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: 18922786,16497588 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

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 ¦Ã (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

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 ¦Ã (IFN-¦Ã) 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.

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 ¦Ã (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: 18922786,16380513 Conversely, proinflammatory stimuli such as interferon ¦Ã (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.

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: 18922786,12444149,16978838,17337450 Furthermore, ERK, JNK, and p38 MAPK have all been suggested to facilitate TLR-induced expression of MKP-1

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 ¦Ã (IFN-gamma) attenuate MKP-1 expression to facilitate their positive effects on MAPK activation

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 ¦Ã (IFN-gamma) attenuate MKP-1 expression to facilitate their positive effects on MAPK activation

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 ¦Ã (IFN-gamma) attenuate MKP-1 expression to facilitate their positive effects on MAPK activation

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 ¦Ã (IFN-gamma) attenuate MKP-1 expression to facilitate their positive effects on MAPK activation

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.

PMID: 18922786 In the presence of the transcription factor nuclear factor-KappaB (NF-KappaB), TNF-alpha induces a rapid and transient activation of JNK.

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: 18922786,11902574 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 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.

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.

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 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 Paradoxically, HDAC inhibitors also possess potent anti-inflammatory effects by shutting down the expression of genes encoding proinflammatory cytokines and molecules.

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 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.

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.

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

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 ¦Ã (IFN-gamma) attenuate MKP-1 expression to facilitate their positive effects on MAPK activation

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