Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-8 is a C-X-C chemokine that plays an important role in acute inflammation through its G protein-coupled receptors CXCR1 and CXCR2. In this study, we investigated the role of IL-8 as an autocrine regulator of IL-8 production and the signaling mechanisms involved in human peripheral blood mononuclear cells (MNCs). Sepharose-immobilized IL-8 stimulated a sevenfold increase in IL-8 production within 2 h. IL-8 induced the expression of its own message, and IL-8 biosynthesis was inhibited by cycloheximide and actinomycin D, indicating de novo RNA and protein synthesis. In contrast to MNCs, polymorphonuclear neutrophils did not respond to the immobilized IL-8 with IL-8 production despite cell surface expression of CXCR1 and CXCR2. Melanoma growth-stimulatory activity/growth-related protein-alpha (MGSA/GROalpha), which binds CXCR2 but not CXCR1, was unable to either stimulate IL-8 secretion in MNCs or desensitize these cells to respond to immobilized IL-8. The involvement of mitogen-activated protein kinase (MAPK) in IL-8-induced IL-8 biosynthesis was suggested by the ability of PD-98059, an inhibitor of MAPK kinase, to block this function. Furthermore, IL-8 induced a significant increase in extracellular signal-regulated kinase 2 phosphorylation, whereas MGSA/GROalpha was much less effective. These findings support the role of IL-8 as an autocrine regulator of IL-8 production and suggest that this function is mediated by CXCR1 through activation of MAPK.
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PMID:Autocrine regulation of interleukin-8 production in human monocytes. 1107 3

Constitutive activation of NF-kappa B is an emerging hallmark of various types of tumors including breast, colon, pancreatic, ovarian, and melanoma. In melanoma cells, the basal expression of the CXC chemokine, CXCL1, is constitutively up-regulated. This up-regulation can be attributed in part to constitutive activation of NF-kappa B. Previous studies have shown an elevated basal I kappa B kinase (IKK) activity in Hs294T melanoma cells, which leads to an increased rate of I kappa B phosphorylation and degradation. This increase in I kappa B-alpha phosphorylation and degradation leads to an approximately 19-fold higher nuclear localization of NF-kappa B. However, the upstream IKK kinase activity is up-regulated by only about 2-fold and cannot account for the observed increase in NF-kappa B activity. We now demonstrate that NF-kappa B-inducing kinase (NIK) is highly expressed in melanoma cells, and IKK-associated NIK activity is enhanced in these cells compared with the normal cells. Kinase-dead NIK blocked constitutive NF-kappa B or CXCL1 promoter activity in Hs294T melanoma cells, but not in control normal human epidermal melanocytes. Transient overexpression of wild type NIK results in increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which is inhibited in a concentration-dependent manner by PD98059, an inhibitor of p42/44 MAPK. Moreover, the NF-kappa B promoter activity decreased with overexpression of dominant negative ERK expression constructs, and EMSA analyses further support the hypothesis that ERK acts upstream of NF-kappa B and regulates the NF-kappa B DNA binding activity. Taken together, our data implicate involvement of I kappa B kinase and MAPK signaling cascades in NIK-induced constitutive activation of NF-kappa B.
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PMID:A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. 1177 61

The G protein-coupled receptor encoded by Kaposi's sarcoma-associated herpesvirus, also referred to as ORF74, has been shown to stimulate oncogenic and angiogenic signaling pathways in a constitutively active manner. The biochemical routes linking ORF74 to these signaling pathways are poorly defined. In this study, we show that ORF74 constitutively activates p44/p42 mitogen-activated protein kinase (MAPK) and Akt via G(i)- and phospholipase C (PLC)-mediated signaling pathways. Activation of Akt by ORF74 appears to be phosphatidylinositol 3-kinase (PI3-K) dependent but, interestingly, is also mediated by activation of protein kinase C (PKC) and p44/p42 MAPK. ORF74 may signal to Akt via p44/p42 MAPK, which can be activated by G(i), through activation of PI3-K or through PKC via the PLC pathway. Signaling of ORF74 to these proliferative and antiapoptotic signaling pathways can be further modulated positively by growth-related oncogene (GROalpha/CXCL1) and negatively by human gamma interferon-inducible protein 10 (IP-10/CXCL10), thus acting as an agonist and an inverse agonist, respectively. Despite the ability of the cytomegalovirus-encoded chemokine receptor US28 to constitutively activate PLC, this receptor does not increase phosphorylation of p44/p42 MAPK or Akt in COS-7 cells. Hence, ORF74 appears to signal through a larger diversity of G proteins than US28, allowing it to couple to proliferative and antiapoptotic signaling pathways. ORF74 can therefore be envisioned as an attractive target for novel treatment of Kaposi's sarcoma.
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PMID:Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via G(i) and phospholipase C-dependent signaling pathways. 1179 69

The CXC subfamily of chemokines plays an important role in diverse processes, including inflammation, wound healing, growth regulation, angiogenesis, and tumorigenesis. The CXC chemokine CXCL1, or MGSA/GROalpha, is traditionally considered to be responsible for attracting leukocytes into sites of inflammation. To better understand the molecular mechanisms by which CXCL1 induces CXCR2-mediated chemotaxis, the signal transduction components involved in CXCL1-induced chemotaxis were examined. It is shown here that CXCL1 induces cdc42 and PAK1 activation in CXCR2-expressing HEK293 cells. Activation of the cdc42-PAK1 cascade is required for CXCL1-induced chemotaxis but not for CXCL1-induced intracellular Ca2+ mobilization. Moreover, CXCL1 activation of PAK1 is independent of ERK1/2 activation, a conclusion based on the observations that the inhibition of MEK-ERK activation by expression of dominant negative ERK or by the MEK inhibitor, PD98059, has no effect on CXCL1-induced PAK1 activation or CXCL1-induced chemotaxis.
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PMID:PAK1 kinase is required for CXCL1-induced chemotaxis. 1203 44

A combination of paclitaxel (Taxol) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK/Erk) inhibitor represents a rational new approach to chemotherapy. We performed Affymetrix microarray analysis to understand the global effects of this combination in lung carcinoma. Genes involved in cell cycle control, apoptosis, adhesion, proliferation, invasion, and metastasis were modulated. We observed similar patterns of gene modulation in ovarian and melanoma cell lines, indicating the general applicability of these findings. Functional genomic analysis identified two genes as new targets of drug-induced tumor apoptosis. The MGSA/Gro1 gene, important in melanoma growth, was induced by paclitaxel and reduced by MEK inhibition. Blockage of paclitaxel-induced melanoma growth stimulatory activity significantly reduced melanoma growth. Additionally, the expression of topoisomerase III beta, which exhibited a clear pattern of gene reduction by a combination of the two drugs, was significantly increased (5.7-fold) in primary lung cancers but not adjacent tissues. These findings provide potential new biomarkers and gene targets for the development of improved cancer treatment.
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PMID:Transcriptional profiling of targets for combination therapy of lung carcinoma with paclitaxel and mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. 1294 40

Infection of mice with murine gammaherpesvirus 68 (MHV-68) is a well-characterized small animal model for the study of gammaherpesvirus infection. MHV-68 belongs to the same herpesvirus family as herpesvirus saimiri (HVS) of New World squirrel monkeys and human herpesvirus 8 (HHV-8) (also referred to as Kaposi's sarcoma-associated herpesvirus [KSHV]). The open reading frame ORF74 of HVS, KSHV, and MHV-68 encodes a protein with homology to G protein-coupled receptors and chemokine receptors in particular. ORF74 of KSHV (human ORF74 [hORF74]) is highly constitutively active and has been implicated in the pathogenesis of Kaposi's sarcoma. MHV-68-encoded ORF74 (mORF74) is oncogenic and has been implicated in viral replication and reactivation from latency. Here, we show that mORF74 is a functional chemokine receptor. Chemokines with an N-terminal glutamic acid-leucine-arginine (ELR) motif (e.g., KC and macrophage inflammatory protein 2) act as agonists on mORF74, activating phospholipase C, NF-kappaB, p44/p42 mitogen-activated protein kinase, and Akt signaling pathways and inhibiting formation of cyclic AMP. Using (125)I-labeled CXCL1/growth-related oncogene alpha as a tracer, we show that murine CXCL10/gamma interferon-inducible protein 10 binds mORF74, and functional assays show that it behaves as an antagonist for this virally encoded G protein-coupled receptor. Profound differences in the upstream activation of signal transduction pathways between mORF74 and hORF74 were found. Moreover, in contrast to hORF74, no constitutive activity of mORF74 could be detected.
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PMID:Differential activation of murine herpesvirus 68- and Kaposi's sarcoma-associated herpesvirus-encoded ORF74 G protein-coupled receptors by human and murine chemokines. 1501 56

Patients with myelodysplasia suffer from recurrent bacterial infections as a result of differentiation defects of the myeloid lineage and a disturbed functioning of neutrophilic granulocytes. Important physiological activators of neutrophils are the cytokines interleukin-8/CXC chemokine ligand 8 (IL-8/CXCL8), which activates CXC chemokine receptor 1 and 2 (CXCR1 and CXCR2), and growth-related oncogene (GROalpha)/CXCL1, which stimulates only CXCR2. In this study, we show that migration toward IL-8/GROalpha gradients is decreased in myelodysplastic syndrome (MDS) neutrophils compared with healthy donors. We investigated the signal transduction pathways involved in IL-8/GROalpha-induced migration and showed that specific inhibitors for extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol-3 kinase (PI-3K) abrogated neutrophil migration toward IL-8/GROalpha. In accordance with these results, we subsequently showed that IL-8/GROalpha-stimulated activation of ERK1/2 was substantially diminished in MDS neutrophils. Activation of the PI-3K downstream target protein kinase B/Akt was disturbed in MDS neutrophils when cells were activated with IL-8 but normal upon GROalpha stimulation. IL-8 stimulation resulted in higher migratory behavior and ERK1/2 activation than GROalpha stimulation, suggesting a greater importance of CXCR1. We then investigated IL-8-induced activation of the small GTPase Rac implicated in ERK1/2-dependent migration and found that it was less efficient in neutrophils from MDS patients compared with healthy donors. In contrast, IL-8 triggered a normal activation of the GTPases Ras and Ral, indicating that the observed defects were not a result of a general disturbance in CXCR1/2 signaling. In conclusion, our results demonstrate a disturbed CXCR1- and CXCR2-induced neutrophil chemotaxis in MDS patients, which might be the consequence of decreased Rac-ERK1/2 and PI-3K activation within these cells.
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PMID:Impaired interleukin-8- and GROalpha-induced phosphorylation of extracellular signal-regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia. 1556 56

beta-Amyloid peptide accumulation in senile plaques in the brains of patients with Alzheimer's disease has been considered as a major cause of neuronal death. The present study demonstrated that the CXCR2 ligands macrophage inflammatory protein 2 (MIP-2), CXCL1, and CXCL8, protected hippocampal neurons against beta-amyloid (1-42) induced death. MIP-2-activated extracellular signal-regulated kinase (ERK)1/2 and Akt and both the mitogen-activated protein kinase kinase 1 (MEK1) and phosphatidylinositol 3-kinase (PI3K) inhibitors 2'-amino-3'-methoxyflavone (PD98059) and wortmannin reduced the neuroprotective effect of MIP-2. MIP-2 induced weak phosphorylation of ribosomal S6 kinase (RSK) 1 but remarkable phosphorylation and nuclear translocation of RSK2. MIP-2-induced phosphorylation of RSK2 was inhibited by PD98059 but not by wortmannin. MIP-2 treatment of the neuronal cells resulted in phosphorylation of Bad at both the Ser-112 and Ser-136. The phosphorylation at Ser-112 was blocked by PD98059, whereas the phosphorylation at Ser-136 was blocked by wortmannin. The transcription factor cyclic AMP response element binding protein (CREB) was phosphorylated by MIP-2 stimulation of the neuronal cells. MIP-2-induced CREB phosphorylation was reduced by both PD98059 and wortmannin. These data demonstrate that both MEK1-ERK1/2 and PI3K-Akt signaling pathways are involved in CXCR2-mediated neuroprotection and that multiple downstream signaling events, including RSKs, Bad, and CREB, are activated in this process.
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PMID:Macrophage inflammatory protein 2 inhibits beta-amyloid peptide (1-42)-mediated hippocampal neuronal apoptosis through activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. 1560 43

Chemokines participate in various processes of monocyte recruitment including monocyte arrest and migration. Our group and others have demonstrated that growth-related oncogene (GRO)-alpha (CXCL1) can support monocyte arrest in models of inflammation. Here we employed a parallel plate-flow chamber and Transwell reconstitution assay to test whether GRO family chemokines were sufficient for Mono Mac 6 (a human monocytic cell line) and isolated human monocyte recruitment. Our study shows that 1) GRO-alpha, -beta (CXCL2), and -gamma (CXCL3) all act as arrest chemokines for monocyte adhesion on vascular cell adhesion molecule (VCAM)-1 under flow in the presence of P-selectin; 2) CXCR2 is the functional receptor for GRO-family chemokines in monocyte arrest; however, CXCR2 is not an arrest chemokine receptor in general, since epithelial neutrophil-activating peptide ENA-78 failed to arrest monocytes; 3) GRO-alpha, -beta, and -gamma all fail to increase intracellular free Ca2+ or mediate monocyte chemotaxis; and 4) signaling through G alpha(i) protein, phosphoinositide 3-kinase, and actin polymerization but not Ca2+ mobilization or the mitogen-activated kinases p38 and MAPK/extracellular signal-related kinase are necessary for GRO-alpha-mediated Mono Mac 6 cell arrest under flow. We conclude that the GRO-family chemokines are specialized monocyte-arrest chemokines. Their role in monocyte recruitment in inflammation can be inhibited by blocking CXCR2 function or downstream signaling events.
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PMID:GRO family chemokines are specialized for monocyte arrest from flow. 1593 99

Ischemia-reperfusion injury in the heart is characterized by marked infiltration of neutrophils in the myocardial interstitial space. Studies in human, canine, and murine models have revealed oncostatin M (OSM) expression in infiltrating leukocytes. In an effort to assess possible roles of OSM in the myocardium, we used cardiac fibroblasts (mCFs) isolated from adult mouse heart to determine whether recombinant murine OSM regulates the synthesis and release of MIP2/CXCL2, KC/CXCL1, and LIX/CXCL5, which are three potent neutrophil chemoattractants in the mouse. Our results demonstrate that mCFs express OSM receptors and that, within the IL-6 cytokine family, OSM uniquely induces significant release of KC and LIX in mCFs. In addition, although OSM activates the JAK-signal transducers and activators of transcription and MAPK pathways, we demonstrate that the OSM-mediated CXC chemokine release in mCFs is also dependent on the activation of the phosphatidylinositol 3-kinase pathway.
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PMID:Oncostatin M differentially regulates CXC chemokines in mouse cardiac fibroblasts. 1645 59


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