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)

A number of phenotypes persist in the progeny of irradiated cells for many generations including delayed reproductive death, cell transformation, genomic instability, and mutations. It appears likely that persistent phenotypes are inherited by an epigenetic mechanism, although very little is known about the nature of such a mechanism or how it is established. One hypothesis is that radiation causes a heritable increase in oxy-radical activity. In the present study, intracellular levels of reactive oxygen species (ROS) in human lymphoblast clones derived from individually X-irradiated cells were monitored for about 55 generations after exposure. A number of clones derived from irradiated cells had an increase in dichlorofluorescein (DCF) fluorescence at various times. Cells with abrogated TP53 expression had a decreased oxidant response. Flow cytometry analysis of clones with increased fluorescence did not detect increases in the sub-G(1) fraction or decreased cell viability compared to nonirradiated clones, indicating that increased levels of apoptosis and cell death were not present. The oxidative stress response protein heme oxygenase 1 (HO1) was induced in some cultures derived from X-irradiated cells but not in cultures derived from unirradiated cells. The expression of the dual specificity mitogen-activated protein (MAP) kinase phosphatase (MPK1/CL100), which is inducible by oxidative stress and has a role in modulating ERK signaling pathways, was also increased in the progeny of some irradiated cells. Finally, there was an increase in the phosphorylated tyrosine content of a prominent protein band of about 45 kDa. These results support the hypothesis that increased oxy-radical activity is a persistent effect in X-irradiated mammalian cells and further suggest that this may lead to changes in the expression of proteins involved in signal transduction.
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PMID:Increases in oxidative stress in the progeny of X-irradiated cells. 1544 41

Diallyl sulfide (DAS), is protective against chemically induced heptotoxicity, mutagenesis, and carcinogenesis. The mechanism of its protective effects is not fully understood. In this study, we found that DAS can induce the expression of heme oxygenase-1 (HO-1), which plays a critical role in the cell defense system against oxidative stress. DAS causes a dose- and time-dependent increase of HO-1 protein and mRNA level without toxicity in HepG2 cells. DAS-induced HO-1 protein expression is dependent on newly synthesized mRNA and newly synthesized protein. DAS increases Nrf2 protein expression, nuclear translocation, and DNA-binding activity. The MAP kinase ERK is activated by DAS. Both ERK and p38 pathways play an important role in DAS-induced Nrf2 nuclear translocation and ho-1 gene activation. DAS stimulates a transient increase of reactive oxygen species (ROS). N-Acetyl-cysteine blocked this increase of ROS production as well as DAS-induced ERK activation, Nrf2 protein expression and nuclear translocation, and ho-1 gene activation. The increase in HO-1 produced by DAS protected the HepG2 cells against toxicity by hydrogen peroxide or arachidonic acid. These results suggest that DAS induces ho-1 through production of ROS, and Nrf2 and MAPK (ERK and p38) mediate this induction. Induction of ho-1 may play a role in the protective effects of DAS.
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PMID:Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. 1554 64

Hemin is a strong inducer of heme oxygenase-1 (HO-1) expression in vitro and in vivo. Whereas moderate overexpression of HO-1 is protective against oxidative stress, uncontrolled levels of HO-1 can be detrimental. Therefore, we evaluated the effects of apigenin (APG), a flavonoid involved in a number of phosphorylation pathways and also known to inhibit inducible genes, such as iNOS and COX-2, on HO-1 expression. Incubation of mouse embryonic fibroblasts with APG (5--40 microM) decreased hemin-induced HO-1 protein and mRNA expression. APG also reduced the induction of HO-1 promoter activity, as assessed by bioluminescence imaging, in NIH3T3 cells transfected with the 15-kb HO-1 promoter fused with the reporter gene luciferase (HO-1-luc). Furthermore, through the use of specific inhibitors, APG's effect was found to be unrelated to its PKC, CK 2, PI 3 K, p38, or ERK inhibitory activities. Quercetin (10--40 microM), also a flavonoid, also inhibited hemin-induced HO-1 expression. Additionally, in vivo studies using HO-1-luc transgenic mice showed that APG (50 mg/kg) decreased hemin-induced HO activity and HO-1 protein expression in the liver. These results suggest that hemin-induced HO-1 expression can be attenuated by flavonoids, such as APG.
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PMID:Apigenin decreases hemin-mediated heme oxygenase-1 induction. 1610 1

Heme oxygenase 1 (HO-1) catalyses the oxidation of heme to biliverdin, and its expression is induced by oxidative stress. This study was aimed at assessing the role of metabolic polymorphisms (CYP1A1, CYP1B1, GSTM1, GSTP1, EPHX) in the modulation of HO-1 gene expression in 37 foundry workers. Blood and urine samples were obtained at the beginning (BS) and at the end (ES) of work shift, in February (T1) and June (T2). Urinary 1-hydroxypyrene (1-OHP) was measured as a tracer of PAH exposure. HO-1 gene expression in ES samples normalized to BS values (HO-1 ES/BS) was higher at T2 respect to T1. HO-1 gene induction was related to ES 1-OHP when considering either T2 samples or the combination of the two samplings. HO-1 ES/BS was significantly increased in subjects with at least a mutant allele for GSTP1 as compared to subjects with GSTP1AA genotype (1.23 +/- 0.002 vs 0.88 +/- 0.002, p < 0.05). Only in subjects with at least one vari.nt allele for GSTP1, a positive correlation between HO-1 ET/IT expression and 1-OHP FT levels was observed (r2 = 0.21, p = 0.016). The present study demonstrates a correlation between PAH exposure, as assessed by urinary 1-OHP, and the induction of HO-1 expression. Such a correlation seems to be limited to subjects bearing variant alleles for GSTP1. At the same exposure levels, these subjects showed a greater expression of HO-1 FT as compared to subjects with GSTP1 wild type genotype, possibly due to a higher oxidative stress in the subjects expressing the mutant GSTP1-1 isoform, which could imply a limited scavenging capacity.
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PMID:[Heme oxygenase 1 expression in foundry workers]. 1624 May 85

Hemin is an oxidant that accumulates in intracranial hematomas. Its neurotoxicity is increased by its breakdown, which is catalyzed by the heme oxygenase (HO) enzymes. In this study we tested the hypothesis that inhibiting signaling events mediating HO-1 induction would protect cultured cortical neurons from hemin. A fivefold increase in HO-1 expression was observed in mixed neuron-astrocyte cultures 4h after hemin exposure. This was markedly reduced by the ERK pathway inhibitor U0126. The JNK inhibitor SP600125 had a weak but statistically significant effect, while the p38 inhibitor SB239063 was ineffective. Hemin neurotoxicity, as assessed by LDH release, propidium iodide staining, and malondialdehyde assay, was also prevented by U0126 but not by SB239063; SP600125 had little or no effect. Consistent with reduced iron release, ferritin expression was also attenuated by U0126, while cell hemin accumulation was increased. These results suggest that targeting the ERK pathway may prevent HO-1 induction in response to hemin, and reduce neuronal injury.
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PMID:Inhibition of the ERK/MAP kinase pathway attenuates heme oxygenase-1 expression and heme-mediated neuronal injury. 1644 26

The molecular mechanisms involved in modulation of the antioxidant cell defence by survival signals remain largely unexplored. Here, we report a mechanistic connection between the survival signal elicited by nerve growth factor (NGF) and the antioxidant cell defence represented by heme oxygenase-1 (HO-1) at the level of a newly identified Sp1 site in the human ho1 proximal promoter. By using luciferase reporter constructs we identified a PI3K-responsive region containing a GC-box that resembled the response element for Sp1. Indeed, transfection of Sp1-deficient SL2 cells, electrophoretic mobility shift assays, the use of the GC-box binding drug mithramycin, and mutation of the GC-box provided evidence for a Sp1-like site in the PI3K-sensitive region. Then, we observed with the use of a Sp1-Gal4 chimera that PI3K regulates the transactivating capacity of Sp1. Cotransfection of active PI3K and PKC-zeta expression vectors resulted in substantial increase of Sp1 phosphorylation and in synergistic activation of both Sp1-Gal4 and endogenous Sp1. Moreover, these effects were mimicked by cotransfection of active MEK and ERK expression vectors and were blocked by the MEK inhibitor PD98059. Inhibition of HO-1 with Sn protoporphyrin IX and blockage of Sp-1-mediatied upregulation of HO-1 with mithramycin attenuated antioxidant and cytoprotective functions of NGF against hydrogen peroxide. This study elucidates how NGF contributes to protection of target cells against oxidative stress.
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PMID:Regulation of heme oxygenase-1 gene expression through the phosphatidylinositol 3-kinase/PKC-zeta pathway and Sp1. 1681 5

In the present study, we examined the protective mechanism of baicalein (BE) and its glycoside, baicalin (BI), on hydrogen-peroxide (H(2)O(2))-induced cell death in rat glioma C6 cells. Results of the MTT assay, LDH release assay, and morphological observation showed that H(2)O(2) addition reduced the viability of C6 cells, and this was prevented by the addition of BE but not BI. Incubation of C6 cells with BE significantly decreased the intracellular peroxide level induced by H(2)O(2) according to flow cytometric analysis using DCHF-DA as a fluorescent substrate. Suppression of H(2)O(2)-induced apoptotic events including DNA ladders, hypodiploid cells, and activation of caspases 3, 8, and, 9 by BE but not BI was identified in C6 cells. The cytotoxicity and phosphorylation of ERK proteins induced by H(2)O(2) were blocked by the ERK inhibitor PD98059. Catalase addition prevented H(2)O(2)-induced ROS production, ERKs protein phosphorylation, and cell death, and BE dose-dependently inhibited H(2)O(2)-induced ERK protein phosphorylation in C6 cells. These data suggest that ROS-scavenging activity is involved in BE prevention of H(2)O(2)-induced cell death via blocking ERKs activation. Additionally, BE but not BI induced heat shock protein 32 (HSP32; HO-1) protein expression in both time- and dose-dependent manners, but not heme oxygenase 2 (HO-2), heat shock protein 70 (HSP70), or heat shock protein 90 (HSP90) protein expression. In the absence of H(2)O(2), BE induces ERKs protein phosphorylation, and HO-1 protein expression induced by BE was blocked by the addition of cycloheximide, actinomycin D, and the ERK inhibitor PD98059. The addition of the HO inhibitor ZnPP inhibited the protective effect of BE against H(2)O(2)-induced cytotoxicity in C6 cells according to the MTT assay and apoptotic morphology under microscopic observation, accompanied by blocking the ROS-scavenging activity of BE in C6 cells. However, BE treatment was unable to protect C6 cells from C2-ceramide-induced cell death. These data indicate that BE possesses abilities to inhibit ROS-mediated cytotoxic effects through modulation of ERKs activation and induction of HO-1 protein expression. The role of HO-1 in ROS-scavenging activity of BE is proposed.
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PMID:Baicalein inhibition of oxidative-stress-induced apoptosis via modulation of ERKs activation and induction of HO-1 gene expression in rat glioma cells C6. 1681 38

Chronic arsenic exposure of rat liver epithelial TRL1215 cells induced malignant transformation in a concentration-dependent manner. To further define the molecular events of these arsenic-transformed cells (termed CAsE cells), gene expressions associated with arsenic carcinogenesis or influenced by methylation were examined. Real-time RT-PCR showed that at carcinogenic concentrations (500 nM, and to a less extent 250 nM of arsenite), the expressions of alpha-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), c-jun, c-myc, H-ras, c-met and hepatocyte growth factor, heme oxygenase-1, superoxide dismutase-1, glutathione-S-transferase-pi and metallothionein-1 (MT) were increased between 3 to 12-fold, while expressions of insulin-like growth factor II (IGF-II) and fibroblast growth factor receptor (FGFR1) were essentially abolished. These changes were not significant at the non-carcinogenic concentration (125 nM), except for IGF-II. The positive cell-cycle regulators cyclin D1 and PCNA were overexpressed in CAsE cells, while the negative regulators p21 and p16 were suppressed. Western-blot confirmed increases in AFP, WT-1, cyclin D1 and decreases in p16 and p21 protein in CAsE cells. The CAsE cells over-expressed MT but the demethylating agent 5-aza-deoxycytidine (5-aza-dC, 2.5 microM, 72 h) stimulated further MT expression. 5-Aza-deoxycytidine restored the loss of expression of p21 in CAsE cells to control levels, but did not restore the expression of p16, IGF-II, or FGFR1, indicating the loss of expression of these genes is due to factors other than DNA methylation changes. Overall, an intricate variety of gene expression changes occur in arsenic-induced malignant transformation of liver cells including oncogene activation and alterations in expression of genes critical to growth regulation.
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PMID:Further studies on aberrant gene expression associated with arsenic-induced malignant transformation in rat liver TRL1215 cells. 1687 16

Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclerosis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experiments using chimeric mice expressing ALS-linked mutations to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuronal cell types on disease phenotype. When perturbed by primary neuronal damage, e.g. expression of SOD-1 mutations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the receptor FGFR1. FGF-1 stimulates nerve growth factor (NGF) expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Nrf2 leads to the expression of antioxidant and cytoprotective enzymes such as heme oxygenase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neurotrophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astrocytes may be a mechanism to eliminate critically damaged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role.
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PMID:Complexity of astrocyte-motor neuron interactions in amyotrophic lateral sclerosis. 1690 19

Proteinuria contributes to chronic kidney disease by stimulating renal tubular epithelial cells to produce cytokines such as monocyte chemoattractant protein-1 (MCP-1). The present study determined whether cellular overexpression of heme oxygenase-1 (HO-1) can influence albumin-stimulated MCP-1 production. In response to bovine serum albumin, NRK-52E cells constitutively overexpressing HO-1 (HO-1 OE cells) exhibit less induction of MCP-1 mRNA and less production of MCP-1 protein compared with similarly treated, control NRK-52E cells (CON cells). In wild-type NRK-52E cells, and under these conditions, we demonstrate that the induction of MCP-1 is critically dependent on intact NF-kappaB binding sites in the MCP-1 promoter. In response to albumin, CON cells exhibit activation of NF-kappaB, and this is reduced in HO-1 OE cells. Albumin also activates ERK1/2 and increases ERK activity, both of which are exaggerated in HO-1 OE cells. Studies with an inhibitor of MAPK/ERK kinase (U0126) demonstrate that the inhibitory effects of U0126 on MCP-1 production are attenuated in HO-1 OE cells. We conclude that HO-1 overexpression in the proximal tubule reduces MCP-1 production in response to albumin, and this occurs, at least in part, by inhibiting an ERK-dependent, NF-kappaB-dependent pathway at a site that is distal to the activation of ERK. These findings suggest that the induction of HO-1 in the proximal tubule, as occurs in chronic kidney disease, may be a countervailing response that reduces albumin-stimulated production of cytokines such as MCP-1.
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PMID:Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease. 1696 90


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