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)

2-(2-hydroxy-ethylsulfanyl)-3-methyl-1,4-naphthoquinone or CPD-5, a K vitamin analog, was previously indicated to be a potent growth inhibitor for Hep 3B hepatoma cells in vitro. Here, we show that CPD-5 and two newly synthesized analogs, 2-(2-hydroxy-ethylsulfanyl)-3-methyl-5- nitro-1,4-naphthoquinone (PD-37) and 2-(2-hydroxy-ethylsulfanyl)-3- methyl-5-acetylamino-1,4-naphthoquinone (PD-42), are potent growth inhibitors of 13 different human cancer cell lines, with IC50 values in the range of 3-54 microM. Phospho-ERK was induced by each of three K vitamin analogs in every cell line in a dose-dependent manner, at growth inhibitory doses. ERK phosphorylation and growth inhibitory effects were strongly correlated, with p=0.0080 for CPD-5, p=0.0076 for PD-37 and p=0.0251 for PD-42. The induction of phospho-ERK and growth inhibition were antagonized by thiol-containing anti-oxidants, but not by catalase, consistent with a possible arylating mechanism. The data show a novel class of growth inhibitors with a wide spectrum of action that induces ERK hyper-phosphorylation, as a possible new growth inhibitory feature.
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PMID:Tumor cell growth inhibition and extracellular signal-regulated kinase (ERK) phosphorylation by novel K vitamins. 1173 95

The reactive oxygen-generating enzyme Nox1 transforms NIH 3T3 cells, rendering them highly tumorigenic and, as shown herein, also increases tumorigenicity of DU-145 prostate epithelial cells. Although Nox1 modestly stimulates cell division in both fibroblasts and epithelial cells, an increased mitogenic rate alone did not account fully for the marked tumorigenicity. Herein, we show that Nox1 is a potent trigger of the angiogenic switch, increasing the vascularity of tumors and inducing molecular markers of angiogenesis. Vascular endothelial growth factor (VEGF) mRNA becomes markedly up-regulated by Nox1 both in cultured cells and in tumors, and VEGF receptors (VEGFR1 and VEGFR2) are highly induced in vascular cells in Nox1-expressing tumors. Matrix metalloproteinase activity, another marker of the angiogenic switch, also is induced by Nox1. Nox1 induction of VEGF is eliminated by coexpression of catalase, indicating that hydrogen peroxide signals part of the switch to the angiogenic phenotype.
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PMID:Reactive oxygen generated by Nox1 triggers the angiogenic switch. 1180 26

This study examined the effect of acute cadmium on stress-related gene expression and free radical production in wild-type and metallothionein-I/II-null (MT-null) mice. Atlas Toxicology arrays showed that acute cadmium (40 micromol/kg as CdCl(2), ip for 3 h) markedly increased the expression of genes encoding heat-shock proteins, heme oxygenase-1, and genes in response to DNA damage/repair. The expression of genes encoding cytochrome P450 enzymes, UDP-glucuronosyltransferases, Mn-superoxide dismutase, and catalase was suppressed by cadmium. MT-null mice were more sensitive than wild-type mice to cadmium-induced, stress-related gene expression, in accord with greater activation of transcription factor AP-1 and phosphorylated JNK and ERK. To evaluate free radical production, mice were simultaneously given the spin trap agent, N-tert-butyl-alpha-phenylnitrone (PBN, 250 mg in DMSO/kg, ip) with cadmium, and livers were removed 30 min later for PBN-trapped radical extraction with chloroform:methanol (2:1), and detected with electron spin resonance (ESR). Cadmium treatment caused detectable ESR signals for PBN adducts as well as lipid peroxidation in the liver similarly in both wild-type and MT-null mice. Thus, the mechanism of acute cadmium toxicity involves multiple facets including oxidative damage and aberrant gene expression, and absence of MT exacerbates Cd-induced aberrant gene expression.
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PMID:Acute cadmium exposure induces stress-related gene expression in wild-type and metallothionein-I/II-null mice. 1195 53

Reactive oxygen species released during the respiratory burst are known to participate in cell signaling. Here we demonstrate that hydrogen peroxide produced by the respiratory burst activates AP-1 binding. Stimulation of the macrophage cell line NR8383 with respiratory burst agonists ADP and C5a increased AP-1 binding activity. Importantly, this increase in binding was blocked by catalase, confirming mediation by endogenous H(2)O(2). Moreover, exogenously added H(2)O(2) mimicked the agonists, and also activated AP-1. Antibodies revealed that the activated AP-1 complex is composed predominantly of c-Fos/c-Jun heterodimers. Treatment of the cells with ADP, C5a and H(2)O(2) (100 microM) all increased the phosphorylation of c-Jun. c-Fos protein was increased in cells treated with C5a or high dose (200 microM) H(2)O(2), but not in cells treated with ADP. The MEK inhibitor, PD98059, partially blocked the C5a-mediated increase in AP-1 binding. A novel membrane-permeable peptide inhibitor of JNK, JNKi, also inhibited AP-1 activation. Together these data suggest that C5a-mediated AP-1 activation requires both the activation of the ERK and JNK pathways, whereas activation of the JNK pathway is sufficient to increase AP-1 binding with ADP. Thus, AP-1 activation joins the list of pathways for which the respiratory burst signals downstream events in the macrophage.
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PMID:AP-1 activation through endogenous H(2)O(2) generation by alveolar macrophages. 1205 68

Oxidative stress in the human brain has been strongly implicated as the cause of neuronal cell losses in Alzheimer's disease patients, but the exact mechanism still remains unknown. In this report several oxidative stress parameters and an associated signalling transduction cascade predating neuronal cell death in cultures treated with the oxidative stressors Fe(2+) (5 microm) and the amyloid beta (A beta(1-40)) peptide (5 microm) were studied. Production of reactive oxygen species as detected by dichlorofluorescein staining was apparent within 5 min in the presence of both agents. Lipid peroxide content increased by approximately 10-fold after 2 h, while mitochondrial activity was impaired by 40% after 6 h. Caspase-3 activity was elevated 5-6 fold, all indicative of oxidative cell stress. The combined presence of A beta(1-40) and Fe(2+) resulted in a rapid (5 min) ERK activation followed by a decline by 30 min and a second activation that continued up to 24 h when nuclear translocation was noticed. Neither treatment with Fe(2+) nor that with A beta(1-40) alone caused similar changes. Addition of either deferroxamine (DFe, 25 microm), catalase (0.4 mg/mL) or N-acetyl cysteine (0.5 mm) - the last two known as suppressants of oxidative stress - attenuated ERK activation and nuclear translocation. The mitogen-activated protein/ERK kinase (MEK) inhibitor U0126 blocked ERK and caspase 3 activation, suppressed ERK translocation and reduced the number of apoptotic cells, suggesting a central role for the ERK signalling cascade in A beta(1-40) plus Fe(2+) (A beta(1-40)/Fe(2+)) -induced apoptotic death. The full peptide A beta(1-42) was very effective at 0.5 microm while the inverse peptide A beta(40-1) at 5 microm was ineffective. The acetyl-amyloid-beta protein amide fragment 15-20 (V-pep) known to be an A beta aggregation inhibitor, prevented A beta(1-40)/Fe(2+)-induced toxicity. These findings indicate that metal ions chelators and antioxidants suppress the A beta(1-40)/Fe(2+)-induced oxidative stress cascade and may be beneficial in reducing the severity of Alzheimer's disease.
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PMID:ERK activation and nuclear translocation in amyloid-beta peptide- and iron-stressed neuronal cell cultures. 1215 30

We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231 cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N-Acetylcysteine and ebselen (but not other antioxidants such as diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and p38 MAPK activation. The intracellular level of GSH affected Aplidin action; pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably, Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is highly refractory to chemotherapy. These data provide a molecular basis for the anticancer activity of Aplidin.
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PMID:Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. 1241 12

A better understanding of cellular mechanisms that occur in Parkinson's disease and related Lewy body diseases is essential for development of new therapies. We previously found that 6-hydroxydopamine (6-OHDA) elicits sustained extracellular signal-regulated kinase (ERK) activation that contributes to neuronal cell death in vitro. As subcellular localization of activated kinases affect accessibility to downstream targets, we examined spatial patterns of ERK phosphorylation in 6-OHDA-treated cells and in human postmortem tissues representing the full spectrum of Lewy body diseases. All diseased human cases exhibited striking granular cytoplasmic aggregates of phospho-ERK (P-ERK) in the substantia nigra (involving 28 +/- 2% of neurons), which were largely absent in control cases (0.3 +/- 0.3%). Double-labeling studies and examination of preclinical cases suggested that these P-ERK alterations could occur relatively early in the disease process. Development of granular cytoplasmic P-ERK staining in 6-OHDA-treated cells was blocked by neuroprotective doses of catalase, supporting a role for oxidants in eliciting neurotoxic patterns of ERK activation. Evidence of nuclear translocation was not observed in degenerating neurons. Moreover, granular cytoplasmic P-ERK was associated with alterations in the distribution of downstream targets such as P-RSK1, but not of P-Elk-1, suggesting functional diversion of ERK-signaling pathways in Lewy body diseases.
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PMID:Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. 1246 25

Reactive oxygen species such as hydrogen peroxide (H(2)O(2)) have taken center stage as bona fide second messengers in various signaling pathways. Here, we report the synthesis, metabolic fate, and effectiveness in modulating such pathways of a Tat-catalase conjugate. Incubation of L2 cells with Tat-catalase greatly increased cell-associated enzymatic activity, reaching close to a plateau by 30 min. The cell-associated catalase activity and antibody-detectable Tat-derivatives declined over time after changing medium, although still remaining at significantly higher levels than baseline even at 4h. While most cell-associated Tat-catalase was apparently tightly attached to the cell surface, a small fraction entered the cells as the proteasome inhibitor MG-132 slightly prevented the disappearance of the enzyme. Tat-catalase, either membrane-bound or intracellular, but not native catalase, inhibited serum-induced Elk phosphorylation and anisomycin- and/or MG-132-induced ERK phosphorylation, suggesting the involvement of H(2)O(2). Thus, Tat-catalase should be a useful tool to dissect H(2)O(2)-dependent events in signaling pathways.
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PMID:Bio-effectiveness of Tat-catalase conjugate: a potential tool for the identification of H2O2-dependent cellular signal transduction pathways. 1264

Ultraviolet irradiation of mammalian cells induces several events that include activation of growth factor receptors and triggering of signal transduction pathway. Most of the UV responses are mediated by the production of reactive oxygen species (ROS) and can be blocked by antioxidants. In this study, we analysed the effect of UVB irradiation at physiologic doses and that of the pro-oxidant agent cumene hydroperoxide (CUH) on the activation of the receptor for keratinocyte growth factor (KGF), a key mediator of epithelial growth and differentiation. Exposure to both UVB (30-150 mJ/cm(2)) and CUH (200 microM of NIH3T3 KGFR (KGF receptors) transfectants caused a rapid tyrosine phosphorylation and activation of KGFR similar to that induced by KGF, and internalization of the activated receptor. The KGFR expression appeared unmodified by the treatments. Ultrastructural observations of both UVB- and CUH-treated cells showed a normal morphology of the plasma membranes and intracellular organelles. The antioxidant N-acetylcysteine inhibited UVB-induced receptor phosphorylation. The generation of an intracellular oxidative stress was detected as a decrease of catalase activity and of vitamin E, and reduced glutathione levels, whereas superoxide dismutase activity was not significantly modified. A peroxidation of polyunsaturated fatty acids of cell membranes was observed after both treatments, associated with the intracellular oxidative stress. Similar biochemical events were observed on NIH3T3 untransfected control cells, suggesting that KGFR activation follows intracellular generation of ROS and is not associated with a scavenging effect. Taken together our results demonstrate that exposure to UVB and to oxidant stimuli induces a rapid intracellular production of ROS, which in turn are capable of triggering KGFR activation and internalization, similar to those induced by KGF.
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PMID:UVB-induced activation and internalization of keratinocyte growth factor receptor. 1271 19

The inducible form of heme oxygenase (HO-1) is increased during oxidative injury, and this may be an important defense mechanism against such injury. Cytochrome P450 2E1 (CYP2E1) generates reactive oxygen species and promotes lipid peroxidation. In this study induction of HO-1 by CYP2E1 and the possible role of mitogen-activated protein kinase (MAPK) in this process were evaluated. HO-1 induction was observed in the livers of chronic alcohol-fed mice or pyrazole-treated rats, conditions known to elevate CYP2E1 levels. Increased levels of HO-1 were observed in HepG2 cells overexpressing CYP2E1 (E47 cells) compared with control HepG2 cells or HepG2 cells expressing CYP3A4. Expression of CYP2E1 in HepG2 cells transcriptionally activated the HO-1 gene, increasing HO-1 mRNA and protein expression and activity of a HO-1 reporter construct. CYP2E1 inhibitors and catalase blocked the increased production of reactive oxygen species as well as HO-1 induction. Increasing oxidative stress by the addition of arachidonic acid or depletion of glutathione further increased HO-1 induction. The phosphorylated form of ERK MAPK but not that of p38 or JNK MAPK was increased in E47 cells compared with the control C34 HepG2 cells. PD98059, a specific inhibitor of ERK MAPK, blocked the activity of a HO-1 reporter in E47 cells but not in C34 cells. These results suggest that increased CYP2E1 activity leads to induction of the HO-1 gene, and the ERK MAPK pathway is important in mediating this process. This induction may serve as an adaptive mechanism to protect the E47 cells against the CYP2E1-dependent oxidative stress.
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PMID:Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway. 1277 98


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