Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated and compared the mechanisms by which two dust mite proteolytic allergens, Der p 1 and Der p 3, and a peptide agonist of proteinase-activated receptor 2 (PAR(2)AP) trigger interleukin (IL)-8 release from human pulmonary epithelial cells (A549). Although all three stimuli tested induced the up-regulation of IL-8 (mRNA and protein), the Der p 1-mediated signaling events did not exactly match those induced by PAR(2)AP and Der p 3. First, Der p 1 was less effective in stimulating IL-8 gene transcriptional activity than PAR(2)AP and Der p 3. Second, Der p 1-mediated IL-8 expression was mainly dependent on NF-kappaB, whereas Der p 3 and PAR(2)AP regulated IL-8 expression through the activation of both NF-kappaB and AP-1. Third, although all three MAP kinases, ERK1/2, p38, and JNK, were activated, Der p 1 induced IL-8 release exclusively via the ERK1/2 signaling pathway, whereas PAR(2)AP and Der p 3 also involved the other kinases. Fourth, in HeLa cells, Der p 1 was able to up-regulate IL-8 secretion independent of PAR(2) expression, and in contrast with PAR(2)AP and Der p 3, Der p 1 was unable to affect calcium signaling via PAR(2) in PAR(2)-expressing KNRK cells. Finally, cleavage by Der p 1 of a synthetic peptide representing the N-terminal activation-cleavage site of PAR(2) did not release a high potency activator of PAR(2) as does Der p 3. We conclude that Der p 1 (but not Der p 3)-induced IL-8 production in A549 epithelial cells is independent of PAR(2) activation.
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PMID:The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. 1629 28

Mast cells are involved in early events crucial to inflammation and autoimmune disease. Recently, proteinase-activated receptor-2 (PAR(2)), a G-protein coupled receptor important to injury responses, was shown to be activated by mast cell tryptase. To investigate whether mast cells and PAR(2) are involved in the development and/or aggravation of testicular inflammation, we studied acute and chronic inflammatory models in the rat. In normal testes, PAR(2) was detected immunohistochemically in macrophages, in peritubular cells (PTCs) and in spermatid acrosomes. In experimentally induced autoimmune orchitis (EAO), PAR(2) was strongly upregulated in macrophages and peritubular-like cells, forming concentric layers around granulomas. Mast cells increased 10-fold in number, were more widely distributed throughout the interstitial tissue, and were partially degranulated. Isolated PTCs expressed functional PAR(2), responded to PAR(2) activation by phosphorylating extracellular signal-regulated kinases 1/2 (ERK1/2) and activating protein kinase c, and increased intracellular Ca(2+) concentrations as well as monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta(2) (TGFbeta(2)), and cyclooxygenase-2 (COX-2) mRNA expression. Expression of these inflammatory mediators, together with iNOS, also increased significantly in testes 50 days after EAO. In vivo, expression of cytokines and inflammatory mediators was upregulated after injection of recombinant tryptase (MCP-1, TGFbeta(2), and COX-2) and a specific PAR(2) peptide agonist (MCP-1, TGFbeta(2)) in the testis after 5 h. These results suggest that PAR(2) activation elicited on PTCs by mast cell tryptase contributes to acute testicular inflammation and that this pathogenetic mechanism may also play a role in autoimmune orchitis.
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PMID:Development of testicular inflammation in the rat involves activation of proteinase-activated receptor-2. 1645 Mar 34

Actin filaments (microfilaments) regulate various dynamic events during oocyte meiotic maturation and fertilization. In most species, microfilaments are not required for germinal vesicle breakdown and meiotic spindle formation, but they mediate peripheral nucleus (chromosome) migration, cortical spindle anchorage, homologous chromosome separation, cortex development/maintenance, polarity establishment, and first polar body emission during oocyte maturation. Peripheral cortical granule migration is controlled by microfilaments, while mitochondria movement is mediated by microtubules. During fertilization, microfilaments are involved in sperm incorporation, spindle rotation (mouse), cortical granule exocytosis, second polar body emission and cleavage ring formation, but are not required for pronuclear apposition (except for the mouse). Many of the events are driven by the dynamic interactions between myosin and actin filaments whose polymerization is regulated by RhoA, Cdc42, Arp2/3 and other signaling molecules. Studies have also shown that oocyte cortex organization and polarity formation mediated by actin filaments are regulated by mitogen-activated protein kinase, myosin light-chain kinase, protein kinase C and its substrate p-MARKS as well as PAR proteins. The completion of several dynamic events, including homologous chromosome separation, spindle anchorage, spindle rotation, vesicle organelle transport and pronuclear apposition (mouse), requires interactions between microfilaments and microtubules, but determination of how the two systems of the cytoskeleton precisely cross-link, and which proteins link microfilaments to microtubules to perform functions in eggs, requires further studies. Finally, the meaning of microfilament-mediated oocyte polarity versus embryo polarity and embryo development in different species (Drosophila, Xenopus and mouse) is discussed.
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PMID:Regulation of dynamic events by microfilaments during oocyte maturation and fertilization. 1645 14

Activation of both PAR-1 (proteinase-activated receptor-1) and PAR-2 resulted in release of the chemokine GRO (growth-regulated oncogene)/CINC-1 (cytokine-induced neutrophil chemoattractant-1), a functional counterpart of human interleukin-8, from rat astrocytes. Here, we investigate whether the two PAR receptor subtypes can signal separately. PAR-2-induced GRO/CINC-1 release was independent of protein kinase C, phosphoinositide 3-kinase and MEK (mitogen-activated protein kinase kinase)-1/2 activation, whereas these three kinases were involved in PAR-1-induced GRO/CINC-1 release. Despite such clear differences between PAR-1 and PAR-2 signalling pathways, JNK (c-Jun N-terminal kinase) was identified in both signalling pathways to play a pivotal role. By isoform-specific loss-of-function studies using small interfering RNA against JNK1-3, we demonstrate that different JNK isoforms mediated GRO/CINC-1 secretion, when it was induced by either PAR-1 or PAR-2 activation. JNK2 and JNK3 isoforms were both activated by PAR-1 and essential for chemokine GRO/CINC-1 secretion, whereas PAR-1-mediated JNK1 activation was mainly responsible for c-Jun phosphorylation, which was not involved in GRO/CINC-1 release. In contrast, PAR-2-induced JNK1 activation, which failed to phosphorylate c-Jun, uniquely contributed to GRO/CINC-1 release. Therefore our results show for the first time that JNK-mediated chemokine GRO/CINC-1 release occurred in a JNK isoform-dependent fashion and invoked PAR subtype-specific mechanisms. Furthermore, here we demonstrate that activation of PAR-2, as well as PAR-1, rescued astrocytes from ceramide-induced apoptosis via regulating chemokine GRO/CINC-1 release. Taken together, our results suggest that PAR-1 and PAR-2 have overlapping functions, but can activate separate pathways under certain pathological conditions to rescue neural cells from cell death. This provides new functional insights into PAR/JNK signalling and the protective actions of PARs in brain.
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PMID:Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain. 1694 65

Although the involvement of protease-activating receptor PAR1 and PAR4 is well established in platelet aggregation, their role in platelet adhesion and spreading has yet to be characterized. We investigated platelet adhesion and spreading on a fibrinogen matrix after PAR1 and PAR4 stimulation in correlation with the activation of two MAPKs, ERK2 and p38. Of the two PAR-activating peptides (PAR-APs), PAR1-AP and PAR4-AP, which both induce adhesion, only PAR4-AP induced full platelet spreading. Although both PAR1-AP and PAR4-AP induced ADP secretion, which is required for platelet spreading, only PAR4-AP induced sustained Ca(2+) mobilization. In these conditions of PAR4 induction, ERK2 and p38 activation were involved in platelet spreading but not in platelet adhesion. p38 phosphorylation was dependent on ADP signaling through P2Y12, its receptor. ERK2 phosphorylation was triggered through integrin alphaIIbbeta3 outside-in signaling and was dependent on the Rho pathway. ERK2 and p38 activation induced phosphorylation of the myosin light chain and actin polymerization, respectively, necessary for cytoskeleton reorganization. These findings provide the first evidence that thrombin requires PAR4 for the full spreading response. ERK2 and p38 and sustained Ca(2+) mobilization, involved in PAR4-induced platelet spreading, contribute to the stabilization of platelet thrombi at sites of high thrombin production.
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PMID:Protease-activating receptor-4 induces full platelet spreading on a fibrinogen matrix: involvement of ERK2 and p38 and Ca2+ mobilization. 1720 Jan 14

Sepsis is associated with increased production of reactive oxidant species. Oxidative and nitrosative stress can lead to activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), with subsequent loss of cellular functions. Activation of PARP may dramatically lower the intracellular concentration of its substrate, NAD thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. In addition, PARP enhances the expression of various pro-inflammatory mediators, via activation of NF-kappaB, MAP kinase and AP-1 and other signal transduction pathways. Preclinical studies in various rodent and large animal models demonstrate that PARP inhibition or PAR deficiency exerts beneficial effects on the haemodynamic and metabolic alterations associated with septic and haemorrhagic shock. Recent human data also support the role of PARP in septic shock: In a retrospective study in 25 septic patients, an increase in plasma troponin level was related to increased mortality risk. In patients who died, significant myocardial damage was detected, and histological analysis of heart showed inflammatory infiltration, increased collagen deposition, and derangement of mitochondrial criptae. Immunohistochemical staining for poly(ADP-ribose) (PAR), the product of activated PARP was demonstrated in septic hearts. There was a positive correlation between PAR staining and troponin I; and a correlation of PAR staining and LVSSW. Thus, there is significant PARP activation in animal models subjected to circulatory shock, as well as in the hearts of septic patients. Based on the interventional studies in animals and the correlations observed in patients we propose that PARP activation may be, in part responsible for the cardiac depression and haemodynamic failure seen in humans with severe sepsis. Interestingly, recent studies reveal that the protective effects of PARP inhibitors are predominant in male animals, and are not apparent in female animals. Oestrogen, by providing a baseline inhibitory effect on PARP activation, may be partially responsible for this gender difference.
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PMID:Poly (ADP-ribose) polymerase activation and circulatory shock. 1738 Jul 90

The reduction in coronary heart disease (CHD) from moderate alcohol intake may be mediated, in part, by increased fibrinolysis; endothelial cell (EC)-mediated fibrinolysis should decrease acute atherothrombotic consequences (eg, plaque rupture) of myocardial infarction (MI). We have shown that alcohol and individual polyphenols modulate EC fibrinolytic protein (t-PA, u-PA, PAI-1, u-PAR and Annexin-II) expression at the cellular, molecular, and gene levels to sustain increased fibrinolytic activity. Herein we describe the sequence of molecular events by which EC t-PA expression is increased through common activation of p38 MAPK signaling. Up-regulation of t-PA gene transcription, through specific alcohol and polyphenol transcription factor binding sites in the t-PA promoter, results in increased in vitro fibrinolysis and in vivo clot lytic activity (using real-time fluorescence [Fl] imaging of Cy5.5-labeled fibrin clot lysis in a mouse model). Fl-labeled fibrin clots injected into untreated C56Bl/6 wild-type control mice are lysed in approximately 2 hours and clot lytic rates significantly increased in mice treated with either alcohol, catechins, or quercetin (4-6 weeks). Fl-labeled clot lysis in ApoE knock-out mice (atherosclerosis model) showed impaired in vivo clot lysis that was "normalized" to wild-type control levels by treatment with alcohol, catechin, or quercetin for 6 to 8 weeks.
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PMID:Mechanism by which alcohol and wine polyphenols affect coronary heart disease risk. 1747 21

Poly(ADP-ribose) polymerase-1 (PARP-1) hyper-activation promotes cell death but the signaling events downstream of PARP-1 activation are not fully identified. To gain further information on the implication of PARP-1 activation and PAR synthesis on signaling pathways influencing cell death, we exposed HeLa cells to the DNA alkylating agent N-methyl-N'-methyl-nitro-N-nitrosoguanidine (MNNG). We found that massive PAR synthesis leads to down-regulation of ERK1/2 phosphorylation, Bax translocation to the mitochondria, release of cytochrome c and AIF and subsequently cell death. Inhibition of massive PAR synthesis following MNNG exposure with the PARP inhibitor PJ34 prevented those events leading to cell survival, whereas inhibition of ERK1/2 phosphorylation by inhibiting MEK counteracted the cytoprotective effect of PJ34. Together, our results provide evidence that PARP-1-induced cell death by MNNG exposure in HeLa cells is mediated in part through inhibition of the MEK/ERK signaling pathway and that inhibition of massive PAR synthesis by PJ34, which promotes sustained activation of ERK1/2, leads to cytoprotection.
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PMID:PARP-1-induced cell death through inhibition of the MEK/ERK pathway in MNNG-treated HeLa cells. 1782 54

Curcumin is known to be a potent wound healer. Despite this, studies on curcumin using certain model systems have shown it to be anti-angiogenic. Results of the present investigations suggest that curcumin causes opposing effects on angiogenesis in serum stimulated and unstimulated conditions. The evidence in support of this are: (a) in serum free conditions, curcumin promoted sprouting in rat aortic ring, increased vascular density in CAM and induced morphological changes indicative of angiogenic phenotype in HUVECs and rat aortic endothelial cells in culture, (b) increased the expression of biochemical markers of angiogenesis such as CD 31, E-selectin, VEGF and VEGFR-2 in HUVECs on treatment with curcumin, and (c) supplementation of curcumin along with serum caused decrease in CD 31 and E-selectin levels, downregulation of VEGF, angiopoietin-1 and VEGFR-2 and delayed formation of capillary network-like structure. Proangiogenic effect of the individual components of the natural curcumin differed and the presence of the three components in the natural mixture has a synergistic effect. Effect of curcuminoids in the absence of serum appears to depend on VEGF as (a) anti-VEGF antibody blocked the effect of curcuminoids (b) curcuminoids caused decrease in PAR modification of VEGF increasing its biological activity. Treatment with curcuminoids in serum-free conditions resulted in activation of PI3K-Akt pathway; but in serum-supplemented condition, curcuminoids caused inhibition of the MAPK pathways thereby inhibiting the expression of angiogenic phenotype. These results suggest that PI3K-Akt and MAPK pathways involved in the expression of angiogenic phenotype respond differently to the extracellular microenvironment.
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PMID:Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response. 1796 May 70

Chronic inflammation of mucosae is associated with an increased cancer risk. Tumorigenesis in these tissues is associated with the activity of some proteinases, cyclooxygenase-2 (COX-2), and beta-catenin. Serine proteinases participate in both inflammation and tumorigenesis through the activation of proteinase-activated receptor-2 (PAR(2)), which up-regulates COX-2 by an unknown mechanism. We sought to determine whether beta-catenin participated in PAR(2)-induced COX-2 expression and through what cellular mechanism. In A549 epithelial cells, we showed that PAR(2) activation increased COX-2 expression through the beta-catenin/T cell factor transcription pathway. This effect was dependent upon ERK1/2 MAPK, which inhibited the beta-catenin-regulating protein, glycogen synthase kinase-3beta, and induced the activity of the cAMP-response element-binding protein (CREB). Knockdown of CREB by small interfering RNA revealed that PAR(2)-induced beta-catenin transcriptional activity and COX-2 expression were CREB-dependent. A co-immunoprecipitation assay revealed a physical interaction between CREB and beta-catenin. Thus, PAR(2) up-regulated COX-2 expression via an ERK1/2-mediated activation of the beta-catenin/Tcf-4 and CREB pathways. These findings reveal new cellular mechanisms by which serine proteinases may participate in tumor development and are particularly relevant to cancers associated with chronic mucosal inflammation, where serine proteinases are abundant and COX-2 overexpression is a common feature.
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PMID:Proteinase-activated receptor-2 induces cyclooxygenase-2 expression through beta-catenin and cyclic AMP-response element-binding protein. 1796 94


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