Constitutive activation of the MAPK pathway mediates v-fes–induced mitogenesis in murine macrophages

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3959-3963 ◽  
Author(s):  
Elisabetta Rovida ◽  
Fabio Marra ◽  
Manuela Baccarini ◽  
Persio Dello Sbarba
Keyword(s):  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Nonreceptor Tyrosine Kinase ◽  
Murine Macrophages ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Infected Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Abstract Fes is a nonreceptor tyrosine kinase expressed at the highest level in macrophages. We previously showed that the overexpression of c-fes in murine macrophages of the BAC-1.2F5 cell line renders these cells independent of macrophage colony-stimulating factor (MCSF) for survival and proliferation, although no direct relationship could be established between tyrosine-phosphorylated substrates of Fes- and MCSF receptor–dependent signaling and mitogenesis. In this study, we investigated whether the mitogen-activated protein kinase (MAPK) pathway is involved in the growth factor–independent growth of v-fes–overexpressing macrophages. We found a constitutively increased phosphorylation of extracellularly regulated kinase (ERK) in v-fes–overexpressing macrophages as compared with mock-infected cells. This finding was associated with activation of mitogen/extracellular signal–regulated kinase (MEK) and with constitutive localization of ERK in the nucleus. Treatment of v-fes–overexpressing cells with the MEK-specific inhibitor PD98059 markedly reduced cell growth, hyperphosphorylation, and nuclear localization of ERK, indicating that the MAPK pathway mediates the mitogenic effect of v-fes.

Constitutive activation of the MAPK pathway mediates v-fes–induced mitogenesis in murine macrophages

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3959-3963 ◽  
Author(s):  
Elisabetta Rovida ◽  
Fabio Marra ◽  
Manuela Baccarini ◽  
Persio Dello Sbarba
Keyword(s):  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Nonreceptor Tyrosine Kinase ◽  
Murine Macrophages ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Infected Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Fes is a nonreceptor tyrosine kinase expressed at the highest level in macrophages. We previously showed that the overexpression of c-fes in murine macrophages of the BAC-1.2F5 cell line renders these cells independent of macrophage colony-stimulating factor (MCSF) for survival and proliferation, although no direct relationship could be established between tyrosine-phosphorylated substrates of Fes- and MCSF receptor–dependent signaling and mitogenesis. In this study, we investigated whether the mitogen-activated protein kinase (MAPK) pathway is involved in the growth factor–independent growth of v-fes–overexpressing macrophages. We found a constitutively increased phosphorylation of extracellularly regulated kinase (ERK) in v-fes–overexpressing macrophages as compared with mock-infected cells. This finding was associated with activation of mitogen/extracellular signal–regulated kinase (MEK) and with constitutive localization of ERK in the nucleus. Treatment of v-fes–overexpressing cells with the MEK-specific inhibitor PD98059 markedly reduced cell growth, hyperphosphorylation, and nuclear localization of ERK, indicating that the MAPK pathway mediates the mitogenic effect of v-fes.

scholarly journals Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 2033-2043 ◽  
Author(s):  
Stephen R. Clark ◽  
Christopher J. Guy ◽  
Martin J. Scurr ◽  
Philip R Taylor ◽  
Ann P. Kift-Morgan ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Extracellular Signal Regulated Kinase ◽  
Bacterial Peritonitis ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract5-Lipoxygenase (5-LOX) plays key roles in infection and allergic responses. Herein, four 5-LOX–derived lipids comprising 5-hydroxyeicosatetraenoic acid (HETE) attached to phospholipids (PLs), either phosphatidylethanolamine (PE) or phosphatidylcholine (18:0p/5-HETE-PE, 18:1p/5-HETE-PE, 16:0p/5-HETE-PE, and 16:0a/5-HETE-PC), were identified in primary human neutrophils. They formed within 2 minutes in response to serum-opsonized Staphylococcus epidermidis or f-methionine-leucine-phenylalanine, with priming by lipopolysaccharide, granulocyte macrophage colony-stimulating factor, or cytochalasin D. Levels generated were similar to free 5-HETE (0.37 ± 0.14 ng vs 0.55 ± 0.18 ng/106 cells, esterified vs free 5-HETE, respectively). They remained cell associated, localizing to nuclear and extranuclear membrane, and were formed by fast esterification of newly synthesized free 5-HETE. Generation also required Ca2+, phospholipase C, cytosolic and secretory phospholipase A2, 5-LOX activating protein, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. 5-HETE-PLs were detected in murine S epidermidis peritonitis, paralleling neutrophil influx, and in effluent from Gram-positive human bacterial peritonitis. Formation of neutrophil extracellular traps was significantly enhanced by 5-LOX inhibition but attenuated by HETE-PE, whereas 5-HETE-PE enhanced superoxide and interleukin-8 generation. Thus, new molecular species of oxidized PL formed by human neutrophils during bacterial infection are identified and characterized.

scholarly journals Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

2004 ◽  
Vol 24 (3) ◽  
pp. 1081-1095 ◽  
Author(s):  
Nicole H. Purcell ◽  
Dina Darwis ◽  
Orlando F. Bueno ◽  
Judith M. Müller ◽  
Roland Schüle ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Interacting Protein ◽  
Hypertrophic Response ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

scholarly journals Anthrax Lethal Toxin Impairs CD1d-Mediated Antigen Presentation by Targeting the Extracellular Signal-Related Kinase 1/2 Mitogen-Activated Protein Kinase Pathway

2010 ◽  
Vol 78 (5) ◽  
pp. 1859-1863 ◽  
Author(s):  
Masood A. Khan ◽  
Richard M. Gallo ◽  
Randy R. Brutkiewicz
Keyword(s):  
Immune System ◽  
Protein Kinase ◽  
Bacillus Anthracis ◽  
Antigen Presentation ◽  
Specific Inhibitor ◽  
Lethal Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Lethal toxin (LT) is a critical virulence factor of Bacillus anthracis and an important means by which this bacterium evades the host's immune system. In this study, we demonstrate that CD1d-expressing cells treated with LT have reduced CD1d-mediated antigen presentation. We earlier showed an important role for the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2) in the regulation of CD1d-mediated antigen presentation, and we report here that LT impairs antigen presentation by CD1d in an ERK1/2-dependent manner. Similarly, LT and the ERK1/2 pathway-specific inhibitor U0126 caused a decrease in major histocompatibility complex (MHC) class II-mediated antigen presentation. Confocal microscopy analyses revealed altered intracellular distribution of CD1d and LAMP-1 in LT-treated cells, similar to the case for ERK1/2-inhibited cells. These results suggest that Bacillus anthracis has the ability to evade the host's innate immune system by reducing CD1d-mediated antigen presentation through targeting the ERK1/2 pathway.

scholarly journals Rotavirus Infects Human Biliary Epithelial Cells and Stimulates Secretion of Cytokines IL-6 and IL-8 via MAPK Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Maria Grazia Clemente ◽  
John T. Patton ◽  
Robert A. Anders ◽  
Robert H. Yolken ◽  
Kathleen B. Schwarz
Keyword(s):  
Animal Models ◽  
Mapk Pathway ◽  
Epidemiologic Studies ◽  
Model System ◽  
Time Dependent ◽  
Mitogen Activated Protein Kinase ◽  
Unknown Etiology ◽  
Mitogen Activated Protein ◽  
Infected Cells ◽  
Viral Hypothesis

Biliary atresia (BA) is an infantile inflammatory cholangiopathy of unknown etiology although epidemiologic studies and animal models utilizing rotavirus (RV) have suggested a role for viral infection. Proinflammatory and profibrotic cytokines have been detected in infants with BA. The purpose of our study was to investigate the susceptibility of human cholangiocytes (H69 cells) to infection with RRV and to determine if this infection resulted in cytokine secretion. Infection of H69 cells by RRV was noncytolytic and resulted in a time-dependent increase in the release of both infectious virions and cytokines IL-6 and IL-8 into the supernate. The greatest difference in cytokine supernatant levels between infected and mock-infected cells was noted at 24 hours postinfection (h p.i.) for IL-8, 556 ± 111 versus 77 ± 68 pg/mL (p<0.0001), and at 48 h p.i. for IL-6, 459 ± 64 versus 67 ± 2 pg/mL (p<0.0001). Production of both cytokines following RRV infection was significantly reduced by pretreating the H69 cells with inhibitors of mitogen-activated protein kinase (MAPK).Conclusion. RRV can infect human cholangiocytes resulting in the production of proinflammatory and profibrotic cytokines via the MAPK pathway. RRV-infected H69 cells could be a useful model system for investigating the viral hypothesis of BA.

scholarly journals MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

2008 ◽  
Vol 115 (7) ◽  
pp. 203-218 ◽  
Author(s):  
Anthony J. Muslin
Keyword(s):  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Mapk Pathway ◽  
Science Research ◽  
Pharmacological Therapy ◽  
Model Systems ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

scholarly journals Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function

1998 ◽  
Vol 329 (1) ◽  
pp. 121-130 ◽  
Author(s):  
J. Paul COFFER ◽  
Niels GEIJSEN ◽  
Laura M'RABET ◽  
C. Rene SCHWEIZER ◽  
Tjander MAIKOE ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Neutrophil Migration ◽  
Platelet Activating Factor ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Cytosolic Phospholipase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Macrophage Colony ◽  
Phosphatidylinositol 3

Although it is known that many stimuli can activate mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinases (PI3K) in human neutrophils, little is known concerning either the mechanisms or function of this activation. We have utilized a selective inhibitor of MAPK kinase (MEK), PD098059, and two inhibitors of PI3K, wortmannin and LY294002, to investigate the roles of these kinases in the regulation of neutrophil effector functions. Granulocyte/macrophage colony-stimulating factor, platelet-activating factor (PAF) and N-formylmethionyl-leucyl-phenylalanine are capable of activating both p44ERK1 and p42ERK2 MAPKs and phosphotyrosine-associated PI3K in human neutrophils. The activation of extracellular signal-related protein kinases (ERKs) is correlated with the activation of p21ras by both tyrosine kinase and G-protein-coupled receptors as measured by a novel assay for GTP loading. Wortmannin and LY294002 inhibit, to various degrees, superoxide generation, neutrophil migration and PAF release. Incubation with PD098059, however, inhibits only the PAF release stimulated by serum-treated zymosan. This demonstrates that, while neither MEK nor ERK kinases are involved in the activation of respiratory burst or neutrophil migration, inhibition of PAF release suggests a potential role in the activation of cytosolic phospholipase A2. PI3K isoforms, however, seem to have a much wider role in regulating neutrophil functioning.

scholarly journals Posttranslational Regulation of Tristetraprolin Subcellular Localization and Protein Stability by p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Pathways

2006 ◽  
Vol 26 (6) ◽  
pp. 2408-2418 ◽  
Author(s):  
Matthew Brook ◽  
Carmen R. Tchen ◽  
Tomas Santalucia ◽  
Joanne McIlrath ◽  
J. Simon C. Arthur ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Subcellular Localization ◽  
Protein Stability ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
P38 Mapk Pathway ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The p38 mitogen-activated protein kinase (MAPK) signaling pathway, acting through the downstream kinase MK2, regulates the stability of many proinflammatory mRNAs that contain adenosine/uridine-rich elements (AREs). It is thought to do this by modulating the expression or activity of ARE-binding proteins that regulate mRNA turnover. MK2 phosphorylates the ARE-binding and mRNA-destabilizing protein tristetraprolin (TTP) at serines 52 and 178. Here we show that the p38 MAPK pathway regulates the subcellular localization and stability of TTP protein. A p38 MAPK inhibitor causes rapid dephosphorylation of TTP, relocalization from the cytoplasm to the nucleus, and degradation by the 20S/26S proteasome. Hence, continuous activity of the p38 MAPK pathway is required to maintain the phosphorylation status, cytoplasmic localization, and stability of TTP protein. The regulation of both subcellular localization and protein stability is dependent on MK2 and on the integrity of serines 52 and 178. Furthermore, the extracellular signal-regulated kinase (ERK) pathway synergizes with the p38 MAPK pathway to regulate both stability and localization of TTP. This effect is independent of kinases that are known to be synergistically activated by ERK and p38 MAPK. We present a model for the actions of TTP and the p38 MAPK pathway during distinct phases of the inflammatory response.

Delivery of Sorafenib and Metformin Against Hepatocellular Carcinoma with Amphiphilic Polypeptide-based Micelles

2021 ◽  
Author(s):  
Lanqing Cao ◽  
Guangmeng Xu ◽  
Hongyu He ◽  
Jiannan Li
Keyword(s):  
Mapk Pathway ◽  
Synergistic Effects ◽  
Mitogen Activated Protein Kinase ◽  
High Recurrence Rate ◽  
Extracellular Signal Regulated Kinase ◽  
Cycle Arrest ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Poly Ethylene

Abstract Hepatoma is a common clinical disease with poor prognosis and a high recurrence rate. Chemotherapy is important for hepatoma treatment because only a small amount of hepatoma patients are suitable for local resection, and the effects of transarterial chemoembolization (TACE) are unsatisfactory. But many limitations restrict further application of chemotherapy. In this study, sorafenib (Sor) and metformin (Met) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)) micelles were developed. Sor is a common molecular target agent which can inhibit the mitogen-activated protein kinase (MAPK) pathway to treat hepatoma clinically. Met can also regulate the MAPK pathway and inhibit the expression of the phosphorylated extracellular signal-regulated kinase (p-ERK). Moreover, both Sor and Met play important roles in cell cycle arrest. The integration of these two drugs aims to achieve synergistic effects against hepatoma. The micelles can be targeted to cancer cells and possess longer blood circulation time. The two agents can be released rapidly in the tumor sites. Both orthotopic and patient-derived xenograft (PDX) hepatoma models were developed to analyze the treatment efficacy of the Sor and Met loaded micelles. The in vivo study showed that the micelles can prevent hepatoma progression by inhibiting the expressions of p-ERK and cyclin D1. This study indicated that the Sor/Met-loaded micelles are suitable for hepatoma treatment.

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