UNIPROT:P30044 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species have been implicated as mediators of tissue injury in glomerular inflammation. The expression of the antioxidant enzyme, manganese superoxide dismutase (MnSOD), was examined in primary cultures of rat glomerular epithelial cells (GEC) in response to inflammatory mediators. The results demonstrate that GEC respond to interleukin-1 (IL-1) and bacterial lipopolysaccharride (LPS) with an increase in MnSOD steady-state mRNA levels. The IL-1 alpha-mediated induction of MnSOD mRNA levels was both time- and dose-dependent. Maximal levels approximately 40-fold above controls, were observed at 12 hours with 2 ng/ml of IL-1 alpha. MnSOD protein levels were also markedly elevated by IL-1 alpha. The induction of MnSOD mRNA by IL-1 alpha required de novo transcription as well as some degree of protein synthesis. To elucidate the potential intracellular signal that mediates IL-1 alpha-dependent MnSOD expression, three classical signaling pathways were examined. We found no evidence that MnSOD induction by IL-1 alpha is mediated by either the cyclooxygenase or lipoxygenase pathway or via activation of protein kinase C. Based on the presence of IL-1 alpha in several forms of glomerular inflammation, the observed increase in MnSOD expression by this immunoregulatory cytokine must have an important role in the antioxidant defense of glomerular epithelial cells.
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PMID:Regulation of manganese superoxide dismutase in glomerular epithelial cells: mechanisms for interleukin 1 induction. 756 2

Reactive oxygen species of mitochondrial origin have been implicated in regulating the expression of several tumor necrosis factor (TNF)-induced genes. Manganese superoxide dismutase (Mn-SOD) is one of many genes, but only antioxidant enzyme, induced in response to tumor necrosis factor. Mn-SOD is a nuclear-encoded mitochondrial matrix protein and serves a protective function by detoxifying superoxide. To address the role of superoxide in regulating gene expression in response to TNF, we have constitutively overexpressed Mn-SOD in a human fibrosarcoma cell line and asked what effect this has on the expression of a number of TNF-responsive genes using reverse transcription-polymerase chain reaction. Of the TNF-induced transcripts analyzed, only interleukin-1alpha (IL-1alpha) was modulated in response to Mn-SOD overexpression. In all cases of Mn-SOD overexpression, IL-1alpha protein and mRNA levels were lowered constitutively and in response to TNF when compared to the parental and mock-transfected cell lines. The induction of IL-1alpha by TNF can also be decreased by growth in 3% oxygen as compared to growth in 21% O2; in addition, growth in low oxygen lowers the basal level of IL-1alpha protein. The effect of Mn-SOD overexpression on IL-1alpha expression can be overcome by treatment with the protein kinase C activator, phorbol 12-myristate 13-acetate. Mn-SOD overexpression and low oxygen alter IL-1alpha mRNA levels by decreasing the stability of the IL-1alpha mRNA. These findings indicate that both Mn-SOD and O2 may regulate the levels of a cellular oxidant involved in both basal and TNF-induced IL-1alpha expression, presumably superoxide.
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PMID:Manganese superoxide dismutase modulates interleukin-1alpha levels in HT-1080 fibrosarcoma cells. 870 51

Apoptosis has been documented as a fundamental component of the life cycle of many cell types. One of the characteristics of this process is the cleavage of genomic DNA into oligonucleosomal fragments. The multifunctional cytokine TGF-beta 1 has been described to induce apoptosis in cultured hepatocytes although in this condition DNA fragmentation has not been detected. We investigated whether TGF-beta 1-induced apoptosis was associated with DNA fragmentation and was affected by PMA. Agarose gel electrophoresis of TGF-beta 1-treated hepatocytes shows a typical ladder-like pattern of DNA fragments and PMA, a selective stimulator of protein kinase C, diminishes the DNA fragmentation and cell death. It has been described that the antioxidant enzyme systems play an important role in the control of apoptosis and that the apoptogenic ability of TGF-beta 1 is through the inhibition of antioxidant enzyme expression in cultured hepatocytes [8]. However, PMA does not induce significant changes levels of manganese superoxide dismutase, copper-zinc superoxide dismutase and catalase mRNAs. Our data reveal that the attenuation of TGF-beta 1-induced DNA fragmentation by PMA is not associated with changes in the expression of antioxidant systems and is probably due selectively to the stimulation of protein kinases C.
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PMID:Effect of phorbol ester (PMA) on antioxidant enzyme expression in TGF-beta 1-induced apoptosis in primary cultures of hepatocytes. 969 11

Hypoxia inducible factor 1 (HIF-1) is a transcription factor which is expressed, when mammalian cells are subjected to hypoxia, activating the transcription of genes encoding proteins thought important for maintaining oxygen hemostasis. The aim of the study was to evaluate HIF-1 mRNA levels in a non-invasive model of perinatal asphyxia (PA). Brain was taken for studies on HIF-1 alpha and beta 10 min following the asphyctic period. To rule out influences by the redox status we also determined antioxidant enzyme mRNA levels for superoxide dismutase, catalase, glutathion peroxidase and performed electron spin resonance studies. To study the link to protein phosphorylation as previously proposed, we evaluated mRNA levels for protein kinase C. As DNA breaks were reported to occur in PA, we determined mRNA levels of two genes representing DNA nucleotide excision repair, ERCC2 and ERCC3, and a DNA repair gene involved in the repair of oxidation mediated DNA damage, XRCC1. mRNAs for HIF-1 were not detectable following 5-20 minutes of asphyxia. The antioxidant enzymes did not show any changes during the asphyctic periods either and electron spin resonance failed to detect the presence of the hydroxyl radical. PKC significantly decreased with the length of the asphyctic period. ERCC2 and XRCC1 mRNAs were inducible during the acute phase of asphyxia indicating early repair phenomena. HIF-1 may not be relevant for periods of PA up to 20 minutes, the maximal survival time in our model. Neonatal factors may be responsible for that phenomenon although we cannot rule out that HIF-1 changes may occur at the protein level.
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PMID:mRNA levels of the hypoxia inducible factor (HIF-1) and DNA repair genes in perinatal asphyxia of the rat. 976 11

Manganese superoxide dismutase (MnSOD) is a nuclear encoded primary antioxidant enzyme localized in mitochondria. Because expression of MnSOD plays a major role in maintaining cellular redox status and reactive oxygen species are known to play a role in signal transduction and carcinogenesis, we investigated the role of MnSOD in the development of cancer using a two-stage [7,12-dimethylbenz(a)-anthracene plus 12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis model. Female transgenic mice expressing the human MnSOD gene in the skin and their nontransgenic counterparts were used in this study. Pathological examination demonstrated significant reduction of papilloma formation in transgenic mice. Quantitative analysis of 4-hydroxy-2-nonenal-modified proteins showed greater accumulation of oxidative damage products in nontransgenic compared with transgenic mice, and this oxidative damage was demonstrated to be present in both mitochondria and nucleus. TPA increased activator protein-1 (AP-1) binding activity within 6 h in nontransgenic mice, but increased AP-1 binding activity was delayed in the transgenic mice. Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families. Overexpression of MnSOD selectively inhibited the TPA-induced activation of protein kinase Cepsilon and prevented subsequent activation of c-Jun NH(2)-terminal kinase in response to TPA. Overall, these results indicate that MnSOD regulates both cellular redox status and selectively modulates PKCepsilon signaling, thereby delaying AP-1 activation and inhibiting tumor promotion, resulting in reduction of tumors in MnSOD transgenic mice.
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PMID:Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. 1150 57

The microsomal enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and the low density lipoprotein (LDL) receptor pathway carry out a key role on cholesterol homeostasis in eucaryotic cells. The HMG-CoA reductase is sensitive to oxidative inactivation and to phosphorylation by many kinases that are able to inactivate the protein and increase its susceptibility to proteolysis. We previously demonstrated that a calf thymus Cu,Zn SOD affects cholesterol metabolism. This protein binds with rat hepatocyte cell membrane by a specific surface membrane receptor. The involvement of Cu,Zn SOD in cholesterol metabolism is confirmed further by the presence of this antioxidant enzyme in circulating serum lipoproteins. We studied the effect of native human Cu,Zn SOD, metal-free SOD (apo SOD), and SOD-inactivated with hydrogen peroxide on cholesterol metabolism in human hepatocarcinoma HepG2 cells. Results showed that all forms of SODs used, at the concentration of 150 ng/ml, are able to affect cholesterol metabolism decreasing both HMG-CoA reductase activity and its protein levels; this inhibitory effect is accompanied by reduced cholesterol synthesis measured as [14C]acetate incorporation into [14C]cholesterol and by an increased [125I]LDL binding to HepG2 cells. Furthermore, the inhibitory effect of Cu,Zn SOD on cholesterol synthesis was completely abolished when the cells were incubated with Cu,Zn SOD in the presence of bisindoilmaleimide (BDM), an inhibitor of protein kinase C (PKC); moreover, we demonstrated that Cu,Zn SOD as well as apo SOD was able to increase PKC activity. Overall, data demonstrate that Cu,Zn SOD affects cholesterol metabolism independently from its dismutase activity and its metal content and that the inhibitory action on cholesterol synthesis is mediated by an activation of protein kinase C.
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PMID:Effect of Cu,Zn superoxide dismutase on cholesterol metabolism in human hepatocarcinoma (HepG2) cells. 1209 81

We report that albumin is translocated to the nucleus in response to oxidative stress. Prior measurements have demonstrated that in concert with known transcription factors albumin binds to an antioxidant response element, which controls the expression of glutathione S-transferase and other antioxidant enzymes that function to mediate adaptive cellular responses [Holderman, M. T., Miller, K. P., Dangott, L. J., and Ramos, K. S. (2002) Mol. Pharmacol. 61, 1174-1183]. To investigate the mechanisms underlying this adaptive cell response, we have identified linkages between calcium signaling and the nuclear translocation of albumin in JB6 epithelial cells. Under resting conditions, albumin and the calcium regulatory protein calmodulin (CaM) co-immunoprecipitate using antibodies against either protein, indicating a tight association. Calcium activation of CaM disrupts the association between CaM and albumin, suggesting that transient increases in cytosolic calcium levels function to mobilize intracellular albumin to facilitate its translocation into the nucleus. Likewise, nuclear translocation of albumin is induced by exposure of cells to hydrogen peroxide or a phorbol ester, indicating a functional linkage between reactive oxygen species, calcium, and PKC-signaling pathways. Inclusion of an antioxidant enzyme (i.e., superoxide dismutase) blocks nuclear translocation, suggesting that the oxidation of sensitive proteins functions to coordinate the adaptive cellular response. These results suggest that elevated calcium transients and associated increases in reactive oxygen species contribute to adaptive cellular responses through the mobilization and nuclear translocation of cellular albumin.
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PMID:Calmodulin involvement in stress-activated nuclear localization of albumin in JB6 epithelial cells. 1518 87

Cellular glutathione peroxidase (GPx-1), a selenocysteine-containing enzyme, plays a central role in protecting cells from oxidative injury. GPx-1 is ubiquitously expressed in eukaryotic cells where it reduces hydrogen and lipid peroxides to alcohols. Adenosine, which is released from stressed or injured cells, protects against ischemia/reperfusion injury and apoptosis. In this study, we hypothesize that the cytoprotective effect of adenosine involves an increase in the activity of GPx-1. Treatment of human primary pulmonary artery endothelial cells (HPAECs) with 50 micromol/L adenosine in the presence of 10 micromol/L erytho-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, for 48 hours increased GPx-1 mRNA levels 2-fold. GPx-1 protein and enzyme activity also increased approximately 2-fold after treatment. The induction of GPx-1 expression was found to be a consequence of increased mRNA stability and not an increase in transcription. Bisindolylmaleimide I (BIM), a protein kinase C signaling pathway inhibitor, significantly attenuated the induction of GPx-1 mRNA by approximately 36%. The adenosine/EHNA-treated cells were more resistant to hydrogen peroxide stress. Both pharmacological inhibition and siRNA knockdown of GPx-1 attenuated the protective affect of adenosine/EHNA treatment, indicating that the adenosine-induced increase in GPx-1 contributes to an increase in cellular protection against oxidative stress. These data suggest that adenosine may protect the cardiovascular system from ischemia/reperfusion injury, in part, by enhancing the expression of the central intracellular antioxidant enzyme, GPx-1.
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PMID:Adenosine-dependent induction of glutathione peroxidase 1 in human primary endothelial cells and protection against oxidative stress. 1580 13

ATP has been shown to mediate stress responses in the brain. The present study examined the ATP-stimulated stress protein expression of RBA-2 type-2 astrocytes. Our results revealed that ATP stimulated HSP60 expression in a dose- and time-dependent manner. The stimulation requires a minimal ATP concentration of 500 microM and high concentration of extracellular ATP (1 mM) stimulated a significant increase of HSP60 expression from 2 to 24 h. In addition, the ATP-stimulated HSP60 expressions were inhibited by inhibitors for protein kinase C (PKC) and phospholipase D (PLD), and by antioxidants, resveratrol, and catalase. Furthermore, ATP stimulated the expression of Cu/Zn superoxide dismutase (SOD). In addition, ATP and P2X7 receptor selective agonist BzATP also decreased mitochondria membrane potential measured by flow cytometry. To further examine the proteins involving in ATP-mediated stress responses, we conducted proteomic analysis. We found that RBA-2 astrocytes possess abundant peroxiredoxin II (Prx II), an antioxidant enzyme. ATP and exogenous H2O2 stimulated Prx II shifting from oxidized form to reduced form. Thus, we concluded that ATP potentiated the expression of HSP60 and Cu/Zn SOD, and decreased mitochondria membrane potential. In addition, RBA-2 astrocytes expressed Prx II that might also serve as a protective mechanism to control the concentration of reactive oxygen species.
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PMID:Elucidation of ATP-stimulated stress protein expression of RBA-2 type-2 astrocytes: ATP potentiate HSP60 and Cu/Zn SOD expression and stimulates pI shift of peroxiredoxin II. 1617 11

In vitro studies have shown that activation of protein kinase C (PKC) is a key mediator of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) in a range of cell types and in response to high glucose, however, its role in the in vivo setting has not been clearly delineated. Streptozotocin-induced diabetic rats were treated with the PKC-beta isoform inhibitor LY333531 for 8 weeks. LY333531 treatment significantly attenuated increased urinary albumin excretion rate and glomerular volume and tubulointerstitial injury index as well as elevated PKC activity and PKC-beta protein expression in the kidney. Level of malondialdehyde was markedly higher and antioxidant enzyme activity such as superoxide diamutase and catalase as well as glutathione peroxidase were significantly lower in the kidney from diabetic rats than that of the control group. LY333531 administration could remit these changes. Increased macrophages recruitment as well as ICAM-1 and MCP-1 protein expression in the kidney were significantly inhibited by LY333531 in diabetic rats. It is concluded that mechanism of renoprotection of LY333531 may be correlated, at least partly, with suppression of increased macrophages recruitment and overexpression of ICAM-1 and MCP-1 in diabetic rats.
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PMID:Protein kinase C beta inhibitor LY333531 attenuates intercellular adhesion molecule-1 and monocyte chemotactic protein-1 expression in the kidney in diabetic rats. 1689 64

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