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)

In this study, we investigated the effects of proteasome inhibibors (MG132 and lactacystin) on interleukin (IL)-8 induction. In human epithelial A549 cells, MG132 and lactacystin induced IL-8 release within the range of 0.1-30 microM. The effect of MG132 resulted from IL-8 gene transcription and was blocked by PD 98059, but was unaffected by GF109203X, Ro 31-8220, or SB 203580. Mutational analysis of the 5' flanking region of the IL-8 gene revealed that activator protein (AP)-1-binding element, but not that element responsive to nuclear factor (NF)-IL-6 or NF-kappaB, was necessary for MG132 stimulation. Consistent with this, MG132 and lactacystin increased the DNA-binding and reporter activities of AP-1, but reduced cytokine-elicited kappaB activation. Moreover, AP-1 stimulation was associated with increased extracellular signal-related kinase (ERK), mitogen-activated protein/ERK kinase (MEK), and c-Jun N-terminal kinase (JNK) phosphorylation, whereas IL-8 activity was sensitive to the dominant-negative mutants of JNK1, JNK2, SEK, ASK, ERK2, and Ras, but not those of MEKK1, TAK, and p38 mitogen-activated protein kinase. In addition, activations of the IL-8 gene and AP-1 by MG132 and lactacystin were inhibited by GSH and NAC. Herein we present a novel action of proteasome inhibitors, possibly through ROS production, of targeting the upstream signaling molecules, ERK and JNK, which leads to AP-1 activation and IL-8 gene expression.
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PMID:Proteasome inhibitors stimulate interleukin-8 expression via Ras and apoptosis signal-regulating kinase-dependent extracellular signal-related kinase and c-Jun N-terminal kinase activation. 1215 16

Cell signaling pathways may be initiated by environmental particulates by indirect mechanisms such as elaboration of reactive oxygen or nitrogen species (ROS/RNS) or directly upon contact of particulates with the plasma membrane and uptake by epithelial or mesothelial cells. Research in the last few years has mainly addressed cell signaling cascades leading to activation of the redox-sensitive transcription factors, nuclear factor kappa-B (NF-kappaB), and activator protein-1 (AP-1). The activation of these transcription factors may be linked to increases in gene expression controlling cell injury or apoptosis, proliferation and/or cell survival, and inflammatory cytokines. Here, we provide an overview of the MAPK signaling pathways and their activation by asbestos, specifically the role of ROS, receptor-dependent and independent activation via the epidermal growth factor receptor (EGFR), and strategies for proving causal relationships between these pathways and changes in epithelial cell phenotype linked to disease causation.
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PMID:Role of mitogen-activated protein kinases (MAPK) in cell injury and proliferation by environmental particulates. 1216 23

Activation of non-cultivar-specific plant defense against attempted microbial infection is mediated through the recognition of pathogen-derived elicitors. Previously, we have identified a peptide fragment (Pep-13) within a 42-kDa cell wall transglutaminase from various Phytophthora species that triggers a multifacetted defense response in parsley cells. Many of these oomycete species have now been shown to possess another cell wall protein (24 kDa), that evoked the same pattern of responses in parsley as Pep-13. Unlike Pep-13, necrosis-inducing Phytophthora protein 1 (NPP1) purified from P. parasitica also induced hypersensitive cell death-like lesions in parsley. NPP1 structural homologs were found in oomycetes, fungi, and bacteria, but not in plants. Structure-activity relationship studies revealed the intact protein as well as two cysteine residues to be essential for elicitor activity. NPP1-mediated activation of pathogen defense in parsley does not employ the Pep-13 receptor. However, early induced cellular responses implicated in elicitor signal transmission (increased levels of cytoplasmic calcium, production of reactive oxygen species, MAP kinase activation) were stimulated by either elicitor, suggesting the existence of converging signaling pathways in parsley. Infiltration of NPP1 into leaves of Arabidopsis thaliana Col-0 plants resulted in transcript accumulation of pathogenesis-related (PR) genes, production of ROS and ethylene, callose apposition, and HR-like cell death. NPP1-mediated induction of the PR1 gene is salicylic acid-dependent, and, unlike the P. syringae pv. tomato DC3000(avrRpm1)-induced PR1 gene expression, requires both functional NDR1 and PAD4. In summary, Arabidopsis plants infiltrated with NPP1 constitute an experimental system that is amenable to forward genetic approaches aiming at the dissection of signaling pathways implicated in the activation of non-cultivar-specific plant defense.
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PMID:NPP1, a Phytophthora-associated trigger of plant defense in parsley and Arabidopsis. 1241 Aug 15

Extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK) were all rapidly activated in a ROS-dependent manner during 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ)-mediated oxidative stress and oncotic cell death in renal proximal tubule epithelial cells (LLC-PK1). TGHQ-induced phosphorylation of ERK1/2 and JNK MAPKs required epidermal growth factor receptor (EGFR) activation, whereas p38 MAPK activation was EGFR independent. In contrast to their established roles in cell survival, TGHQ-activated ERK1/2 and p38 MAPK (but not JNK) appear to contribute to cell death, since inhibition of ERK1/2 or p38 MAPKs with PD098059 or SB202190 respectively, attenuated TGHQ-mediated cell death. TGHQ increased AP-1 and NFkappaB DNA-binding activity, but whereas pharmacological inhibition of ERK1/2 or p38 MAPKs attenuated AP-1 DNA binding activity, it potentiated TGHQ-mediated NFkappaB activation. Consistent with a role for NFkappaB activation in the cytoprotective response to ROS in renal epithelial cells, an anti-NFkappaB peptide SN50 suppressed the protective effects of ERK inhibition (PD098059 treatment). The data provide evidence that the activation of MAPKs by ROS in renal epithelial cells plays an important role in oncotic cell death, and NF-kB is involved in the cytoprotective effects of PD098059.
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PMID:Mitogen-activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells. 1248 47

Mitochondrial dysfunction leads to oxygen free radical (ROS) generation with consequent oxidative stress and cellular damage. Recently, activation of the cellular antioxidant system and apoptosis were demonstrated in skeletal muscle fibres from patients with mitochondrial diseases, but the underlying mechanisms remain unknown. Hydrogen peroxide, a by-product of ROS generation, is a chemical inducer of gene expression able to activate apoptosis and to promote the antioxidant response through the activation of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) transcription factor. Using immunohistochemistry and confocal microscopy, we evaluated the expression of NF-kappaB and AP-1 in muscle biopsies from patients with mitochondrial disease. In addition, we examined the expression of factors involved in their activation, such as NF-kappaB inducing kinase (NIK) and phosphorylated Jun-N-terminal kinase (p-JNK). Most fibres with respiratory chain dysfunction displayed nuclear staining for activated c-Jun/AP-1, but not for NF-kappaB. The same fibres reacted for p-JNK. Only some ragged red fibres immunoreacted for NIK. These data suggest that AP-1 is involved in the oxidative stress response in muscle fibres from patients with mitochondrial disease.
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PMID:Transcription factors c-Jun/activator protein-1 and nuclear factor-kappa B in oxidative stress response in mitochondrial diseases. 1258 40

Nitric oxide (NO) plays a key role in attenuation of tumor growth by activated macrophages that generate large amount of cytotoxic/cytostatic free radicals. However, some tumor cells may survive from NO cytotoxicity and continue to proliferate to malignant tumors. Since a protooncogene product Ras was shown to be activated by NO, this study investigated the involvement of Ras in the cell survival in response to NO cytotoxicity in pheochromocytoma (PC12) cells. Treatment with Ras inhibitor or constitutive expression of dominant negative Ras markedly increased NO-induced cell death. NO-resistant PC12 cells (PC12-NO-R) exhibited higher steady state Ras activity than the parental PC12 cells. Inducible expression using tetracycline-on (Tet-on) system of Ras mutants (dominant negative Ras or dominant active Ras) demonstrated that blockade of Ras activity increased NO-induced cell death whereas enhancement of Ras activity attenuated NO-induced cell death. Furthermore, inducible expression of NO-insensitive mutant Ras selectively increased cellular vulnerability to NO but not to ROS. NO, Ras inhibitor and extracellular signal-regulated kinase (Erk) blocker synergistically increased cell death. These observations suggest that Ras activity may be a critical factor for survival response of tumor cells to NO toxicity and pharmacological agents affecting Ras activity may enhance efficacy of NO-mediated tumor therapies.
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PMID:Involvement of Ras in survival responsiveness to nitric oxide toxicity in pheochromocytoma cells. 1263 56

Neutrophils are mobilized to the vascular wall during vessel inflammation. Published data are conflicting on phagocytic nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activation during the hypertensive state, and the capacity of angiotensin II (Ang II) to modulate the intracellular redox status has not been analyzed in neutrophils. We here describe that Ang II highly stimulates endogenous and extracellular O2- production in these cells, consistent with the translocation to the cell membrane of the cytosolic components of NADPH oxidase, p47phox, and p67phox. The Ang II-dependent O2- production was suppressed by specific inhibitors of AT1 receptors, of the p38MAPK and ERK1/2 pathways, and of flavin oxidases. Furthermore, Ang II induced a robust phosphorylation of p38MAPK, ERK1/2, and JNK1/2 (particularly JNK2), which was hindered by inhibitors of NADPH oxidase, tyrosine kinases, and ROS scavengers. Ang II increased cytosolic Ca2+ levels-released mainly from calcium stores-enhanced the synthesis de novo and activity of calcineurin, and stimulated the DNA-binding activity of the transcription factor NF-kappaB in cultured human neutrophils. Present data demonstrate for the first time a stimulatory role of Ang II in the activation of phagocytic cells, underscore the relevant role of ROS as mediators in this process, and uncover a variety of signaling pathways by which Ang II operates in human neutrophils.
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PMID:Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-kappaB. 1266 41

Signal transduction by reactive oxygen species (ROS; "redox signaling") has recently come into focus in cellular biology studies. The signaling properties of ROS are largely due to the reversible oxidation of redox-sensitive target proteins, and especially of protein tyrosine phosphatases, whose activity is dependent on the redox state of a low pKa active site cysteine. A variety of mitogenic signals, including those released by receptor tyrosine kinase (RTKs) ligands and oncogenic H-Ras, involve as a critical downstream event the intracellular generation of ROS. Signaling by integrins is also essential for the growth of most cell types and is constantly integrated with growth factor signaling. We provide here evidence that intracellular ROS are generated after integrin engagement and that these oxidant intermediates are necessary for integrin signaling during fibroblast adhesion and spreading. Moreover, we propose a synergistic action of integrins and RTKs for redox signaling. Integrin-induced ROS are required to oxidize/inhibit the low molecular weight phosphotyrosine phosphatase, thereby preventing the enzyme from dephosphorylating and inactivating FAK. Accordingly, FAK phosphorylation and other downstream events, including MAPK phosphorylation, Src phosphorylation, focal adhesion formation, and cell spreading, are all significantly attenuated by inhibition of redox signaling. Hence, we have outlined a redox circuitry whereby, upon cell adhesion, oxidative inhibition of a protein tyrosine phosphatase promotes the phosphorylation/activation and the downstream signaling of FAK and, as a final event, cell adhesion and spreading onto fibronectin.
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PMID:Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. 1279 79

Many research findings revealed that oxidative stress may induce apoptosis. At present, the explanations for this phenomenon are: 1) ROS activated nuclear factor-KB and induction of the expression of nuclear factor-KB; 2) mitochondria-mediated cell apoptosis; 3) ROS mediated DNA damage and P53 activation; 4) ROS activated SAPK pathway to apoptosis. In this paper, the progress on oxidative stress and apoptosis was reviewed.
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PMID:[Research progress on oxidative stress and apoptosis]. 1291 97

Trichothecene mycotoxins cause immunosuppression by inducing apoptosis in lymphoid tissue. Trichothecene-induced leukocyte apoptosis can be augmented by bacterial lipopolysaccharide (LPS) but the mechanisms involved in this potentiating effect are not completely understood. The objective of this study was to test the hypothesis that the trichothecene deoxynivalenol (DON, vomitoxin) can interact with LPS directly and other mediators or agonists associated with immune/inflammatory responses to induce apoptosis in primary murine leukocyte cultures. Primary leukocyte suspensions were prepared from murine thymus (TH), spleen (SP), bone marrow (BM) and Peyer's patches (PP) and then cultured with DON in the absence or presence of LPS, prostaglandin E2 (PGE2), anti-immunoglobulin (as antigen mimic), dexamethasone, Fas ligand, or TNF-alpha. Cytotoxicity and apoptosis were evaluated by MTT assay and morphologic assays, respectively. DON was found to inhibit LPS-induced proliferation and dexamethasone-induced apoptosis in SP cultures. In contrast, potentiation of DON-induced apoptosis and cytotoxicity was observed in BM cultures treated with anti-Fas and in TH cultures treated with TNF-alpha. When potentiation of DON-induced apoptosis by TNF-alpha was assessed using pharmacological inhibitors, generation of ROS, intracellular Ca2+, p38/SAPK, and caspase-3 activation were found to play roles. Taken together, these data demonstrate that LPS and its downstream mediators can interact with trichothecenes to modulate proliferative, cytotoxic and apoptotic outcomes in leukocytes in a tissue-specific manner.
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PMID:Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation. 1459 25


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