PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
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indirect
PMID: 18922786,11902574
HDAC inhibitors
induce the expression of a subset of genes
involved in cell growth arrest, differentiation,
and apoptosis, which accounts for the
antitumor effects of these compounds
indirect
PMID: 18922786,11902574
HDAC inhibitors
induce the expression of a subset of genes
involved in cell growth arrest, differentiation,
and apoptosis, which accounts for the
antitumor effects of these compounds
indirect
PMID: 18922786,11902574
HDAC inhibitors
induce the expression of a subset of genes
involved in cell growth arrest, differentiation,
and apoptosis, which accounts for the
antitumor effects of these compounds
PMID: 18922786
Paradoxically, HDAC inhibitors also possess
potent anti-inflammatory effects by
shutting down the expression of genes encoding
proinflammatory cytokines and
molecules.
indirect
PMID: 18922786
Activation of MAPK is mediated by a core
kinase module consisting of MAPK kinase
kinase (MAPKKK, also known as
MAP3K), MAPK kinase (MAPKK, also
known as MAP2K), and MAPK through
sequential protein phosphorylations.
indirect
PMID: 18922786
Activation of MAPK is mediated by a core
kinase module consisting of MAPK kinase
kinase (MAPKKK, also known as
MAP3K), MAPK kinase (MAPKK, also
known as MAP2K), and MAPK through
sequential protein phosphorylations.
indirect
PMID: 18922786,11274345,11861597
Activated
MAPKs, in turn, phosphorylate activating
protein 1 (AP-1) transcription factors
and other targets to stimulate gene
transcription and immune responses
indirect
PMID: 18922786,16461893,16380513,12444149,15590669,16978838
In macrophages responding to TLR
stimulation, there is a strong and rapid induction
of MKP-1 mRNA and increase in
MKP-1 protein abundance, peaking at 1 hour after stimulation
PMID: 18922786,16461893
TLR-induced expression
of MKP-1 is reduced in mice lacking either
MyD88 or TRIF compared to that in wildtype
mice, suggesting that MKP-1 is induced
through both MyD88- and TRIF-dependent
pathways in response to activation
of TLRs
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786,16461893,16380513,12444149,15590669,16978838
In macrophages responding to TLR
stimulation, there is a strong and rapid induction
of MKP-1 mRNA and increase in
MKP-1 protein abundance, peaking at 1 hour after stimulation
PMID: 18922786,16461893
TLR-induced expression
of MKP-1 is reduced in mice lacking either
MyD88 or TRIF compared to that in wildtype
mice, suggesting that MKP-1 is induced
through both MyD88- and TRIF-dependent
pathways in response to activation
of TLRs
PMID: 18922786,16497588
The signals involved in
TLR-induced expression of MKP-1 are beginning
to be defined. Stimulation of TLRs
activates two distinct pathways that are mediated
by the adaptor proteins myeloid differentiation
marker 88 (MyD88) and TRIF
[Toll-IL-1 receptor (TIR) domain-containing
adapter-inducing interferon-beta (IFN-beta)],
respectively
PMID: 18922786,16497588
The signals involved in
TLR-induced expression of MKP-1 are beginning
to be defined. Stimulation of TLRs
activates two distinct pathways that are mediated
by the adaptor proteins myeloid differentiation
marker 88 (MyD88) and TRIF
[Toll-IL-1 receptor (TIR) domain-containing
adapter-inducing interferon-beta (IFN-beta)],
respectively
indirect
PMID: 18922786,16461893,16380513,12444149,15590669,16978838
In macrophages responding to TLR
stimulation, there is a strong and rapid induction
of MKP-1 mRNA and increase in
MKP-1 protein abundance, peaking at 1 hour after stimulation
PMID: 18922786,16461893
TLR-induced expression
of MKP-1 is reduced in mice lacking either
MyD88 or TRIF compared to that in wildtype
mice, suggesting that MKP-1 is induced
through both MyD88- and TRIF-dependent
pathways in response to activation
of TLRs
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
PMID: 18922786,16709817,10604989
In addition, a signaling
pathway consisting of the
MAP3K Raf-1 and protein kinase
C epsilon (PKCepsilon) is required for
TLR-induced expression of
MKP-1 in macrophages
PMID: 18922786,16709817,10604989
In addition, a signaling
pathway consisting of the
MAP3K Raf-1 and protein kinase
C epsilon (PKCepsilon) is required for
TLR-induced expression of
MKP-1 in macrophages
indirect
PMID: 18922786,16709817,10604989
In addition, a signaling
pathway consisting of the
MAP3K Raf-1 and protein kinase
C epsilon (PKCepsilon) is required for
TLR-induced expression of
MKP-1 in macrophages
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-γ) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
PMID: 18922786
They found that
HDAC inhibitors reduced the activation of
p38 MAPK and ERK, but not JNK or the
NF-KappaB pathway.
indirect
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
PMID: 18922786
They found that
HDAC inhibitors reduced the activation of
p38 MAPK and ERK, but not JNK or the
NF-KappaB pathway.
indirect
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
indirect
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786
MKP-1 is also induced by
multiple immunosuppressive
agents, including glucocorticoids
and anti-inflammatory cytokines,
and this induction partially
mediates the inhibitory effects
of these agents on MAPK
activation and inflammation
PMID: 18922786
Figure 1A
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786,16184516,11842088
Induction
of MKP-1 by transforming
growth factor beta (TGF-beta) and
IL-10 also contributes to the
suppressive effects of these potent
anti-inflammatory cytokines on the expression of genes encoding proinflammatory
mediators.
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786,16184516,11842088
Induction
of MKP-1 by transforming
growth factor beta (TGF-beta) and
IL-10 also contributes to the
suppressive effects of these potent
anti-inflammatory cytokines on the expression of genes encoding proinflammatory
mediators.
PMID: 18922786,16380513
Conversely,
proinflammatory stimuli such as interferon γ
(IFN-gamma) attenuate MKP-1 expression to facilitate
their positive effects on MAPK activation
indirect
PMID: 18922786
Interestingly, MKP-1 is phosphorylated by
ERK in two distinct regions, which have
opposing effects on its stability
PMID: 1892786,10617468
Transient
activation of ERK phosphorylates MKP-1
at the two extreme C-terminal Ser359 and
Ser364, which enhances MKP-1 stabilization
without altering its phosphatase activity
PMID: 18922786,12676937,16286470
This facilitates the interaction
of MKP-1 with the Skp-cullin-F-box
(SCFSkp2) ubiquitin ligase, which targets
MKP-1 for proteasomal degradation
PMID: 18922786,12676937,16286470
This facilitates the interaction
of MKP-1 with the Skp-cullin-F-box
(SCFSkp2) ubiquitin ligase, which targets
MKP-1 for proteasomal degradation
PMID: 18922786
For example, glucocorticoids
increase the expression of MKP-1 as
well as attenuating proteasomal degradation
of MKP-1.
indirect
indirect
PMID: 18922786
In the presence
of the transcription factor nuclear
factor-KappaB (NF-KappaB), TNF-alpha
induces a rapid and transient
activation of JNK.
indirect
indirect
PMID: 18922786
Reactive
oxygen species (ROS) mediate
sustained JNK activation in NF-
KappaB–deficient cells by inactivating
MKP-1 and several other
MKP molecules.
inidrect
PMID: 18922786
Reactive
oxygen species (ROS) mediate
sustained JNK activation in NF-
KappaB–deficient cells by inactivating
MKP-1 and several other
MKP molecules.
PMID: 18922786
This is
achieved by ROS-induced oxidation
of the catalytic Cys
residue in the MKP molecules,
resulting in the loss of phosphatase
activity.
indirect
PMID: 18922786,15766528
Consequently,
JNK activation becomes unconstrained,
eventually leading to
cellular apoptosis (
PMID: 18922786
HDAC inhibitors
down-regulated a subset of inflammationassociated
genes, including nitric oxide synthase
2 (NOS2), TNFalpha, and IL-6.
PMID: 18922786
HDAC inhibitors
down-regulated a subset of inflammationassociated
genes, including nitric oxide synthase
2 (NOS2), TNFalpha, and IL-6.
PMID: 18922786
HDAC inhibitors
down-regulated a subset of inflammationassociated
genes, including nitric oxide synthase
2 (NOS2), TNFalpha, and IL-6.
indirect
PMID: 18922786
In particular, HDAC inhibitors
decreased phosphorylation of p38
MAPK and its downstream target Elk-1 but
not the upstream MAP2Ks MKK3 or
MKK6, suggesting that these inhibitors act
upon the MAPK pathway at the level of
p38, possibly upon a kinase or phosphatase
that modifies p38 MAPK.
indirect
PMID: 18922786
To identify the
acetylated component of the p38 MAPK
pathway, Cao et al. immunoprecipitated the
histone acetylase p300 and showed that it
was associated with MKP-1.
PMID: 18922786
Upon stimulation
of TLRs, MKP-1 was acetylated at
Lys57, and mutation of this residue abrogated
the acetylation of MKP-1 by p300 in vitro
and in TLR-stimulated cells, suggesting
that Lys57 is the crucial residue required
for the acetylation of MKP-1.
PMID: 18922786
Through a number of biochemical approaches,
the authors demonstrated that
acetylation of MKP-1 potentiated the interaction
between MKP-1 and p38 and, consequently,
increased the dephosphorylation
of p38 by MKP-1.
PMID: 18922786
In particular, HDAC inhibitors
decreased phosphorylation of p38
MAPK and its downstream target Elk-1 but
not the upstream MAP2Ks MKK3 or
MKK6, suggesting that these inhibitors act
upon the MAPK pathway at the level of
p38, possibly upon a kinase or phosphatase
that modifies p38 MAPK.
PMID: 18922786
Through a number of biochemical approaches,
the authors demonstrated that
acetylation of MKP-1 potentiated the interaction
between MKP-1 and p38 and, consequently,
increased the dephosphorylation
of p38 by MKP-1.