_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
_enti_e4
_enti_e2
_enti_e3
_enti_e55
_enti_e59
_enti_e53
_enti_e50
_enti_e54
_enti_e56
_enti_e52
_enti_e51
_enti_e61
_enti_e58
_enti_e57
_enti_e62
_enti_e60
g1_fact_g1
g1_fact_g14
g2_fact_g12
g2_fact_g13
p1_propro_p1
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
c1 cso30:c:InputAssociation connector
c2 cso30:c:OutputProcess connector
p1_propro_p2
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
c3 cso30:c:InputAssociation connector
c4 cso30:c:OutputProcess connector
p1_propro_p3
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
c5 cso30:c:InputAssociation connector
c6 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 18922786
Paradoxically, HDAC inhibitors also possess
potent anti-inflammatory effects by
shutting down the expression of genes encoding
proinflammatory cytokines and
molecules.
c7 cso30:c:InputInhibitor connector
c8 cso30:c:OutputProcess connector
p5_propro_p5
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.
c9 cso30:c:InputAssociation connector
c10 cso30:c:InputProcess connector
c11 cso30:c:OutputProcess connector
p5_propro_p6
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.
c12 cso30:c:InputAssociation connector
c13 cso30:c:InputProcess connector
c14 cso30:c:OutputProcess connector
p7_propro_p7
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
c15 cso30:c:InputAssociation connector
c16 cso30:c:InputProcess connector
c17 cso30:c:OutputProcess connector
p8_propro_p8
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
c24 cso30:c:InputAssociation connector
c61 cso30:c:InputInhibitor connector
c19 cso30:c:OutputProcess connector
p9_propro_p9
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
c20 cso30:c:InputAssociation connector
c21 cso30:c:OutputProcess connector
p10_propro_p10
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
c18 cso30:c:InputProcess connector
c22 cso30:c:InputProcess connector
c23 cso30:c:OutputProcess connector
p10_propro_p11
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
c25 cso30:c:InputProcess connector
c26 cso30:c:InputProcess connector
c27 cso30:c:OutputProcess connector
p8_propro_p12
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
c28 cso30:c:InputAssociation connector
c62 cso30:c:InputInhibitor connector
c29 cso30:c:OutputProcess connector
p13_propro_p13
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
c31 cso30:c:InputProcess connector
c30 cso30:c:InputAssociation connector
c32 cso30:c:OutputProcess connector
p13_propro_p14
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
c33 cso30:c:InputAssociation connector
c34 cso30:c:InputProcess connector
c35 cso30:c:OutputProcess connector
p15_propro_p15
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
c36 cso30:c:InputAssociation connector
c66 cso30:c:InputInhibitor connector
c37 cso30:c:OutputProcess connector
p16_propro_p16
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.
c38 cso30:c:InputAssociation connector
c39 cso30:c:InputProcess connector
c96 cso30:c:InputInhibitor connector
c40 cso30:c:OutputProcess connector
p17_propro_p17
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
c41 cso30:c:InputAssociation connector
c65 cso30:c:InputInhibitor connector
c42 cso30:c:OutputProcess connector
p17_propro_p18
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
c46 cso30:c:InputAssociation connector
c64 cso30:c:InputInhibitor connector
c47 cso30:c:OutputProcess connector
p16_propro_p19
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.
c43 cso30:c:InputAssociation connector
c44 cso30:c:InputProcess connector
c97 cso30:c:InputInhibitor connector
c45 cso30:c:OutputProcess connector
p16_propro_p20
PMID: 18922786,12444149,16978838,17337450
Furthermore, ERK, JNK,
and p38 MAPK have all been
suggested to facilitate TLR-induced
expression of MKP-1
c48 cso30:c:InputAssociation connector
c49 cso30:c:InputProcess connector
c50 cso30:c:OutputProcess connector
p17_propro_p21
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
c51 cso30:c:InputAssociation connector
c63 cso30:c:InputInhibitor connector
c52 cso30:c:OutputProcess connector
p22_propro_p22
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
c53 cso30:c:InputAssociation connector
c67 cso30:c:InputInhibitor connector
c54 cso30:c:OutputProcess connector
p23_propro_p23
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
c55 cso30:c:InputAssociation connector
c59 cso30:c:InputInhibitor connector
c56 cso30:c:OutputProcess connector
p23_propro_p24
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
c58 cso30:c:InputAssociation connector
c60 cso30:c:InputInhibitor connector
c57 cso30:c:OutputProcess connector
p25_propro_p25
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
c68 cso30:c:InputAssociation connector
c69 cso30:c:InputProcess connector
c70 cso30:c:OutputProcess connector
p26_propro_p26
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
c71 cso30:c:InputProcess connector
c72 cso30:c:InputProcess connector
c73 cso30:c:OutputProcess connector
p27_propro_p27
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.
c74 cso30:c:InputProcess connector
c77 cso30:c:InputInhibitor connector
c75 cso30:c:OutputProcess connector
c76 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 18922786
In the presence
of the transcription factor nuclear
factor-KappaB (NF-KappaB), TNF-alpha
induces a rapid and transient
activation of JNK.
c78 cso30:c:InputAssociation connector
c79 cso30:c:InputAssociation connector
c80 cso30:c:InputProcess connector
c81 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 18922786
Reactive
oxygen species (ROS) mediate
sustained JNK activation in NF-
KappaBdeficient cells by inactivating
MKP-1 and several other
MKP molecules.
c82 cso30:c:InputAssociation connector
c83 cso30:c:InputAssociation connector
c84 cso30:c:InputProcess connector
c85 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 18922786
Reactive
oxygen species (ROS) mediate
sustained JNK activation in NF-
KappaBdeficient 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.
c86 cso30:c:InputAssociation connector
c87 cso30:c:InputProcess connector
c88 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 18922786,15766528
Consequently,
JNK activation becomes unconstrained,
eventually leading to
cellular apoptosis (
c89 cso30:c:InputAssociation connector
p32_propro_p32
PMID: 18922786
HDAC inhibitors
down-regulated a subset of inflammationassociated
genes, including nitric oxide synthase
2 (NOS2), TNFalpha, and IL-6.
c90 cso30:c:InputInhibitor connector
c91 cso30:c:OutputProcess connector
p32_propro_p33
PMID: 18922786
HDAC inhibitors
down-regulated a subset of inflammationassociated
genes, including nitric oxide synthase
2 (NOS2), TNFalpha, and IL-6.
c92 cso30:c:InputInhibitor connector
c93 cso30:c:OutputProcess connector
p32_propro_p34
PMID: 18922786
HDAC inhibitors
down-regulated a subset of inflammationassociated
genes, including nitric oxide synthase
2 (NOS2), TNFalpha, and IL-6.
c94 cso30:c:InputInhibitor connector
c95 cso30:c:OutputProcess connector
p35_propro_p35
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.
c99 cso30:c:InputProcess connector
c111 cso30:c:InputAssociation connector
c100 cso30:c:OutputProcess connector
p36_propro_p36
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.
c102 cso30:c:InputAssociation connector
c103 cso30:c:InputProcess connector
c104 cso30:c:InputAssociation connector
c105 cso30:c:OutputProcess connector
p37_propro_p37
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.
c106 cso30:c:InputProcess connector
c107 cso30:c:OutputProcess connector
c108 cso30:c:OutputProcess connector
p38_propro_p38
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.
c112 cso30:c:InputProcess connector
c109 cso30:c:InputProcess connector
c113 cso30:c:OutputProcess connector
p35_propro_p39
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.
c98 cso30:c:InputProcess connector
c101 cso30:c:InputInhibitor connector
c110 cso30:c:OutputProcess connector
p40_propro_p40
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.
c114 cso30:c:InputProcess connector
c115 cso30:c:OutputProcess connector
HDAC inhibitors_enti_e5
HDAC inhibitors
cell growth arrest genes_enti_e6
cell growth arrest genes
differentiation genes_enti_e11
differentiation genes
apoptosis_enti_e12
apoptosis
proinflammatory cytokines_enti_e13
proinflammatory cytokines
MAP3K_enti_e14
MAP3K
MAP2K{p}_enti_e15
MAP2K{p}
MAP2K_enti_e16
MAP2K
MAPK_enti_e17
MAPK
MAPK{p}_enti_e18
MAPK{p}
AP-1_enti_MO000000276
AP-1
AP-1{p}_enti_e19
AP-1{p}
TLR_enti_e20
TLR
MKP-1_enti_MO000016814
MKP-1
MKP-1_enti_e21
MKP-1
MyD88_enti_MO000016573
MyD88
TLR:MyD88_enti_e22
TLR:MyD88
TLR:TRIF_enti_e23
TLR:TRIF
TRIF_enti_MO000041125
TRIF
Raf-1_enti_MO000000015
Raf-1
Raf-1{active}_enti_e24
Raf-1{active}
PKCepsilon_enti_MO000016645
PKCepsilon
PKCepsilon{active}_enti_e25
PKCepsilon{active}
ERK_enti_MO000000011
ERK
ERK{active}_enti_e26
ERK{active}
p38_enti_MO000000022
p38
JNK_enti_MO000000023
JNK
p38{active}_enti_e27
p38{active}
JNK{active}_enti_e28
JNK{active}
glucocorticoids_enti_MO000021732
glucocorticoids
TGFbeta_enti_MO000016808
TGFbeta
IL-10_enti_MO000017247
IL-10
IFNgamma_enti_MO000016665
IFNgamma
MKP-1{p}_enti_e29
MKP-1{p}
SCF ubiquitin liagse_enti_e30
SCF ubiquitin liagse
MKP-1{p}:SCF ubiquitin liagse_enti_e31
MKP-1{p}:SCF ubiquitin liagse
degradants_enti_e32
TNF-alpha_enti_MO000000289
TNF-alpha
NF-kappaB_enti_MO000000058
NF-kappaB
ROS_enti_e33
ROS
NOS2_enti_e34
NOS2
TNF-alpha_enti_G010329
TNF-alpha
IL-6_enti_G010262
IL-6
Elk-1_enti_MO000000038
Elk-1
Elk-1{p}_enti_e35
Elk-1{p}
p300_enti_MO000019984
p300
MKP-1:p300_enti_e36
MKP-1:p300
MKP-1{Ac}_enti_e37
MKP-1{Ac}
p38{p}_enti_e38
p38{p}
MKP-1{Ac}:p38{p}_enti_e39
MKP-1{Ac}:p38{p}
MKP-1{Ac}:p38_enti_e40
MKP-1{Ac}:p38
MKP-1{inactive}_enti_e41
MKP-1{inactive}