Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

H2O2, like other oxidants, is known to act as a mitogen at low concentrations in resting Balb/3T3 or mouse epidermal JB6 cells. We described previously that H2O2 induces some early response genes in Balb/3T3 cells. We extended these observations using another cell line, MC3T3 (mouse osteoblastic) cells by examination of transcriptional activity of these genes and by using inhibitors of protein kinases. H2O2 increased the expressions of c-fos, c-jun, egr-1 and JE genes which are known to be early response genes and are induced by mitogenic stimuli in many types of cells. Exogenous addition of H2O2 increased the mRNA levels of these genes, the kinetics of increase being similar to those of their inductions by a phorbol ester or serum. Nuclear run-on transcription showed that this induction occurred at the transcriptional level. H2O2 at 0.1-0.2 mM induced maximal expressions of c-fos and c-jun, whereas 0.3 mM H2O2 was required for induction of stress-induced heme oxygenase mRNA. The inductions of c-fos and c-jun were inhibited by 50 microM H7, a protein kinase inhibitor that is relatively specific for protein kinase C, but were not affected by H9, relatively specific for cAMP-dependent protein kinase. In cells pretreated with 12-O-tetradecanoylphorbol 13-acetate, however, in which protein kinase was supposed to be downregulated, H2O2 induced c-fos and heme oxygenase as efficiently as in untreated cells. H2O2 did not increase the phosphorylation of p80 protein, which is known to be a substrate for protein kinase C. Thus, H2O2 seemed to induce c-fos and c-jun by activating protein kinases distinct from protein kinase C. Activity of the chloramphenicol acetyltransferase gene under control of the serum-response element of human c-fos genes was increased by H2O2 treatment, whereas that under control of cAMP-response element was not affected. These results indicate that the inductions by H2O2 of c-fos and possibly other early response genes are mediated through activation of the serum-response element in their enhancer.
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PMID:Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. 191 80

Post-ischaemic reperfusion increases the level of the major heat-shock (stress) protein hsp 70 and of its mRNA by transcriptional mechanisms, and activates the binding of the heat-shock factor HSF to the consensus sequence HSE. In common with CoCl2 treatment, post-ischaemic reperfusion increases the level of haem oxygenase mRNA, an indicator of oxidative stress, but CoCl2 does not seem to induce the expression of the hsp 70 gene [Tacchini, Schiaffonati, Pappalardo, Gatti and Bernelli-Zazzera (1993) Lab. Invest. 68, 465-471]. Starting from these observations, we have now studied the expression of two genes of the hsp 70 family and of other possibly related genes under conditions of oxidative stress. Three different chemicals, which cause oxidative stress by various mechanisms and induce haem oxygenase, enhance the expression of the cognate hsc 73 gene, but do not activate the inducible hsp 70 gene. Expression of the other genes that have been studied seems to vary in intensity and/or time course, in relation to the particular mechanism of action of any single agent. The pattern of induction of the early-immediate response genes c-fos and c-jun observed during oxidative stress differs from that found in post-ischaemic reperfused livers. Oxidative-stress-inducing agents do not promote the binding of HSF to its consensus sequence HSE, such as occurs in heat-shock and post-ischaemic reperfusion, and fail to activate AP-1 (activator protein 1). With the possible exception of Phorone, the oxidative stress chemically induced in rat liver activates NFkB (nuclear factor kB) and AP-2 (activator protein 2) transcription factors.
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PMID:Differential activation of heat-shock and oxidation-specific stress genes in chemically induced oxidative stress. 762 9

Kainic acid-induced seizures in the rat brain cause severe brain damage that is thought to result, in part, from oxidative stress. In this study, we examine the consequences of systemic administration of kainic acid on expression of several genes that encode proteins thought to play roles in protection from oxidative stress, including metallothionein-I, and -III. Kainic acid causes an increase in metallothionein-I and heme oxygenase-I mRNAs, as well as an increase in c-fos, heat shock protein-70, and interleukin-1 beta mRNAs. The induction of these mRNAs is seizure dependent, and is greater in brain areas with extensive damage (e.g. piriform cortex) than in areas with minimal damage (e.g. frontal cortex and cerebellum). In contrast, little or no change in mRNA for metallothionein-III, manganese superoxide dismutase, copper-zinc superoxide dismutase, glutathione-s-transferase ya subunit or glutathione peroxidase occur. The prolonged and robust concordant induction of the metallothionein-I and heme oxygenase-I genes may reflect the oxidative stress produced by kainic acid-induced seizures. In addition, the induction of interleukin-1 beta gene expression suggests an inflammatory response in brain regions damaged by kainic acid-induced seizures. Delineating the regulation of genes associated with oxidative and inflammatory responses can contribute to a fuller understanding of seizures and associated brain damage.
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PMID:Temporalspatial patterns of expression of metallothionein-I and -III and other stress related genes in rat brain after kainic acid-induced seizures. 765 48

Asbestos fibers cause dose-dependent, persistent increases in mRNA levels of c-jun and c-fos proto-oncogenes in rat pleural mesothelial (RPM) cells, the progenitor cells of asbestos-induced mesothelioma (N. Heintz, Y. M. W. Janssen, and B. T. Mossman. Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993). Here we report that addition of N-acetyl-L-cysteine decreases asbestos-mediated induction of c-fos and c-jun mRNA levels in a dose-dependent fashion. Exposure of RPM cells to asbestos causes depletion of total cellular glutathione, a response that can be abolished by pretreatment with N-acetyl-L-cysteine. Pretreatment of cells with buthionine sulfoximine, an agent which diminishes glutathione pools, increases the magnitude of induction of c-fos and c-jun mRNA by asbestos. To determine whether asbestos-induced effects on proto-oncogene expression could be attributed to extracellular generation of active oxygen species (AOS), RPM cells were exposed to H2O2 or xanthine and xanthine oxidase, a generating system of AOS. These oxidant stresses did not decrease cellular glutathione levels nor alter mRNA levels of c-fos or c-jun. However, increased mRNA levels of manganese-containing superoxide dismutase and heme oxygenase were observed, indicating that RPM cells respond to AOS by increased expression of genes encoding antioxidant enzymes. These data indicate that the signaling pathways leading to c-fos/c-jun proto-oncogene induction by asbestos are not triggered directly by formation of extracellular AOS. However, intracellular thiol levels appear to influence the expression of c-fos and c-jun, suggesting a redox-sensitive component in the signaling cascade which modulates gene expression of c-fos and c-jun by asbestos.
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PMID:Induction of c-fos and c-jun proto-oncogene expression by asbestos is ameliorated by N-acetyl-L-cysteine in mesothelial cells. 774 7

We have explored the mechanisms involved in the induction of five stress-response genes (heme oxygenase [HO], c-fos, Egr-1, gadd153, and HSP70) in human diploid fibroblasts growth-arrested by treatment with the antiproliferative prostaglandin A2 (PGA2). The kinetics of c-fos and Egr-1 induction were found to be rapid with maximum expression occurring within 60 min of treatment, whereas maximum expression of HO, gadd153, and HSP70 occurred between 4 and 8 h of treatment. Nuclear run-on assays and measurements of mRNA clearance in the presence of actinomycin D demonstrated that increases in both the rates of gene transcription and/or mRNA stability contribute to the genetic response to PGA2. Although the mechanisms responsible for increasing the mRNA levels differ for the individual genes, additional experiments provided evidence that alterations in intracellular calcium ([Ca2+]i) levels were important in initiating the genetic response to PGA2. PGA2 treatment resulted in a rapid increase in [Ca2+]i with the dose-response relationship for Ca2+ mobilization consistent with that seen for the induction of all five genes. [Ca2+]i chelators that attenuate Ca2+ mobilization by PGA2 also blocked the mRNA induction by PGA2 treatment. Density-inhibited confluent cells were less responsive than proliferating subconfluent cells with respect to Ca2+ mobilization after PGA2 treatment. This was correlated with a lower level of gene induction. These studies support the hypothesis that increased Ca2+ mobilization is an early and central event in the signal transduction pathway (or pathways) mediating the activation of genes in response to PGA2 treatment.
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PMID:Calcium mediates expression of stress-response genes in prostaglandin A2-induced growth arrest. 792 70

The expression of hsp70-the inducible member of the corresponding heat shock gene family-of the oxidative stress marker gene heme oxygenase (HOx), and of the immediate early response genes c-fos and c-jun has been studied in FAO hepatocarcinoma cells depleted of polyamines and exposed to heat shock. Depletion of polyamines was obtained in short-term experiments (24-48 hours) by the use of alpha difluoromethylornithine (DFMO), a classical inhibitor of ornithine decarboxylase (ODC), or of the combination of the newly available inhibitors of ODC and S-adenosylmethionine decarboxylase, i.e., (2R,5R)-hept-6-yne-2,5-diamine (MAP) and 5'{[(Z)-4-aminobut-2-enyl]methylanino}-5-deoxyadeno-si ne (AbeAdo). Under our experimental conditions polyamine imbalance was realized without appreciable growth-related genes. Decreases of putrescine and spermidine 48 hours after DFMO prevented the induction of hsp70 messenger RNA (mRNA), whereas depletion spermidine and spermine obtained with MAP/AbeAdo decreased intensity and duration of post-heat shock accumulation of hsp70 mRNA. Inductions of HOx, c-jun and c-fos were also inhibited. Because MAP/AbeAdo caused also an intracelluar accumulation of putrescine, we tested the effect of exogenous putrescine, which was found to stabilize the mRNAs for hsp70 and c-jun. Hsp70 and HOx are thought to play a protective role, and the proteins of c-jun and c-fos constitute the transcription factor activator protein-1, which is involved in the transcription of many defensive products. Therefore, the integrity of polyamine pool seems to be a necessary permissive condition for an effective response of the cells to adverse environmental changes.
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PMID:Effects of polyamine imbalance on the induction of stress genes in hepatocarcinoma cells exposed to heat shock. 870 55

Previous studies have shown that exposure of Swiss 3T3 cells to mainstream cigarette smoke (CS) trapped in phosphate-buffered saline (smoke-bubbled PBS) resulted in the expression of stress response genes, i.e. haem oxygenase and c-fos, partial inhibition of protein phosphatases 1 and 2A, as well as partial depletion of the cellular glutathione (GSH) pool. Using c-fos gene expression in Swiss 3T3 cells as an indicator for a cellular response against oxidative stress, the following observations are consistent with peroxynitrite as an active principal formed by CS in aqueous solutions: (i) sustained c-fos expression was obtained for smoke-bubbled PBS, peroxynitrite itself and a compound known to stoichiometrically release superoxide and nitric oxide (NO) (3-morpholino-sydnonimine, SIN-1); (ii) c-fos expression in cells exposed to aqueous smoke fractions was inhibited by either the superoxide-scavenging enzyme superoxide dismutase (SOD), in combination with catalase, or the NO-scavenger oxyhaemoglobin (HbO2); and (iii) activation of guanylate cyclase in rat lung cells was observed only when bubbling was performed with filtered smoke and with whole smoke in the presence of SOD/catalase. These results are consistent with a rapid NO-consuming reaction coupled with superoxide-generating properties of the particulate phase of CS. Moreover, (iv) the half-life of the c-fos-inducing activity in smoke-bubbled PBS was found to be <1 h which can be explained by a sustained peroxynitrite formation. Finally, depletion of intracellular thiol levels by smoke-bubbled PBS appears to favour the activation of a redox-sensitive component of the c-fos-inducing pathway.
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PMID:Evidence for peroxynitrite as an oxidative stress-inducing compound of aqueous cigarette smoke fractions. 905 21

In the liver, CCl4 induces cell necrosis followed by regeneration. Cell injury is caused by free radical damage and may be due, at least in part, to oxidative stress and the subsequent formation of reactive oxygen intermediates (ROIs). In a rat model of acute CCl4-induced hepatic injury, we examined the expression of genes involved in cellular response to different kinds of stress, including oxidative stress (hsp 70 family, heme oxygenase), in free radical detoxification (Mn superoxide dismutase and Cu/ Zn superoxide dismutase), in iron homeostasis (H and L ferritin subunits) and in the cell cycle (c-fos, c-jun, histone H3). As an experimental approach, we first analysed the pattern of protein synthesised by liver slices in vitro. Then we studied the mechanisms regulating the expression of different genes, by analysing both mRNA steady state levels and transcription rates. Activation of the specific heat shock transcription factor (HSF) by CCl4 was also investigated. We observed that different members of the hsp70 family (hsp70, hsc73, grp78) are activated by different kinetics and are regulated mainly at the transcriptional level. Induction of the hsp70 gene occurs rapidly and transiently and is preceded by the activation of HSF DNA-binding activity. We demonstrated an increase in the steady-state levels of mRNAs for heme oxygenase, Mn and Cu/Zn superoxide dismutases and H and L ferritin subunits. However, different kinetics and regulatory mechanisms occurred with different genes. We showed that induction of c-fos and c-jun protooncogenes is the earliest event after CCl4 administration, whereas histone H3 expression peaked at 24-48 h. The results of this study are interpreted as evidence that activation of specific stress response genes is primarily related to the defence against the rapidly occurring cell damage, but may also be related to subsequent processes of tissue inflammation and cell proliferation.
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PMID:Gene expression in liver after toxic injury: analysis of heat shock response and oxidative stress-inducible genes. 929 88

Mainstream cigarette smoke (CS) trapped in phosphate-buffered saline solutions (smoke-bubbled PBS) has been shown to induce a strong stress response in cultured cells. This is reflected, for example, by the expression of stress genes such as c-fos and haem oxygenase, a transient decrease in the translation efficiency and the induction of cell cycle arrest. In these studies, peroxynitrite, the reaction product of nitric oxide (NO) and superoxide (O2-.), was identified as an active principle formed by CS in aqueous solutions. In the present study, we show that the CS-induced stress response is critically dependent on the intracellular glutathione (GSH) content which itself becomes diminished in cells exposed to smoke-bubbled PBS. Investigations using c-fos expression as a measure for cellular stress revealed a direct correlation between the smoke-bubbled PBS concentration necessary for stress-dependent c-fos expression and the intracellular GSH concentration observed in different cell lines. Correspondingly, 3T3 fibroblasts artificially depleted of GSH by pretreatment with buthionine-sulphoximine (BSO), an inhibitor of GSH synthesis, require significantly lower amounts of smoke-bubbled PBS to obtain a detectable c-fos expression, whereas, supplementation of the medium with N-acetyl-cysteine is an efficient treatment for the inhibition of a CS-induced c-fos response. We also show that the smoke-bubbled PBS-dependent loss of intracellular GSH is mainly attributable to the aldehyde fraction of CS, although these aldehydes by themselves cannot induce c-fos in these cells. The smoke-bubbled PBS-dependent c-fos response can, however, be mimicked when peroxynitrite and CS-related aldehydes, at the concentrations calculated to appear in smoke-bubbled PBS, are used in combination for cell exposure. Taken together, these results suggest that in cells exposed to aqueous extracts of CS, smoke-related aldehydes decrease the intracellular GSH content significantly, allowing peroxynitrite to interfere with specific target molecules resulting in the stress-specific expression of c-fos.
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PMID:The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration. 963 65

Oxidative stress has been proposed to play a role in the early events of acute pancreatitis, and metallothionein (MT) can provide protection against oxidative stress. Using transgenic mice, we characterized the effects of depletion of MT-I and -II, or overexpression of MT-I, on pancreatic responses during cerulein-induced acute pancreatitis. In MT-I/-II knockout mice, repeated injections of cerulein caused (a) higher serum amylase levels at 3 and 7 h after the initiation of acute pancreatitis; (b) earlier and stronger upregulation of oxidative stress-responsive genes, including heme oxygenase (HO)-1 and c-fos; and (c) exacerbated tissue damage (edema and polymorphonuclear neutrophil infiltration) compared with nontransgenic 129/SvCPJ mice. Total pancreatic glutathione (GSH + GSSG) content was similar between the knockout and nontransgenic 129/SvCPJ mice. Interestingly, during acute pancreatitis, CD-1 mice pretreated with L-buthionine-[S,R]-sulfoximine (BSO), which dramatically depleted pancreatic GSH, also had more severe pancreatitis, based on the same three criteria listed above, relative to untreated controls. No effects were observed with BSO treatment alone. Finally, during cerulein-induced acute pancreatitis, MT-I overexpressing transgenic mice (>20-fold increase in pancreatic MT-I content) had lower serum alpha-amylase levels between 7 and 24 h and delayed upregulation of HO-1 mRNA levels, but no difference in c-fos mRNA induction relative to the appropriate strain of nontransgenic mice. Diminished tissue damage (particularly cellular necrosis) was noted in these MT-I overexpressing transgenic mice. Total pancreatic GSH content was similar in these transgenic and nontransgenic mice during cerulein-induced acute pancreatitis. These studies suggest that pancreatic MT can function as an intracellular antioxidant as does GSH and that these intracellular antioxidants play a protective role during cerulein-induced acute pancreatitis.
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PMID:Metallothionein protects against cerulein-induced acute pancreatitis: analysis using transgenic mice. 978 36


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