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Huihua Li - One of the best experts on this subject based on the ideXlab platform.
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induction of MAPK Phosphatase 1 by hypothermia inhibits tnf alpha induced endothelial barrier dysfunction and apoptosis
Cardiovascular Research, 2010Co-Authors: Dan Yang, Huihua LiAbstract:AIMS: Hypothermia therapy has been shown to confer robust protection against brain injury and cardiac arrest. However, the mechanisms underlying endothelial cell protection of hypothermia have not yet been completely elucidated. Here, we investigated molecular effects of hypothermia on tumour necrosis factor-alpha (TNF-alpha)-induced endothelial barrier dysfunction and apoptosis. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) treated with TNF-alpha were incubated under normothermia (37 degrees C) or hypothermia (33 degrees C). [corrected] Endothelial permeability, actin alterations, and apoptosis were examined. The protein levels were determined by immunoblot analysis. Treatment of HUVECs with TNF-alpha resulted in a significant increase of permeability, actin reorganization, and apoptosis. Hypothermia markedly attenuated TNF-alpha-induced effects. The inhibitory action of hypothermia on stress fibre formation was mediated via inactivation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (HSP27), and the decrease in TNF-alpha-induced apoptosis by hypothermia was associated with inhibition of p38 MAPK and c-Jun N-terminal kinase (JNK) activity. Hypothermia had no action on p38 MAPK and JNK upstream kinases MAPK kinase 3/6 (MKK3/6) and MAPK kinase 7 (MKK7), but it markedly induced the expression of MAPK Phosphatase-1 (MKP-1). Furthermore, siRNA experiments showed that MKP-1 was an important mediator of hypothermia in reducing TNF-alpha-induced inflammatory responses and activation of p38 MAPK and JNK in HUVECs. CONCLUSION: These results for the first time demonstrate that hypothermia protects against TNF-alpha-induced endothelial barrier dysfunction and apoptosis through an MKP-1-dependent mechanism.
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erratum to induction of MAPK Phosphatase 1 by hypothermia inhibits tnf α induced endothelial barrier dysfunction and apoptosis
Cardiovascular Research, 2010Co-Authors: Dan Yang, Huihua LiAbstract:Aims Hypothermia therapy has been shown to confer robust protection against brain injury and cardiac arrest. However, the mechanisms underlying endothelial cell protection of hypothermia have not yet been completely elucidated. Here, we investigated molecular effects of hypothermia on tumour necrosis factor-α (TNF-α)-induced endothelial barrier dysfunction and apoptosis. Methods and results Human umbilical vein endothelial cells (HUVECs) treated with TNF-α were incubated under normothermia (37°C) or hypothermia (3°C). Endothelial permeability, actin alterations, and apoptosis were examined. The protein levels were determined by immunoblot analysis. Treatment of HUVECs with TNF-α resulted in a significant increase of permeability, actin reorganization, and apoptosis. Hypothermia markedly attenuated TNF-α-induced effects. The inhibitory action of hypothermia on stress fibre formation was mediated via inactivation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (HSP27), and the decrease in TNF-α-induced apoptosis by hypothermia was associated with inhibition of p38 MAPK and c-Jun N-terminal kinase (JNK) activity. Hypothermia had no action on p38 MAPK and JNK upstream kinases MAPK kinase 3/6 (MKK3/6) and MAPK kinase 7 (MKK7), but it markedly induced the expression of MAPK Phosphatase-1 (MKP-1). Furthermore, siRNA experiments showed that MKP-1 was an important mediator of hypothermia in reducing TNF-α-induced inflammatory responses and activation of p38 MAPK and JNK in HUVECs. Conclusion These results for the first time demonstrate that hypothermia protects against TNF-α-induced endothelial barrier dysfunction and apoptosis through an MKP-1-dependent mechanism.
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atrogin 1 mafbx enhances simulated ischemia reperfusion induced apoptosis in cardiomyocytes through degradation of MAPK Phosphatase 1 and sustained jnk activation
Journal of Biological Chemistry, 2009Co-Authors: Hua Zhang, Dongfeng Gu, Huihua LiAbstract:Abstract Atrogin-1/MAFbx is a major atrophy-related E3 ubiquitin ligase that is expressed specifically in striated muscle. Although the contribution of atrogin-1 to cardiac and muscle hypertrophy/atrophy has been examined extensively, it remains unclear whether atrogin-1 plays an essential role in the simulated ischemia/reperfusion-induced apoptosis of primary cardiomyocytes. Here we showed that atrogin-1 markedly enhanced ischemia/reperfusion-induced apoptosis in cardiomyocytes via activation of JNK signaling. Overexpression of atrogin-1 increased phosphorylation of JNK and c-Jun and decreased phosphorylation of Foxo3a. In addition, atrogin-1 decreased Bcl-2, increased Bax, and enhanced the activation of caspases. Furthermore, JNK inhibitor SP600125 markedly blocked the effect of atrogin-1 on cell apoptosis and the expression of apoptotic-related proteins and caspases. Importantly, atrogin-1 induced sustained activation of JNK through a mechanism that involved degradation of MAPK Phosphatase-1 (MKP-1) protein. Atrogin-1 interacted with and triggered MKP-1 for ubiquitin-mediated degradation. In contrast, proteasome inhibitors markedly blocked the degradation of MKP-1. Taken together, these results demonstrate that atrogin-1 promotes degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby leading to persistent activation of JNK signaling and further cardiomyocyte apoptosis following ischemia/reperfusion injury.
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Atrogin-1/MAFbx enhances simulated ischemia/reperfusion-induced apoptosis in cardiomyocytes through degradation of MAPK Phosphatase-1 and sustained JNK activation.
Journal of Biological Chemistry, 2008Co-Authors: Hua Zhang, Dongfeng Gu, Huihua LiAbstract:Abstract Atrogin-1/MAFbx is a major atrophy-related E3 ubiquitin ligase that is expressed specifically in striated muscle. Although the contribution of atrogin-1 to cardiac and muscle hypertrophy/atrophy has been examined extensively, it remains unclear whether atrogin-1 plays an essential role in the simulated ischemia/reperfusion-induced apoptosis of primary cardiomyocytes. Here we showed that atrogin-1 markedly enhanced ischemia/reperfusion-induced apoptosis in cardiomyocytes via activation of JNK signaling. Overexpression of atrogin-1 increased phosphorylation of JNK and c-Jun and decreased phosphorylation of Foxo3a. In addition, atrogin-1 decreased Bcl-2, increased Bax, and enhanced the activation of caspases. Furthermore, JNK inhibitor SP600125 markedly blocked the effect of atrogin-1 on cell apoptosis and the expression of apoptotic-related proteins and caspases. Importantly, atrogin-1 induced sustained activation of JNK through a mechanism that involved degradation of MAPK Phosphatase-1 (MKP-1) protein. Atrogin-1 interacted with and triggered MKP-1 for ubiquitin-mediated degradation. In contrast, proteasome inhibitors markedly blocked the degradation of MKP-1. Taken together, these results demonstrate that atrogin-1 promotes degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby leading to persistent activation of JNK signaling and further cardiomyocyte apoptosis following ischemia/reperfusion injury.
Alaina J. Ammit - One of the best experts on this subject based on the ideXlab platform.
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Role of Dual-Specificity Phosphatase 1 in Glucocorticoid-Driven Anti-inflammatory Responses.
Frontiers in Immunology, 2019Co-Authors: Jessica Hoppstädter, Alaina J. AmmitAbstract:Glucocorticoids (GCs) potently inhibit pro-inflammatory responses and are widely used for the treatment of inflammatory diseases, such as allergies, autoimmune disorders, and asthma. Dual-specificity Phosphatase 1 (DUSP1), also known as mitogen-activated protein kinase (MAPK) Phosphatase-1 (MKP-1), exerts its effects by dephosphorylation of MAPKs, i.e., extracellular-signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Endogenous DUSP1 expression is tightly regulated at multiple levels, involving both transcriptional and post-transcriptional mechanisms. DUSP1 has emerged as a central mediator in the resolution of inflammation, and upregulation of DUSP1 by GCs has been suggested to be a key mechanism of GC actions. In this review, we discuss the impact of DUSP1 on the efficacy of GC-mediated suppression of inflammation and address the underlying mechanisms.
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prostaglandin e2 induces expression of MAPK Phosphatase 1 mkp 1 in airway smooth muscle cells
European Journal of Pharmacology, 2016Co-Authors: Nowshin N Rumzhum, Alaina J. AmmitAbstract:Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK Phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved.
Kunihiro Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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integration of caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by mek 1 MAPK kinase and vhp 1 MAPK Phosphatase
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Nicole T Liberati, Tomoaki Mizuno, Naoki Hisamoto, Kunihiro Matsumoto, Hideki Inoue, Frederick M AusubelAbstract:The p38 and JNK classes of mitogen-activated protein kinases (MAPKs) have evolutionarily conserved roles in the control of cellular responses to microbial and abiotic stresses. The mechanisms by which crosstalk between distinct p38 and c-Jun N-terminal kinase (JNK) MAPK pathways occurs with resultant integration of signaling information have been difficult to establish, particularly in the context of whole organism physiology. In Caenorhabditis elegans a PMK-1 p38 MAPK pathway is required for resistance to bacterial infection, and a KGB-1 JNK-like MAPK pathway has recently been shown to mediate resistance to heavy metal stress. Here, we show that two components of the KGB-1 pathway, MEK-1 MAPK kinase (MAPKK), a homolog of mammalian MKK7, and VHP-1 MAPK Phosphatase (MKP), a homolog of mammalian MKP7, also regulate pathogen resistance through the modulation of PMK-1 activity. The regulation of p38 and JNK-like MAPK pathways mediating immunity and heavy metal stress by common MAPKK and MKP signaling components suggests pivotal roles for MEK-1 and VHP-1 in the integration of diverse stress signals contributing to pathogen resistance in C. elegans. In addition, these data point to mechanisms in multicellular organisms by which signals transduced by distinct MAPK pathways may be subject to physiological integration at the level of regulation of MAPK activity by MAPKKs and MKPs.
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the caenorhabditis elegans MAPK Phosphatase vhp 1 mediates a novel jnk like signaling pathway in stress response
The EMBO Journal, 2004Co-Authors: Tomoaki Mizuno, Naoki Hisamoto, Takashi Terada, Tae Kondo, Makoto Adachi, Eisuke Nishida, Frederick M Ausubel, Kunihiro MatsumotoAbstract:Mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli and to a wide variety of environmental stresses. MAPK cascades can be inactivated at the MAPK activation step by members of the MAPK Phosphatase (MKP) family. However, the components that act in MKP-regulated pathways have not been well characterized in the context of whole organisms. Here we characterize the Caenorhabditis elegans vhp-1 gene, encoding an MKP that acts preferentially on the c-Jun N-terminal kinase (JNK) and p38 MAPKs. We found that animals defective in vhp-1 are arrested during larval development. This vhp-1 defect is suppressed by loss-of-function mutations in the kgb-1, mek-1, and mlk-1 genes encoding a JNK-like MAPK, an MKK7-type MAPKK, and an MLK-type MAPKKK, respectively. The genetic and biochemical data presented here demonstrate a critical role for VHP-1 in the KGB-1 pathway. Loss-of-function mutations in each component in the KGB-1 pathway result in hypersensitivity to heavy metals. These results suggest that VHP-1 plays a pivotal role in the integration and fine-tuning of the stress response regulated by the KGB-1 MAPK pathway.
Frederick M Ausubel - One of the best experts on this subject based on the ideXlab platform.
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integration of caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by mek 1 MAPK kinase and vhp 1 MAPK Phosphatase
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Nicole T Liberati, Tomoaki Mizuno, Naoki Hisamoto, Kunihiro Matsumoto, Hideki Inoue, Frederick M AusubelAbstract:The p38 and JNK classes of mitogen-activated protein kinases (MAPKs) have evolutionarily conserved roles in the control of cellular responses to microbial and abiotic stresses. The mechanisms by which crosstalk between distinct p38 and c-Jun N-terminal kinase (JNK) MAPK pathways occurs with resultant integration of signaling information have been difficult to establish, particularly in the context of whole organism physiology. In Caenorhabditis elegans a PMK-1 p38 MAPK pathway is required for resistance to bacterial infection, and a KGB-1 JNK-like MAPK pathway has recently been shown to mediate resistance to heavy metal stress. Here, we show that two components of the KGB-1 pathway, MEK-1 MAPK kinase (MAPKK), a homolog of mammalian MKK7, and VHP-1 MAPK Phosphatase (MKP), a homolog of mammalian MKP7, also regulate pathogen resistance through the modulation of PMK-1 activity. The regulation of p38 and JNK-like MAPK pathways mediating immunity and heavy metal stress by common MAPKK and MKP signaling components suggests pivotal roles for MEK-1 and VHP-1 in the integration of diverse stress signals contributing to pathogen resistance in C. elegans. In addition, these data point to mechanisms in multicellular organisms by which signals transduced by distinct MAPK pathways may be subject to physiological integration at the level of regulation of MAPK activity by MAPKKs and MKPs.
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the caenorhabditis elegans MAPK Phosphatase vhp 1 mediates a novel jnk like signaling pathway in stress response
The EMBO Journal, 2004Co-Authors: Tomoaki Mizuno, Naoki Hisamoto, Takashi Terada, Tae Kondo, Makoto Adachi, Eisuke Nishida, Frederick M Ausubel, Kunihiro MatsumotoAbstract:Mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli and to a wide variety of environmental stresses. MAPK cascades can be inactivated at the MAPK activation step by members of the MAPK Phosphatase (MKP) family. However, the components that act in MKP-regulated pathways have not been well characterized in the context of whole organisms. Here we characterize the Caenorhabditis elegans vhp-1 gene, encoding an MKP that acts preferentially on the c-Jun N-terminal kinase (JNK) and p38 MAPKs. We found that animals defective in vhp-1 are arrested during larval development. This vhp-1 defect is suppressed by loss-of-function mutations in the kgb-1, mek-1, and mlk-1 genes encoding a JNK-like MAPK, an MKK7-type MAPKK, and an MLK-type MAPKKK, respectively. The genetic and biochemical data presented here demonstrate a critical role for VHP-1 in the KGB-1 pathway. Loss-of-function mutations in each component in the KGB-1 pathway result in hypersensitivity to heavy metals. These results suggest that VHP-1 plays a pivotal role in the integration and fine-tuning of the stress response regulated by the KGB-1 MAPK pathway.
Isaac P Witz - One of the best experts on this subject based on the ideXlab platform.
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cDNA microarray analysis reveals an overexpression of the dual-specificity MAPK Phosphatase PYST2 in acute leukemia.
Methods in Enzymology, 2004Co-Authors: Orlev Levy-nissenbaum, Pia Raanani, Abraham Avigdor, Orit Sagi-assif, Isaac Ben-bassat, Isaac P WitzAbstract:Publisher Summary This chapter gives an overview on cDNA microarray analysis. The identification of novel biological targets for cancer diagnosis or therapy is a major goal in cancer research. However, only relatively few molecules were hitherto identified as biological target candidates in acute myelogenous leukemia (AML). The chapter discusses the identification of potential biologic targets in AML. To identify the potential biologic targets in AML, the chapter presents the employment of the cDNA expression array technology and focuses on genes whose expression differs in leukemic and corresponding non-leukemic leukocytes derived from the same AML patients. Bone marrow (BM) or peripheral blood mononuclear cells (PBMC) from AML patients, before and after remission induction chemotherapy, are analyzed. Leukemic-phase leukocytes are cells derived from AML patients prior to treatment whereas remission-phase leukocytes are cells derived from the same patients following chemotherapy mediated induction of remission. Several genes were differentially expressed in leukemic and in remission-phase leukocytes derived from three different patients. The chapter discusses those genes that are more highly expressed by leukemic-phase leukocytes than by remissionphase leukocytes in all three patients. One of these genes was PYST2, a newly discovered dual-specificity (Thr/Tyr) MAPK Phosphatase.
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overexpression of the dual specificity MAPK Phosphatase pyst2 in acute leukaemia
Cancer Letters, 2003Co-Authors: Orlev Levynissenbaum, Orit Sagiassif, Pia Raanani, Abraham Avigdor, Isaac Benbassat, Isaac P WitzAbstract:In a previous study we used gene expression arrays to identify genes that are more highly expressed by leukemic than by non-leukemic leukocytes from acute myelogenous leukemia patients. One of such genes was Phosphorylates tyrosine serine threonine 2 (PYST2), a dual-specificity Mitogen-activated protein (MAP) kinase (MAPK) Phosphatase. In the present study, high levels of PYST2 mRNA were detected by RT-PCR and by Northern blotting in bone marrow (BM) leukocytes and in peripheral blood mononuclear cells from additional eight AML patients. No PYST2 mRNA was detected in nine out of twelve samples of Peripheral blood mononuclear cells (PBMC) from healthy blood bank donors and very low levels were detected by the same techniques in the other three PBMC samples from the healthy donors. Relatively high levels of PYST2 were detected in a variety of myeloid leukemia and other cancer cell lines. In view of the potential role played by PYST2 in MAPK signaling cascades we propose that an over expression of PYST2 in malignant cells may reflect a disrupted or an altered MAPK signaling pathway in malignancy processes.