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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sclerotinia sclerotiorum is a necrotrophic, omnivorous plant pathogen with worldwide distribution. Sclerotia of S. sclerotiorum are pigmented, multihyphal structures that play a central role in the life and infection cycles of this pathogen. Plant infection depends on the formation of melanin-rich infection cushions, and secretion of hydrolytic enzymes and oxalic acid. Type 2A Ser/Thr phosphatases (PP2As) are involved in the regulation of a variety of cellular process. In the presence of cantharidin, a PP2A-specific inhibitor, hyphal elongation and sclerotia numbers were impaired whereas sclerotial size increased. We partially inactivated PP2A by antisense expression of the gene (pph1) encoding the PP2A catalytic subunit. When antisense expression was induced, almost complete cessation of fungal growth was observed, indicative of a crucial role for PP2A in fungal growth. RNAi-based gene silencing was employed to alter the expression of the 55-kDa R2 (B regulatory subunit). Isolates in which rgb1 RNA levels were decreased were slow growing, but viable. Melanin biosynthesis, infection-cushion production, and pathogenesis were significantly impaired in the rgb1 mutants, yet theses mutants were pathogenic on wounded leaves. Reduced ERK (extracellular signal-regulated kinases)-like mitogen-activated protein kinase (MAPK) function conferred a reduction in NADPH oxidase and PP2A activity levels, suggesting a functional link between MAPK, reactive oxygen species, and PP2A activity in S. sclerotiorum.
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PMID:Type 2A phosphoprotein phosphatase is required for asexual development and pathogenesis of Sclerotinia sclerotiorum. 1772 98

We previously showed that ANG II induces mesangial cell (MC) proliferation via the JNK-activator protein-1 pathway. The present study attempted to determine the upstream mediators of JNK activation, with emphasis on reactive oxygen species (ROS) and the epidermal growth factor (EGF) receptor (EGFR). In cultured human MCs (HMCs), as early as 3 min, ANG II time dependently increased intracellular ROS production, which was sensitive to 10 microM diphenyleneiodonium sulfate and 500 microM apocynin, two structurally distinct NADPH oxidase inhibitors. In contrast, inhibitors of other oxidant-producing enzymes, including the mitochondrial complex I inhibitor rotenone, the xanthine oxidase inhibitor allopurinol, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguiaretic acid, the cytochrome P-450 oxygenase inhibitor ketoconazole, and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester, were without effect. ANG II-induced ROS generation was inhibited by the angiotensin type 1 receptor antagonist losartan (10 muM) but not the angiotensin type 2 receptor antagonist PD-123319 (10 microM). ANG II induced translocation of p47(phox) and p67(phox) from the cytosol to the membrane. The antioxidants almost abolished the ANG II mitogenic response, as assessed by [(3)H]thymidine incorporation and cell number, associated with a remarkable blockade of the activation of EGFR (90% inhibition) and JNK (83% inhibition). The EGFR inhibitor AG-1478 was able to mimic the effect of antioxidants, in that it inhibited the mitogenic response and the JNK activation following ANG II treatment. Together, these data suggest that the ROS-EGFR-JNK pathway is involved in transducing the proliferative effect of ANG II in cultured HMCs.
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PMID:ANG II induces c-Jun NH2-terminal kinase activation and proliferation of human mesangial cells via redox-sensitive transactivation of the EGFR. 1788 65

We have shown that NADPH oxidase NOX5-S is overexpressed in Barrett's esophageal adenocarcinoma (EA) cells and may contribute to the progression from Barrett's esophagus (BE) to EA presumably by increasing cell proliferation and decreasing apoptosis (Fu X, Beer DG, Behar J, Wands J, Lambeth D, Cao W. J Biol Chem 281: 20368-20382, 2006). The mechanism(s) of NOX5-S overexpression in EA, however, is not fully understood. In SEG1 EA cells we found that acid treatment significantly increased platelet-activating factor (PAF) production, which in turn markedly increased NOX5-S expression and hydrogen peroxide (H(2)O(2)) production. Knockdown of NOX5-S by NOX5-S small interfering RNA (siRNA) blocked PAF-dependent H(2)O(2) production. PAF-dependent induction of NOX5-S expression and H(2)O(2) production were significantly decreased by the MAPK kinase 1 inhibitor PD-98059, by the cytosolic phospholipase A(2) (cPLA(2)) inhibitor AACOCF3, and by STAT5 downregulation with STAT5 siRNA. PAF significantly increased the phosphorylation of ERK1/2 MAPK, cPLA(2), and STAT5. Using inhibitors, we demonstrated that PAF-induced STAT5 phosphorylation depends on activation of ERK1/2 MAPK and cPLA(2), whereas PAF-induced cPLA(2) phosphorylation was associated with activation of ERK1/2 MAPK. Given that STAT5 bound to the c-sis-inducible element (TTCTGGTAA) of the NOX5-S promoter, overexpression of STAT5 significantly increased NOX5-S promoter activity. We conclude that acid-induced NOX5-S expression and H(2)O(2) production is mediated in part by production of PAF in SEG1 EA cells, and that PAF-induced increase in NOX5-S expression depends on sequential activation of ERK MAP kinases, cPLA(2), and STAT5 in these cells.
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PMID:STAT5 mediates PAF-induced NADPH oxidase NOX5-S expression in Barrett's esophageal adenocarcinoma cells. 1794 54

Reactive oxygen species (ROS) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis. One source of ROS in the vasculature is free heme released from hemoglobin. Because Egr-1, the regulator of cell proliferation and apoptosis, is also induced by oxidant stress and is likewise implicated in atherosclerosis, we examined the regulation of Egr-1 by heme in vascular smooth muscle cells (SMCs). Hemin increased Egr-1 expression (mRNA, protein) within 30 minutes and ERK-1/2 phosphorylation and nuclear translocation within 5 minutes. Inhibiting hemin-induced ERK-1/2 activation by U0126 (MAPK-inhibitor), the antioxidant N-acetyl cysteine, the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride, the superoxide scavenger tiron, or tricarbonyldichlororuthenium(II)-dimer (carbon-monoxide donor; CORM-2) blocked hemin-induced Egr-1 expression. Hemin activated Elk-1, SRF, and NF-kappaB and promoted their interaction with the Egr-1 promoter. Downregulating Elk-1 (via siRNA) or blocking NF-kappaB activation (via BAY-11-7082) abolished hemin induction of Egr-1. Finally, hemin-induced Egr-1 bound the promoters of tissue factor (TF), Plasminogen Activator Inhibitor (PAI)-1, and NGF-1A Binding (NAB)-2, upregulating their expression, and increased the biochemical activity of TF and PAI-1. Upregulation of Egr-1 and its target genes by heme-induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis.
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PMID:Hemin upregulates Egr-1 expression in vascular smooth muscle cells via reactive oxygen species ERK-1/2-Elk-1 and NF-kappaB. 1817 70

In addition to ultraviolet radiation, human skin is also exposed to infrared radiation (IR) from natural sunlight. IR typically increases the skin temperature. This study examined whether or not heat shock-induced ROS stimulates MMPs in keratinocyte HaCaT cells. In HaCaT cells, heat shock was found to increase the intracellular ROS levels, including hydrogen peroxide and superoxide. The heat shock treatment induced MMP-1 and MMP-9, but not MMP-2, at the mRNA and protein levels. Moreover, heat shock caused the rapid activation of the three distinct MAPKs, ERK, JNK, and p38 kinase. The heat shock-induced expression of MMP-1 and MMP-9 was significantly suppressed by a pretreatment with the antioxidant NAC or catalase. On the other hand, SOD inhibited heat shock-induced activity of MMP-9 induction, but not MMP-1. A pretreatment with NAC or catalase, but not SOD, attenuated the phosphorylation of ERK, JNK, and p38 kinase by heat shock. The potential sites of ROS generation by heat shock along with its role in the heat shock-induced expression of MMP-1 and MMP-9 were next analyzed. These results indicate that heat shock-induced ROS is promoted via NADPH oxidase, xanthine oxidase, and mitochondria. Indeed, the NADPH oxidase and xanthine oxidase activities were increased by heat shock. Overall, the ROS produced by heat shock may play an important role in the heat shock-induced activation of MAPKs, which can induce MMP-1 and-9 expressions.
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PMID:Reactive oxygen species produced by NADPH oxidase, xanthine oxidase, and mitochondrial electron transport system mediate heat shock-induced MMP-1 and MMP-9 expression. 1803 52

We used Western blot analysis to examine the effect of dietary K intake on the expression of serine/threonine protein phosphatase in the kidney. K restriction significantly decreased the expression of catalytic subunit of protein phosphatase (PP)2B but increased the expression of PP2B regulatory subunit in both rat and mouse kidney. However, K depletion did not affect the expression of PP1 and PP2A. Treatment of M-1 cells, mouse cortical collecting duct (CCD) cells, or 293T cells with glucose oxidase (GO), which generates superoxide anions through glucose metabolism, mimicked the effect of K restriction on PP2B expression and significantly decreased expression of PP2B catalytic subunits. However, GO treatment increased expression of regulatory subunit of PP2B and had no effect on expression of PP1, PP2A, and protein tyrosine phosphatase 1D. Moreover, deletion of gp91-containing NADPH oxidase abolished the effect of K depletion on PP2B. Thus superoxide anions or related products may mediate the inhibitory effect of K restriction on the expression of PP2B catalytic subunit. We also used patch-clamp technique to study the effect of inhibiting PP2B on renal outer medullary K (ROMK) channels in the CCD. Application of cyclosporin A or FK506, inhibitors of PP2B, significantly decreased ROMK channels, and the effect of PP2B inhibitors was abolished by blocking p38 mitogen-activated protein kinase (MAPK) and ERK. Furthermore, Western blot demonstrated that inhibition of PP2B with cyclosporin A or small interfering RNA increased the phosphorylation of ERK and p38 MAPK. We conclude that K restriction suppresses the expression of PP2B catalytic subunits and that inhibition of PP2B decreases ROMK channel activity through stimulation of MAPK in the CCD.
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PMID:K restriction inhibits protein phosphatase 2B (PP2B) and suppression of PP2B decreases ROMK channel activity in the CCD. 1818 75

Vascularization, under physiological or pathophysiological conditions, typically takes place by one or more of the following processes: angiogenesis, vasculogenesis, arteriogenesis, and lymphangiogenesis. Although all of these mechanisms of vascularization have sufficient contrasting features to warrant consideration under separate cover, one common feature shared by all is their sensitivity to the VEGF signaling pathway. Conditions such as wound healing and physical exercise result in increased production of reactive oxygen species such as H(2)O(2), and both are associated with increased tissue vascularization. Understanding these two scenarios of adult tissue vascularization in tandem offers the potential to unlock the significance of redox regulation of the VEGF signaling pathway. Does H(2)O(2) support tissue vascularization? H(2)O(2) induces the expression of the most angiogenic form of VEGF, VEGF-A, by a HIF-independent and Sp1-dependent mechanism. Ligation of VEGF-A to VEGFR2 results in signal transduction leading to tissue vascularization. Such ligation generates H(2)O(2) via an NADPH oxidase-dependent mechanism. Disruption of VEGF-VEGFR2 ligation-dependent H(2)O(2) production or decomposition of such H(2)O(2) stalls VEGFR2 signaling. Numerous antioxidants exhibit antiangiogenic properties. Current evidence lends firm credence to the hypothesis that low-level endogenous H(2)O(2) supports vascular growth.
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PMID:Redox regulation of the VEGF signaling path and tissue vascularization: Hydrogen peroxide, the common link between physical exercise and cutaneous wound healing. 1819 54

In this paper we report that diphenyliodonium (DPI), a NADPH oxidase inhibitor, shows potent anti-inflammatory and neuroprotective effects at femtomolar concentrations (10(-13) to 10(-14) M) in primary midbrain cultures. Mechanistic studies revealed that DPI-elicited effects were mediated by the inhibition of LPS-induced microglial ROS production and the subsequent release of pro-inflammatory cytokine TNFa, and the production of nitric oxide. Further studies showed that 10(-14) M DPI significantly reduced LPS-induced ERK phosphorylation. Taken together, our results demonstrate that femtomolar concentrations of DPI exert potent anti-inflammatory and neuroprotective effects by inhibiting microglial activation through the inhibition of ERK-regulated PHOX activity.
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PMID:NADPH oxidase inhibitor DPI is neuroprotective at femtomolar concentrations through inhibition of microglia over-activation. 1826 57

Effects of hyaluronic acid (HA) on allergic inflammation were investigated. HA exerted negative effects on beta-hexoaminidase secretion and histamine release in antigen-stimulated rat basophilic leukemia (RBL2H3) cells. HA inhibited interaction between IgE and FcepsilonRI and between FcepsilonRI and PKCdelta. HA inhibited CD44 interaction with PKCalpha, indicating that HA targets CD44. PKCalpha and -delta were responsible for increased Rac1 activity and expression of p47(phox), p67(phox). HA inhibited phosphorylation of PKCalpha and -delta. Rac1 was responsible for increased ROS, and NADPH oxidase was the main source for ROS. The inhibition of PKC prevented antigen from increasing phosphorylation of ERK and p38 MAPK. ERK, p38 MAPK, and ROS, were responsible for secretion of beta-hexosaminidase, histamine release, and induction of chemokines. HA suppressed induction of chemokines, such as MIP-2 and Sprr-2a. CD44 mediated effect of antigen on phosphorylation of ERK, p38MAPK, ROS production, secretion of beta-hexosaminidase, and histamine release. GPCR did not mediate allergic function of antigen or affect anti-allergic function of HA. In vivo anti-allergic effect of HA was investigated using Nc/Nga mice model of DNFB-induced atopic dermatitis. HA reduced skin lesions in Nc/Nga mice treated with DNFB, decreased expression levels of MIP-2, Sprr-2a, and serum IgE level. In conclusion, hyaluronic acid exerts negative effect on allergic inflammation by targeting CD44 and inhibiting FcepsilonRI signaling.
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PMID:Hyaluronic acid targets CD44 and inhibits FcepsilonRI signaling involving PKCdelta, Rac1, ROS, and MAPK to exert anti-allergic effect. 1828 79

Low levels of endogenous reactive oxygen species (ROS) originating from NADPH oxidase have been implicated in various signaling pathways induced by growth factors and mediated by cytokines. However, the main source of ROS is known to be the mitochondria, and increased levels of ROS from the mitochondria have been observed in many cancer cells. Thus far, the mechanism of ROS production in cancer cell proliferation in the mitochondria is not well-understood. We recently identified a novel protein, ROS modulator 1 (Romo1), and reported that increased expression of Romo1-triggered ROS production in the mitochondria. The experiments conducted in the present study showed that Romo1-derived ROS were indispensable for the proliferation of both normal and cancer cells. Furthermore, whilst cell growth was inhibited by blocking the ERK pathway in cells transfected with siRNA directed against Romo1, the cell growth was recovered by addition of exogenous hydrogen peroxide. The results of this study suggest that Romo1-induced ROS may play an important role in redox signaling in cancer cells.
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PMID:A critical role for Romo1-derived ROS in cell proliferation. 1831 94


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