The Experts below are selected from a list of 3441 Experts worldwide ranked by ideXlab platform
Stephen M Keyse - One of the best experts on this subject based on the ideXlab platform.
-
Phosphorylation of the Kinase Interaction Motif in Mitogen-activated Protein (MAP) Kinase Phosphatase-4 Mediates Cross-talk between Protein Kinase A and MAP Kinase Signaling Pathways
The Journal of biological chemistry, 2011Co-Authors: Robin J. Dickinson, Laurent Delavaine, Rocío Cejudo-marín, Graeme Stewart, Christopher J. Staples, Mark P. Didmon, Antonio García Trinidad, Andres Alonso, Rafael Pulido, Stephen M KeyseAbstract:MAP Kinase Phosphatase 4 (DUSP9/MKP-4) plays an essential role during placental development and is one of a subfamily of three closely related cytoplasmic dual-specificity MAPK Phosphatases, which includes the ERK-specific enzymes DUSP6/MKP-3 and DUSP7/MKP-X. However, unlike DUSP6/MKP-3, DUSP9/MKP-4 also inactivates the p38α MAP Kinase both in vitro and in vivo. Here we demonstrate that inactivation of both ERK1/2 and p38α by DUSP9/MKP-4 is mediated by a conserved arginine-rich Kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. Furthermore, DUSP9/MKP-4 is unique among these cytoplasmic MKPs in containing a conserved PKA consensus phosphorylation site 55RRXSer-58 immediately adjacent to the Kinase interaction motif. DUSP9/MKP-4 is phosphorylated on Ser-58 by PKA in vitro, and phosphorylation abrogates the binding of DUSP9/MKP-4 to both ERK2 and p38α MAP Kinases. In addition, although mutation of Ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of DUSP9/MKP-4, phospho-mimetic (Ser-58 to Glu) substitution inhibits both the interaction of DUSP9/MKP-4 with ERK2 and p38α in vivo and its ability to dephosphorylate and inactivate these MAP Kinases. Finally, the use of a phospho-specific antibody demonstrates that endogenous DUSP9/MKP-4 is phosphorylated on Ser-58 in response to the PKA agonist forskolin and is also modified in placental tissue. We conclude that DUSP9/MKP-4 is a bona fide target of PKA signaling and that attenuation of DUSP9/MKP-4 function can mediate cross-talk between the PKA pathway and MAPK signaling through both ERK1/2 and p38α in vivo.
-
expression of the erk specific MAP Kinase Phosphatase pyst1 mkp3 in mouse embryos during morphogenesis and early organogenesis
Mechanisms of Development, 2002Co-Authors: Robin J. Dickinson, Stephen M Keyse, Maxwell C. Eblaghie, Gillian M MorrisskayAbstract:Mitogen-activated-protein Kinase (MAP Kinase) cascades are effector mechanisms for many growth factor signals implicated in developmental processes, including appendage outgrowth and organogenesis. The cascade culminates in extracellular-signal-regulated MAP Kinase (ERK), which enters the nucleus. ERK activity reflects the competing actions of upstream activator Kinases and inhibitory MAP Kinase Phosphatases. We have studied embryonic expression of the dual-specificity MAP Kinase Phosphatase PYST1/MKP3, which is a specific and potent regulator of the ERK class of MAP Kinases. We found dynamic patterns of mPyst1 messenger RNA in important signalling centres associated with cell proliferation and patterning in developing mouse embryos, including presegmental paraxial mesoderm, limb bud and branchial arch mesenchyme, midbrain/hindbrain isthmus, and nasal, dental, hair, and mammary placodes. Most of these have been characterised as sites of FGF/FGFR signalling.
-
Expression of the ERK-specific MAP Kinase Phosphatase PYST1/MKP3 in mouse embryos during morphogenesis and early organogenesis.
Mechanisms of development, 2002Co-Authors: Robin J. Dickinson, Stephen M Keyse, Maxwell C. Eblaghie, Gillian M. Morriss-kayAbstract:Mitogen-activated-protein Kinase (MAP Kinase) cascades are effector mechanisms for many growth factor signals implicated in developmental processes, including appendage outgrowth and organogenesis. The cascade culminates in extracellular-signal-regulated MAP Kinase (ERK), which enters the nucleus. ERK activity reflects the competing actions of upstream activator Kinases and inhibitory MAP Kinase Phosphatases. We have studied embryonic expression of the dual-specificity MAP Kinase Phosphatase PYST1/MKP3, which is a specific and potent regulator of the ERK class of MAP Kinases. We found dynamic patterns of mPyst1 messenger RNA in important signalling centres associated with cell proliferation and patterning in developing mouse embryos, including presegmental paraxial mesoderm, limb bud and branchial arch mesenchyme, midbrain/hindbrain isthmus, and nasal, dental, hair, and mammary placodes. Most of these have been characterised as sites of FGF/FGFR signalling.
-
distinct binding determinants for erk2 p38α and jnk MAP Kinases mediate catalytic activation and substrate selectivity of MAP Kinase Phosphatase 1
Journal of Biological Chemistry, 2001Co-Authors: David N Slack, Olemorten Seternes, Mads Gabrielsen, Stephen M KeyseAbstract:Abstract Mitogen-activated protein (MAP) Kinase Phosphatase 1 (MKP-1/CL100) is an inducible nuclear dual specificity protein Phosphatase that can dephosphorylate and inactivate both mitogen- and stress-activated protein Kinases in vitro andin vivo. However, the molecular mechanism responsible for the substrate selectivity of MKP-1 is unknown. In addition, it has been suggested that the signal transducers and activators of transcription 1 (STAT1) transcription factor is a physiological non-MAP Kinase substrate for MKP-1. We have used the yeast two-hybrid assay to demonstrate that MKP-1 is able to interact selectively with the extracellular signal-regulated Kinase 1/2 (ERK1/2), p38α, and c-Jun NH2-terminal Kinase (JNK) MAP Kinase isoforms. Furthermore, this binding is accompanied by catalytic activation of recombinant MKP-1 protein in vitro, and these end points show an absolute correlation with MKP-1 substrate selectivity in vivo. In contrast, MKP-1 does not interact with STAT1. Recombinant STAT1 does not cause catalytic activation of MKP-1; nor does MKP-1 block tyrosine phosphorylation of STAT1 in vivo.Both binding and catalytic activation of MKP-1 are abrogated by mutation of a conserved docking site in ERK2, p38α, and JNK1 MAP Kinases. Within MKP-1, MAP Kinase binding is mediated by the amino-terminal noncatalytic domain of the protein. However, mutation of a conserved cluster of positively charged residues within this domain abolishes the binding and activation of MKP-1 by ERK2 and p38α but not JNK1, indicating that there are distinct binding determinants for these MAP Kinase isoforms. We conclude that the substrate selectivity of MKP-1 is determined by specific protein-protein interactions coupled with catalytic activation of the Phosphatase and that these interactions are restricted to members of the MAP Kinase family of enzymes.
-
Distinct Binding Determinants for ERK2/p38α and JNK MAP Kinases Mediate Catalytic Activation and Substrate Selectivity of MAP Kinase Phosphatase-1
The Journal of biological chemistry, 2001Co-Authors: David N Slack, Olemorten Seternes, Mads Gabrielsen, Stephen M KeyseAbstract:Abstract Mitogen-activated protein (MAP) Kinase Phosphatase 1 (MKP-1/CL100) is an inducible nuclear dual specificity protein Phosphatase that can dephosphorylate and inactivate both mitogen- and stress-activated protein Kinases in vitro andin vivo. However, the molecular mechanism responsible for the substrate selectivity of MKP-1 is unknown. In addition, it has been suggested that the signal transducers and activators of transcription 1 (STAT1) transcription factor is a physiological non-MAP Kinase substrate for MKP-1. We have used the yeast two-hybrid assay to demonstrate that MKP-1 is able to interact selectively with the extracellular signal-regulated Kinase 1/2 (ERK1/2), p38α, and c-Jun NH2-terminal Kinase (JNK) MAP Kinase isoforms. Furthermore, this binding is accompanied by catalytic activation of recombinant MKP-1 protein in vitro, and these end points show an absolute correlation with MKP-1 substrate selectivity in vivo. In contrast, MKP-1 does not interact with STAT1. Recombinant STAT1 does not cause catalytic activation of MKP-1; nor does MKP-1 block tyrosine phosphorylation of STAT1 in vivo.Both binding and catalytic activation of MKP-1 are abrogated by mutation of a conserved docking site in ERK2, p38α, and JNK1 MAP Kinases. Within MKP-1, MAP Kinase binding is mediated by the amino-terminal noncatalytic domain of the protein. However, mutation of a conserved cluster of positively charged residues within this domain abolishes the binding and activation of MKP-1 by ERK2 and p38α but not JNK1, indicating that there are distinct binding determinants for these MAP Kinase isoforms. We conclude that the substrate selectivity of MKP-1 is determined by specific protein-protein interactions coupled with catalytic activation of the Phosphatase and that these interactions are restricted to members of the MAP Kinase family of enzymes.
Atsushi Yamaguchi - One of the best experts on this subject based on the ideXlab platform.
-
over expression of MAP Kinase Phosphatase 1 mkp 1 suppresses neuronal death through regulating jnk signaling in hypoxia re oxygenation
Brain Research, 2012Co-Authors: Shunsuke Koga, Shunsuke Kojima, Takashi Kishimoto, Satoshi Kuwabara, Atsushi YamaguchiAbstract:A pivotal role of c-jun N-terminal Kinase (JNK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP Kinase Phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein Phosphatase (DUSP) family, which inactivates mitogen-activated protein Kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by JNK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over-expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction.
-
Over-expression of MAP Kinase Phosphatase-1 (MKP-1) suppresses neuronal death through regulating JNK signaling in hypoxia/re-oxygenation
Brain research, 2011Co-Authors: Shunsuke Koga, Shunsuke Kojima, Takashi Kishimoto, Satoshi Kuwabara, Atsushi YamaguchiAbstract:A pivotal role of c-jun N-terminal Kinase (JNK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP Kinase Phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein Phosphatase (DUSP) family, which inactivates mitogen-activated protein Kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by JNK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over-expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction.
Moez Hanin - One of the best experts on this subject based on the ideXlab platform.
-
Regulation of the wheat MAP Kinase Phosphatase 1 by 14-3-3 proteins
Plant science : an international journal of experimental plant biology, 2017Co-Authors: Mouna Ghorbel, Ikram Zaidi, Valérie Cotelle, Chantal Ebel, Mélanie Ormancey, Jean-philippe Galaud, Moez HaninAbstract:Plant MAP Kinase Phosphatases (MKPs) are major regulators of MAPK signaling pathways and play crucial roles in controlling growth, development and stress responses. The presence of several functional domains in plant MKPs such as a dual specificity Phosphatase catalytic domain, gelsolin, calmodulin-binding and serine-rich domains, suggests that MKPs can interact with distinct cellular partners, others than MAPKs. In this report, we identified a canonical mode I 14-3-3-binding motif (574KLPSLP579) located at the carboxy-terminal region of the wheat MKP, TMKP1. We found that this motif is well-conserved among other MKPs from monocots including Hordeum vulgare, Brachypodium distachyon and Aegilops taushii. Using co-immunoprecipitation assays, we provide evidence for interaction between TMKP1 and 14-3-3 proteins in wheat. Moreover, the Phosphatase activity of TMKP1 is increased in a phospho-dependent manner by either Arabidopsis or yeast 14-3-3 isoforms. TMKP1 activation by 14-3-3 proteins is enhanced by Mn2+, whereas in the presence of Ca2+ ions, TMKP1 activation was limited to Arabidopsis 14-3-3φ (phi), an isoform harboring an EF-hand motif. Such findings strongly suggest that 14-3-3 proteins, in conjunction with specific divalent cations, may stimulate TMKP1 activity and point-out that 14-3-3 proteins bind and regulate the activity of a MKP in eukaryotes.
-
The wheat MAP Kinase Phosphatase 1 confers higher lithium tolerance in yeast
FEMS yeast research, 2012Co-Authors: Ikram Zaidi, Asier González, Majdi Touzri, María C. Álvarez, José Ramos, Khaled Masmoudi, Joaquín Ariño, Moez HaninAbstract:The durum wheat TMKP1 gene encodes a MAP Kinase Phosphatase. When overexpressed in Saccharomyces cerevisiae , TMKP1 leads to salt stress tolerance (especially LiCl), which is dependent on the Phosphatase activity of the protein. The TMKP1-associated Li+ resistance is restricted to a galactose-containing medium. Interestingly, this salt tolerance is abolished in the absence of one member of the yeast type 2C Ser/Thr protein Phosphatase family (Ptc1) but not when other members such as Ptc2 or Ptc3 are lacking. Increased Li+ tolerance is not mediated by regulation of the P-type ATPase Ena1, a major determinant for salt tolerance. In contrast, the effect of TMKP1 depends on Hal3 (a negative regulator of Ppz Phosphatases) and on the presence of the high-affinity potassium transporters Trk1/Trk2. Tolerance to Li+ is also abolished in cells lacking the aldose reductase Gre3, previously shown to be involved in the resistance to this cation. This study provides evidence that the wheat TMKP1 Phosphatase is contributing to reduce the exacerbated lithium toxicity in galactose-grown cells, in a way that depends on the presence of the potassium Trk transporters.
-
TMKP1 is a novel wheat stress responsive MAP Kinase Phosphatase localized in the nucleus
Plant Molecular Biology, 2010Co-Authors: Ikram Zaidi, Majdi Touzri, Khaled Masmoudi, Chantal Ebel, Etienne Herzog, Jean-luc Evrard, Anne Catherine Schmit, Moez HaninAbstract:The regulation of plant signalling responses by Mitogen-Activated Protein Kinases (MAPKs)-mediated protein phosphorylation is well recognized. MAP Kinase Phosphatases (MKPs) are negative regulators of MAPKs in eukaryotes. We report here the identification and the characterization of TMKP1, the first wheat MKP ( Triticum turgidum L. subsp. Durum ). Expression profile analyses performed in two durum wheat cultivars showing a marked difference in salt and drought stress tolerance, revealed a differential regulation of TMKP1 . Under salt and osmotic stress, TMKP1 is induced in the sensitive wheat variety and repressed in the tolerant one. A recombinant TMKP1 was shown to be an active Phosphatase and capable to interact specifically with two wheat MAPKs (TMPK3 and TMPK6). In BY2 tobacco cells transiently expressing GFP::TMKP1, the fusion protein was localized into the nucleus. Interestingly, the deletion of the N-terminal non catalytic domain results in a strong accumulation of the truncated fusion protein in the cytoplasm. In addition, when expressed in BY2 cells, TMPK3 and TMPK6 fused to red fluorescent protein (RFP) were shown to be present predominantly in the nucleus. Surprisingly, when co-expressed with the N-terminal truncated TMKP1 fusion protein; both Kinases are excluded from the nuclear compartment and accumulate in the cytoplasm. This strongly suggests that TMKP1 interacts in vivo with TMPK3 and TMPK6 and controls their subcellular localization. Taken together, our results show that the newly isolated wheat MKP might play an active role in modulating the plant cell responses to salt and osmotic stress responses.
Yusen Liu - One of the best experts on this subject based on the ideXlab platform.
-
MAP Kinase Phosphatase 1 a gatekeeper of the acute innate immune response
Life Sciences, 2020Co-Authors: Sean G Kirk, Yusen Liu, Lobelia SamavatiAbstract:Mitogen-activated protein Kinase (MAPK)§ cascades are crucial signaling pathways in the regulation of the host immune response to infection. MAPK Phosphatase (MKP)-1, an archetypal member of the MKP family, plays a pivotal role in the down-regulation of p38 and JNK. Studies using cultured macrophages have demonstrated a pivotal role of MKP-1 in the restraint of the biosynthesis of both pro-inflammatory and anti-inflammatory cytokines as well as chemokines. Using MKP-1 knockout mice, several groups have not only confirmed the critical importance of MKP-1 in the regulation of the cytokine synthesis in vivo during the acute host response to bacterial infections, but also revealed novel functions of MKP-1 in maintaining bactericidal functions and host metabolic activities. RNA-seq analyses on livers of septic mice infected with E. coli have revealed that MKP-1 deficiency caused substantial perturbation in the expression of over 5000 genes, an impressive >20% of the entire murine genome. Among the genes whose expression are dramatically affected by MKP-1 deficiency are those encoding metabolic regulators and acute phase response proteins. These studies demonstrate that MKP-1 is an essential gate-keeper of the acute innate immune response, facilitating pathogen killing and regulating the metabolic response during pathogenic infection. In this review article, we will summarize the studies on the function of MKP-1 during acute innate immune response in the regulation of inflammation, metabolism, and acute phase response. We will also discuss the role of MKP-1 in the actions of numerous immunomodulatory agents.
-
MAP Kinase Phosphatase-1 and Septic Shock.
Journal of organ dysfunction, 2009Co-Authors: Yusen Liu, Thomas P. ShanleyAbstract:Mitogen-activated protein (MAP) Kinase cascades are crucial signal transduction pathways in the biosynthesis of pro-inflammatory cytokines. MAP Kinase Phosphatase (MKP)-1, an archetypal member of the MKP family, plays a pivotal role in the feedback control of p38 and c-Jun N-terminal Kinase (JNK). In vitro studies using cultured macrophages have provided strong evidence for a critical role of MKP-1 in the restraint of pro-inflammatory cytokine biosynthesis. Recently, a number of studies conducted using MKP-1 knockout mice have verified the importance of MKP-1 in the regulation of p38 and JNK and also in the regulation of pro-inflammatory cytokine synthesis. Upon lipopolysaccharide challenge, MKP-1 knockout mice produced dramatically greater amounts of inflammatory cytokines, developed severe hypotension, and multi-organ failure, and exhibited a remarkable increase in mortality. These studies demonstrate that MKP-1 is an essential feedback regulator of the innate immune response, and that it plays a critic...
-
MAP Kinase Phosphatase-1, a critical negative regulator of the innate immune response.
International journal of clinical and experimental medicine, 2009Co-Authors: Shuang-feng Chen, Yusen LiuAbstract:Mitogen-activated protein (MAP) Kinase cascades are crucial signal transduction pathways in the regulation of the host inflammatory response to infection. MAP Kinase Phosphatase (MKP)-1, an archetypal member of the MKP family, plays a pivotal role in the deactivation of p38 and JNK. In vitro studies using cultured macrophages have provided compelling evidence for a central role of MKP-1 in the restraint of pro-inflammatory cytokine biosynthesis. Studies using MKP-1 knockout mice have strengthened the findings from in vitro studies and defined the critical importance of MKP-1 in the regulation of pro-inflammatory cytokine synthesis in vivo during the host response to bacterial cell wall components. Upon challenge with Toll-like receptor ligands MKP-1 knockout mice produced dramatically greater amounts of inflammatory cytokines, developed severe hypotension and multi-organ failure, and exhibited a remarkable increase in mortality. More recent investigations using intact bacteria confirmed these observations and further revealed novel functions of MKP-1 in host defense against bacterial infection. These studies demonstrate that MKP-1 is an essential feedback regulator of the innate immune response, and that it plays a critical role in preventing septic shock and multi-organ dysfunction during pathogenic infection. In this review, we will summarize the studies on the function of MKP-1 in innate immune responses and discuss the regulation of this novel protein Phosphatase.
-
The role of MAP Kinase Phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia.
Life sciences, 2008Co-Authors: Xianxi Wang, Leif D Nelin, Joshua R Kuhlman, Xiaomei Meng, Stephen E Welty, Yusen LiuAbstract:We have previously shown that glucocorticoids induce the expression of MAP Kinase Phosphatase (Mkp)(a)-1 in innate immune cells. Since Mkp-1 is a critical negative regulator of the innate immune response, we hypothesize that Mkp-1 plays a significant role in the anti-inflammatory action of glucocorticoids. The specific aim of the present study is to understand the role of Mkp-1 in the anti-inflammatory function of glucocorticoids. Wild-type and Mkp-1(-/-) mice were treated with different doses of dexamethasone and then challenged with different doses of lipopolysaccharide (LPS). The survival and blood cytokines were assessed. The effects of dexamethasone on cytokine production in wild-type and Mkp-1(-/-) primary macrophages ex vivo were also examined. We found that dexamethasone induced the expression of Mkp-1 in vivo. Dexamethasone treatment completely protected wild-type mice from the mortality caused by a relatively high dose of LPS. However, dexamethasone treatment offered only a partial protection to Mkp-1(-/-) mice. Dexamethasone attenuated TNF-alpha production in both wild-type and Mkp-1(-/-) mice challenged with LPS, although TNF-alpha production in Mkp-1(-/-) mice was significantly more robust than that in wild-type mice. Dexamethasone pretreatment shortened the duration of p38 and JNK activation in LPS-stimulated wild-type macrophages, but had little effect on p38 or JNK activation in similarly treated Mkp-1(-/-) macrophages. Our results indicate that the inhibition of p38 and JNK activities by glucocorticoids is mediated by enhanced Mkp-1 expression. These results demonstrate that dexamethasone exerts its anti-inflammatory effects through both Mkp-1-dependent and Mkp-1-indepent mechanisms.
-
The role of MAP Kinase Phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia.
Life Sciences, 2008Co-Authors: Xianxi Wang, Leif D Nelin, Joshua R Kuhlman, Xiaomei Meng, Stephen E Welty, Yusen LiuAbstract:Abstract Aims We have previously shown that glucocorticoids induce the expression of MAP Kinase Phosphatase (Mkp) a -1 in innate immune cells. Since Mkp-1 is a critical negative regulator of the innate immune response, we hypothesize that Mkp-1 plays a significant role in the anti-inflammatory action of glucocorticoids. The specific aim of the present study is to understand the role of Mkp-1 in the anti-inflammatory function of glucocorticoids. Main methods Wild-type and Mkp-1 −/− mice were treated with different doses of dexamethasone and then challenged with different doses of lipopolysaccharide (LPS). The survival and blood cytokines were assessed. The effects of dexamethasone on cytokine production in wild-type and Mkp-1 −/− primary macrophages ex vivo were also examined. Key findings We found that dexamethasone induced the expression of Mkp-1 in vivo . Dexamethasone treatment completely protected wild-type mice from the mortality caused by a relatively high dose of LPS. However, dexamethasone treatment offered only a partial protection to Mkp-1 −/− mice. Dexamethasone attenuated TNF-α production in both wild-type and Mkp-1 −/− mice challenged with LPS, although TNF-α production in Mkp-1 −/− mice was significantly more robust than that in wild-type mice. Dexamethasone pretreatment shortened the duration of p38 and JNK activation in LPS-stimulated wild-type macrophages, but had little effect on p38 or JNK activation in similarly treated Mkp-1 −/− macrophages. Significance Our results indicate that the inhibition of p38 and JNK activities by glucocorticoids is mediated by enhanced Mkp-1 expression. These results demonstrate that dexamethasone exerts its anti-inflammatory effects through both Mkp-1-dependent and Mkp-1-indepent mechanisms.
Shunsuke Koga - One of the best experts on this subject based on the ideXlab platform.
-
over expression of MAP Kinase Phosphatase 1 mkp 1 suppresses neuronal death through regulating jnk signaling in hypoxia re oxygenation
Brain Research, 2012Co-Authors: Shunsuke Koga, Shunsuke Kojima, Takashi Kishimoto, Satoshi Kuwabara, Atsushi YamaguchiAbstract:A pivotal role of c-jun N-terminal Kinase (JNK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP Kinase Phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein Phosphatase (DUSP) family, which inactivates mitogen-activated protein Kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by JNK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over-expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction.
-
Over-expression of MAP Kinase Phosphatase-1 (MKP-1) suppresses neuronal death through regulating JNK signaling in hypoxia/re-oxygenation
Brain research, 2011Co-Authors: Shunsuke Koga, Shunsuke Kojima, Takashi Kishimoto, Satoshi Kuwabara, Atsushi YamaguchiAbstract:A pivotal role of c-jun N-terminal Kinase (JNK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP Kinase Phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein Phosphatase (DUSP) family, which inactivates mitogen-activated protein Kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by JNK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over-expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction.