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)

In a previous study, E47 HepG2 cells that overexpress human CYP2E1 were shown to be more sensitive to cisplatin than C34 cells that do not express CYP2E1. In this study, we found that this sensitivity was due to an earlier activation of ERK in the E47 cells compared to the C34 cells. Glutathione depletion by L-buthionine sulfoximine (BSO) enhanced cisplatin cytotoxicity via increasing production of reactive oxygen species (ROS) and activation of ERK. In contrast, elevation of glutathione by glutathione ethyl ester (GSHE) decreased cisplatin/BSO cytotoxicity by decreasing ROS production and ERK activation. Inhibition of ERK activation by U0126 protected against cisplatin/BSO cytotoxicity via inhibiting ROS production but not restoring intracellular glutathione content. Examination of the mode of cell death showed that U0126 inhibited cisplatin-induced necrosis but not apoptosis. Cisplatin-induced apoptosis was caspases-dependent; BSO switched cisplatin-induced apoptosis to necrosis via decreasing activity of caspases, and GSHE switched cisplatin/BSO-induced necrosis back to apoptosis through maintaining activity of caspases. Similar to GSHE, U0126 partially switched cisplatin/BSO induced necrosis to apoptosis via restoring activity of caspases. Cisplatin lowered levels of thioredoxin, especially in the presence of BSO. Although U0126 failed in restoring intracellular glutathione levels, it restored thioredoxin levels, which maintain the activity of the caspases. These results suggest that thioredoxin can replace glutathione to promote the active thiol redox state necessary for caspase activity, and thus glutathione and thioredoxin regulate the mode of cisplatin toxicity in E47 cells via redox regulation of caspase activity.
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PMID:The mode of cisplatin-induced cell death in CYP2E1-overexpressing HepG2 cells: modulation by ERK, ROS, glutathione, and thioredoxin. 1776 2

Oxidative modifications of proteins are fundamental biochemical events that regulate cellular signaling, protein expression, and function. The redox status is balanced by reductants in which GSH plays a major role. This study investigated whether or not p21Waf1 expression and TNFalpha biosynthesis in macrophage differentiation/activation were regulated by GSH modulators and whether or not the JNK and ERK pathway were involved. We observed an increase of p21Waf1 expression and TNFalpha biosynthesis in the THP1 monocyte/macrophage cell line treated with PMA. Treatment of THP1 cultures with NAC prior to adding PMA abrogates the expression of p21Waf1 mRNA and decreases the level of TNFalpha whereas GSH depletion by BSO enhances the levels of TNFalpha with minor effects on p21Waf1 expression. To assess whether or not ERK and JNK were involved in the redox mechanism of p21Waf1 and TNFalpha, we used pharmacological inhibitors for JNK and ERK. Both PD98095 and dicoumarol were capable of blocking TNFalpha production but had only a small effect on p21Waf1 expression. We next observed that activation of JNK was significantly inhibited in cells pretreated with NAC with no effect on ERK. Taken together, our findings suggest that the modulation of GSH regulate the magnitude the cell response to PMA in which JNK and ERK have a particular role in redox signaling.
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PMID:Regulation of p21Waf1 expression and TNFalpha biosynthesis by glutathione modulators in PMA induced-THP1 differentiation: involvement of JNK and ERK pathways. 1792 36

Mycotoxin fumonisin B(1) (FB(1)) is a frequent contaminant of grain, particularly maize, but the mechanism of its toxicity in the kidney and liver is not fully understood. FB(1)-stimulated oxidative stress might disturb cellular redox state and signal transduction pathways of the target cells. In this study we measured total intracellular glutathione (GSH), and assessed mitogen-activated protein kinases (MAPKs) activation and the expression of heat shock proteins (Hsps) Hsp25 and Hsp70 in the liver and kidney of male Wistar rats given 0.5 mg FB(1)/kg b.w. intraperitoneally for 2 or 7 days. The effect of FB(1) on GSH levels, MAPK activation and Hsp expression was found to be related to the type of tissue affected and the length of treatment. In rat liver, cellular GSH content increased, Hsp expression was up-regulated, and ERK and p38 were activated after the 7-day treatment, while even the 2-day treatment sufficed to produce phospho-JNK signal. In rat kidney, GSH levels decreased after the 2- and 7-day treatment with FB(1), while after the 7-day treatment all three MAPKs were activated, Hsp25 expression increased and Hsp70 expression decreased. In conclusion, FB(1) alters cellular redox balance, which leads to tissue-specific activation and expression of redox-sensitive signalling molecules. It seems that kidney cells are more sensitive to adverse effects of FB(1).
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PMID:Mycotoxin fumonisin B1 alters cellular redox balance and signalling pathways in rat liver and kidney. 1794 82

We investigated the antidepressant-like effect of zinc chloride (zinc) administered acutely during 7 days (i.p. route), or chronically during 30 days (oral route) in the forced swimming test (FST) in rats. It was also investigated whether the antidepressant-like effect of zinc is associated with changes in the glutathione antioxidant system in the Wistar rat brain. Animals receiving a single zinc dose (5, 15 and 30 mg/kg, i.p.) 24 h prior to analysis showed no changes in the FST, but glutathione reductase and glutathione S-transferase activity were reduced in the hippocampus and cerebral cortex. This treatment did not, however, affect the glutathione status (GSH and GSSG) in both brain structures. The 7-day zinc treatment (1, 5 and 15 mg/kg, i.p.) caused a mild though significant antidepressant-like effect in the FST at the highest dosing, without affecting the glutathione antioxidant system. Finally, a consistent antidepressant-like effect was achieved in the FST after chronic (30 days) zinc treatment (300 mg/L, p.o.). This was accompanied by a significant increase in total glutathione levels in the hippocampus and cerebral cortex. The good response to oral treatment in the FST led us to investigate other variables, such as ERK phosphorylation and BDNF expression. Similar to therapeutic antidepressants, zinc in chronic oral treatment produced an increase in ERK phosphorylation and BDNF expression in the cerebral cortex. It is our hypothesis that up-regulation of neuroprotective effectors (GSH, ERK and BDNF) may be related to the antidepressant properties of zinc, but this will require additional work to be confirmed.
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PMID:Involvement of glutathione, ERK1/2 phosphorylation and BDNF expression in the antidepressant-like effect of zinc in rats. 1819 Dec 37

Glutathione depletion is a key factor in the development of acute pancreatitis. Our aim was to study the regulation of glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis, in edematous or necrotizing pancreatitis in rats. Glutathione levels were kept low in necrotizing pancreatitis for several hours, with no increase in protein or mRNA levels of glutamate cysteine ligase subunits, despite binding of RNA polymerase II to their promoters and coding regions. The survival signal pathway mediated by ERK and c-MYC was activated, and c-MYC was recruited to the promoters. The failure in gene up-regulation seems to be due to a marked increase in cytosolic ribonuclease activity. In contrast, in edematous pancreatitis glutathione levels were depleted and rapidly restored, and protein and mRNA expression of glutamate cysteine ligase increased markedly due to enhanced transcription mediated by recruitment of c-MYC, NF-kappaB, and SP-1 to the promoters. No increase in cytosolic ribonuclease activity was found in this case. We propose a novel pathophysiological mechanism to differentiate necrotizing from edematous pancreatitis, which is the inefficient up-regulation of glutamate cysteine ligase caused by increased cytosolic ribonuclease activity in the severe form of the disease. This mechanism would abrogate a rapid recovery of glutathione levels.
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PMID:Glutamate cysteine ligase up-regulation fails in necrotizing pancreatitis. 1827 77

Cigarette smoke is a major environmental air pollutant that injures airway epithelium and incites subsequent diseases including chronic obstructive pulmonary disease. The lesion that smoke induces in airway epithelium is still incompletely understood. Using a LIVE/DEAD cytotoxicity assay, we observed that subconfluent cultures of bronchial epithelial cells derived from both human and monkey airway tissues and an immortalized normal human bronchial epithelial cell line (HBE1) were more susceptible to injury by cigarette smoke extract (CSE) and by direct cigarette smoke exposure than cells in confluent cultures. Scraping confluent cultures also caused an enhanced cell injury predominately in the leading edge of the scraped confluent cultures by CSE. Cellular ATP levels in both subconfluent and confluent cultures were drastically reduced after CSE exposure. In contrast, GSH levels were significantly reduced only in subconfluent cultures exposed to smoke and not in confluent cultures. Western blot analysis demonstrated ERK activation in both confluent and subconfluent cultures after CSE. However, activation of apoptosis signal-regulating kinase 1 (ASK1), JNK, and p38 were demonstrated only in subconfluent cultures and not in confluent cultures after CSE. Using short interfering RNA (siRNA) to JNK1 and JNK2 and a JNK inhibitor, we attenuated CSE-mediated cell death in subconfluent cultures but not with an inhibitor of the p38 pathway. Using the tetracycline (Tet)-on inducible approach, overexpression of thioredoxin (TRX) attenuated CSE-mediated cell death and JNK activation in subconfluent cultures. These results suggest that the TRX-ASK1-JNK pathway may play a critical role in mediating cell density-dependent CSE cytotoxicity.
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PMID:TRX-ASK1-JNK signaling regulation of cell density-dependent cytotoxicity in cigarette smoke-exposed human bronchial epithelial cells. 1828 6

The recognition of peptide antigens by T cells through their antigen receptors (T cell receptors, or TCR), together with the ligation of additional surface molecules called costimulatory receptors, rapidly induces interactive signaling pathways that lead to transcriptional initiation at genes such as that of the autocrine growth factor interleukin 2 (IL-2). Activation of the ERK and JNK subfamilies of MAPK mediates some of these signals. This unit presents procedures for a solid-phase kinase assay and immune-complex kinase assay to measure JNK and ERK activities, respectively, in T cells that have been appropriately stimulated. Also described is a procedure for preparing GSThyphen;cJun/GSH-Sepharose beads needed in the solid-phase JNK protein kinase activity assay.
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PMID:Analyzing mitogen-activated protein kinase (MAPK) activities in T cells. 1843 22

As the applications of industrial nanoparticles are being developed, the concerns on the environmental health are increasing. Cytotoxicities of titanium dioxide nanoparticles of different concentrations (5, 10, 20 and 40 microg/ml) were evaluated in this study using a cultured human bronchial epithelial cell line, BEAS-2B. Exposure of the cultured cells to nanoparticles led to cell death, reactive oxygen species (ROS) increase, reduced glutathione (GSH) decrease, and the induction of oxidative stress-related genes such as heme oxygenase-1, thioredoxin reductase, glutathione-S-transferase, catalase, and a hypoxia inducible gene. The ROS increase by titanium dioxide nanoparticles triggered the activation of cytosolic caspase-3 and chromatin condensation, which means that titanium dioxide nanoparticles exert cytotoxicity by an apoptotic process. Furthermore, the expressions of inflammation-related genes such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), TNF-a, and C-X-C motif ligand 2 (CXCL2) were also elevated. The induction of IL-8 by titanium dioxide nanoparticles was inhibited by the pre-treatment with SB203580 and PD98059, which means that the IL-8 was induced through p38 mitogen-activated protein kinase (MAPK) pathway and/or extracellular signal (ERK) pathway. Uptake of the nanoparticles into the cultured cells was observed and titanium dioxide nanoparticles seemed to penetrate into the cytoplasm and locate in the peri-region of the nucleus as aggregated particles, which may induce direct interactions between the particles and cellular molecules, to cause adverse biological responses.
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PMID:Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. 1866 54

We have previously shown that Hg(2+), Pb(2+), and Cu(2+), significantly modulate the expression of NAD(P):quinone oxidoreductase 1 (Nqo1) in Hepa 1c1c7 cells through oxidative stress-dependent mechanisms. In the current study, we examined the role of redox-sensitive transcription factors, NF-kappaB and AP-1 signaling pathways in the modulation of Nqo1 by heavy metals. Our results show that the depletion of cellular GSH using L-buthionine-(S,R)-sulfoximine further potentiated the heavy metal-mediated induction of Nqo1 at the mRNA and activity levels. The NF-kappaB activator, PMA, significantly abolished the metal-mediated effects on Nqo1 mRNA and activity. In parallel, the NF-kappaB inhibitor, PDTC, further potentiated the Pb(2+)- and Hg(2+)-mediated induction of Nqo1 mRNA and activity levels, respectively. Inhibition of AP-1 upstream signaling pathway such as JNK by SP600125 significantly suppressed heavy metal-mediated induction of Nqo1 mRNA and activity levels. In contrast, inhibition of ERK by U0126 further potentiated heavy metal-mediated effects on Nqo1 mRNA, while only potentiated Hg(2+)-mediated induction of Nqo1 activity. Furthermore, p38 MAPK inhibitor, SB203580 further potentiated Pb(2+)- and Cu(2+)-mediated effects at the mRNA levels, whereas did not alter the activity levels. These results clearly demonstrate that activation of NF-kappaB negatively regulates the expression of Nqo1 by heavy metals, whereas AP-1 signaling pathways differentially modulates the heavy metal-mediated effects.
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PMID:NF-kappaB and AP-1 are key signaling pathways in the modulation of NAD(P)H:quinone oxidoreductase 1 gene by mercury, lead, and copper. 1875 16

Asiatic acid is a triterpenoid component possessing antioxidative, anti-inflammatory and hepatoprotective activity. In this issue, we explored the protective effects of asiatic acid and the relative mechanism in the D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system. The cultures were pretreated with asiatic acid for 12 h, followed by D-GalN/LPS exposure for 12 h. Asiatic acid reduced aspartate aminotransferase and lactate dehydrogenase generation and increased cell viability in a concentration-dependent manner. Meanwhile, the effects of asiatic acid in leukotriene C(4) synthase (LTC(4)S) expression and cellular redox status including reactive oxygen species and GSH content were detected. The results showed that D-GalN/LPS induced the increase of reactive oxygen species followed by extracellular signal-regulated kinase 1/2 (ERK 1/2) and nuclear factor-kappaB (NF-kappaB) activation. Treatment with ERK 1/2 specific inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) abolished the ERK1/2 protein phosphorylation and blunted LTC(4)S expression. Reactive oxygen species signaling pathway inhibitor pyrrolidine dithiocarbamate (PDTC) inhibited reactive oxygen species generation and NF-kappaB activation, which in turn blocked LTC(4)S expression and attenuated the injury. Asiatic acid can protect the hepatocytes against D-GalN/LPS-induced hepatotoxicity. During which, the cell redox was ameliorated and increased expression of LTC(4)S was reversed by the pretreatment of asiatic acid. Taken together, asiatic acid can protect against D-GalN/LPS-induced hepatotoxicity partly via redox-regulated LTC(4)S expression pathway.
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PMID:Protective effects of asiatic acid against D-galactosamine/lipopolysaccharide-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system via redox-regulated leukotriene C4 synthase expression pathway. 1908 74


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