analysis was performed to detect
phosphorylated MAPK proteins.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Research was supported by the Interuniversitaire Attractiepolen.
1 Research Director with the Fonds voor Wetenschappelijk
Onderzoek-Vlaanderen. 
Received for publication March 16, 2000. Revision received October 12, 2000. Accepted for publication October 13, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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B-driven
genes by disturbing the interaction of p65 with the basal transcription
machinery, irrespective of coactivator levels in the cell. Proc Natl
Acad Sci USA 97:3919–3924 B engages CBP/p300 and histone
acetyltransferase activity for transcriptional activation of the
interleukin-6 gene promoter. J Biol Chem 274:32091–32098B. Int J Biochem Cell Biol 29:1433–1448[CrossRef][Medline]
-B-dependent mechanism. Mol Pharmacol 56:797–806B p65 transactivation mediated by tumor necrosis
factor. J Biol Chem 273:3285–3290B-dependent transcription involves direct interference with
transactivation. Proc Natl Acad Sci USA 94:13504–13509 negatively regulates the vascular
inflammatory gene response by negative cross-talk with transcription
factors NF- B and AP-1. J Biol Chem 274:32048–32054This article has been cited by other articles:
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