UNIPROT:P30044 - FACTA Search

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Query: UNIPROT:P30044 (antioxidant enzyme)
8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Manganese-containing superoxide dismutase (MnSOD) is an essential primary antioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen within the mitochondrial matrix. Cytosolic glutathione peroxidase (GPX) converts hydrogen peroxide into water. MnSOD is reduced in a variety of tumor types and has been proposed to be a new kind of tumor suppressor gene, but the mechanism(s) by which MnSOD suppresses malignancy is unclear. According to the enzymatic reactions catalyzed by MnSOD and cytosolic GPX, change in the cellular redox status, especially change attributable to accumulation of hydrogen peroxide or other hydroperoxides, is a possible reason to explain the suppression of tumor growth observed in MnSOD-overexpressing cells. To test this possible mechanism, we transfected human cytosolic GPX cDNA into human glioma cells overexpressing MnSOD. The results showed that GPX overexpression not only reversed the tumor cell growth inhibition caused by MnSOD overexpression but also altered the cellular contents of total glutathione, reduced glutathione, oxidized glutathione, and intracellular reactive oxygen species. Overexpression of GPX also inhibited degradation of the inhibitory subunit alpha of nuclear factor-KB. These results suggest that hydrogen peroxide or other hydroperoxides appear to be key reactants in the tumor suppression by MnSOD overexpression, and growth inhibition correlates with the intracellular redox status. This work suggests that manipulations that inhibit peroxide removal should enhance the tumor suppressive effect of MnSOD overexpression.
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PMID:The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase. 1091 71

Manganese superoxide dismutase (MnSOD), an inductive antioxidant enzyme, can protect cells from oxidative injury to the mitochondria. The elevation of MnSOD activity in cells can effectively prevent many diseases associated with oxidative stress. Polysaccharide Krestin (PSK), a kind of protein-bound polysaccharide extracted from Coriolus versicolor, is used as an immune response modifier in anti-tumor therapy. We have previously found that PSK could alleviate the oxidative injury that oxidized low density lipoprotein (Ox-LDL) brought to monocytes/macrophages, and therefore had some preventive or therapeutic effect on atherosclerosis. In order to find out if the effects of PSK were associated with the alteration ofantioxidant enzymes, we investigated its effect on MnSOD activity and gene expression in mouse peritoneal macrophages. The results showed that PSK could enhance SOD activity and increase the contents ofMnSOD mRNA in mouse peritoneal macrophages. Furthermore, the induction of MnSOD by PSK could be blocked by cycloheximide and actinomycin D.
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PMID:Polysaccharide Krestin enhances manganese superoxide dismutase activity and mRNA expression in mouse peritoneal macrophages. 1115 46

The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) functions as a tumor suppressor gene. Reconstitution of MnSOD expression in several human cancer cell lines leads to reversion of malignancy and induces a resistant phenotype to the cytotoxic effects of TNF and hyperthermia. The signaling pathways that underlie these phenotypic changes in MnSOD-overexpressing cells are unknown, although alterations in the activity of several redox-sensitive transcription factors, including AP-1 and NF-kappaB, have been observed. To determine the downstream signaling molecules involved in MnSOD-induced cell resistant phenotype, in the present study we analyzed the expression profile of several groups of genes related to stress response, DNA repair, and apoptosis, in a human breast cancer MCF-7 cell line overexpressing MnSOD (MCF+SOD). Of 588 genes examined, 5 (0.85%) were up-regulated (2-42-fold), and 11 (1.9%) were down-regulated (2-33-fold) in the MCF+SOD cells compared to the parental MCF-7 cells. The five up-regulated genes were MET, GADD153, CD9, alpha-catenin and plakoglobin. The genes with the most significant down-regulation included: vascular endothelial growth factor receptor 1, TNF-alpha converting enzyme, and interleukin-1beta. GADD153 (involved in the repair of DNA double strand breaks) showed a 33-fold increase in microarray analysis and these results were confirmed by RT-PCR. To further determine the specificity in MnSOD-induced gene regulation, MCF+SOD cells were stably transfected with an antisense MnSOD sequence whose expression was controlled by a tetracycline-inducible regulator. Expression of three up-regulated genes was measured after induction of antisense MnSOD expression. Interestingly, expression level of GADD153 but not MET or CD9 was reduced 24 h after antisense MnSOD induction. Together, these results suggest that reconstitution of MnSOD in tumor cells can specifically modulate the expression of down-stream effector genes. GADD153 and other elements observed in the MCF+SOD cells may play a key role in signaling the MnSOD-induced cell phenotypic change.
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PMID:Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase. 1116 72

Manganese superoxide dismutase (Mn-SOD) is a primary antioxidant enzyme whose expression is essential for life in oxygen. Mn-SOD has tumor suppressor activity in a wide variety of tumors and transformed cell systems. Our initial observations revealed that Mn-SOD expression was inversely correlated with expression of AP-2 transcription factors in normal human fibroblasts and their SV-40 transformed counterparts. Thus we hypothesized that AP-2 may down-regulate Mn-SOD expression. To examine the functional role of AP-2 on Mn-SOD promoter transactivation we cotransfected AP-2-deficient HepG2 cells with a human Mn-SOD promoter-reporter construct and expression vectors encoding each of the three known AP-2 family members. Our results indicated that AP-2 could significantly repress Mn-SOD promoter activity, and that this repression was both Mn-SOD promoter and AP-2-specific. The three AP-2 proteins appeared to play distinct roles in Mn-SOD gene regulation. Moreover, although all three AP-2 proteins could repress the Mn-SOD promoter, AP-2alpha and AP-2gamma were more active in this regard than AP-2beta. Transcriptional repression by AP-2 was not a general effect in this system, because another AP-2-responsive gene, c-erbB-3, was transactivated by AP-2. Repression of Mn-SOD by AP-2 was dependent on DNA binding, and expression of AP-2B, a dominant negative incapable of DNA binding, relieved the repression on Mn-SOD promoter and reactivated Mn-SOD expression in the AP-2 abundant SV40-transformed fibroblast cell line MRC-5VA. These results indicate that AP-2-mediated transcriptional repression contributes to the constitutively low expression of Mn-SOD in SV40-transformed fibroblasts and suggest a mechanism for Mn-SOD down-regulation in cancer.
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PMID:A family of AP-2 proteins down-regulate manganese superoxide dismutase expression. 1127 50

Chronic lymphocytic leukemia (CLL) is a neoplastic disease susceptible to antioxidant enzyme alterations and oxidative stress. We have examined the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and the oxidized/reduced glutathione (GSSG/GSH) ratio together with the levels of malondialdehyde (MDA) and 8-oxo-2'-deoxyguanosine (8-oxo-dG) in lymphocytes of CLL patients and compared them with those of normal subjects of the same age. SOD and CAT activity decreased in CLL lymphocytes while GPx activity increased. GSH content of CLL lymphocytes also increased, and GSSG concentration remained constant. Thus, a reduced GSSG/GSH ratio was obtained. The oxidation product MDA, and the damaged DNA base 8-oxo-dG were also increased in CLL. The observed changes in enzyme activities, GSSG/GSH ratio, and MDA were significantly enhanced as the duration of the disease increased in years. The results support a predominant oxidative stress status in CLL lymphocytes and emphasize the role of the examined parameters as markers of the disease evolution.
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PMID:Antioxidant enzyme activities and the production of MDA and 8-oxo-dG in chronic lymphocytic leukemia. 1136 26

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

Copper zinc superoxide dismutase (CuZnSOD) is an essential primary antioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen in the cytoplasm. Cytosolic glutathione peroxidase (GPx) converts hydrogen peroxide into water. The overall goal of the present study was to explore the possible role of the antioxidant enzyme CuZnSOD in expression of the malignant phenotype. We hypothesized that overexpression of CuZnSOD would lead to the suppression of at least part of the human malignant phenotype. To test this hypothesis, human CuZnSOD cDNA was transfected into U118-9 human malignant glioma cells. CuZnSOD activity levels increased 1.5-, 2.0-, 2.6-, and 3.5-fold, respectively, in four table transfected cell lines compared with wild type and vector controls. Overexpression of CuZnSOD altered cellular antioxidant enzyme profiles, including those of manganese superoxide dismutase, catalase, and GPx. The transfected clone with the highest CuZnSOD:GPx ratio (3.5) showed a 42% inhibition of tumor cell growth in vitro. The decreased rate of tumor cell growth in vitro was strongly correlated with the enzyme activity ratio of CuZnSOD:GPx. Glioma cells that stably overexpressed CuZnSOD demonstrated additional suppressive effects on the malignant phenotype when compared with the parental cells and vector controls. These cells showed decreased plating efficiency, elongated cell population doubling time, lower clonogenic fraction in soft agar, and, more significantly, inhibition of tumor formation in nude mice. This work suggested that CuZnSOD is a new tumor suppressor gene. Increased intracellular ROS levels were found in cells with high activity ratios of CuZnSOD:GPx. Change in the cellular redox status, especially change attributable to the accumulation of hydrogen peroxide or other hydroperoxides, is a possible reason to explain the suppression of tumor growth observed in CuZnSOD-overexpressing cells.
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PMID:Overexpression of copper zinc superoxide dismutase suppresses human glioma cell growth. 1186 5

The levels of some organochlorine pesticides (OCP)s (hexachlorobenzene, HCB, alpha-hexachlorocyclohexane, alpha-HCH, beta-HCH, gamma-HCH, heptachlorepoxide, HE, bis (4-chlorophenyl)-1,1-dichloroethene, p.p'DDE, bis (4-chlorophenyl)-1,1,1-trichloroethane, p.p' DDT and total DDT (E-DDT) and antioxidant enzyme activities namely Cu, Zn superoxide dismutase (SOD), catalase (CAT), selenium-dependent glutathione peroxidase (Se-GSH-Px), total glutathione peroxidase (T-GSH-Px), selenium independent glutathione peroxidase (GSH-Px II), glutathione reductase (GRd), level of reduced glutathione (GSH) and lipid peroxidation (LP), glutathione S-transferase (GST) activity toward several substrates including 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP) were measured in tumor and surrounding tumor free tissues of 24 female breast cancer patients and was evaluated whether there exist any association between the levels of OCPs and antioxidants. The mean levels of GSH, alpha-BHC, gamma-BHC and HE, and activities of SOD, Se-GSH-Px, T-GSH-Px, GSH-Px II,GRd, GST CDNB, and GST DCNB were significantly higher in tumors than in controls. In tumors, significant correlations were noted between: SOD and y-BHC; Se-GSH-Px and gamma-BHC; T-GSH-Px and gamma-BHC; GSH-Px II and alpha-BHC, gamma-BHC; GSH and alpha-BHC, gamma-BHC, HE; GRd and alpha-BHC; CDNB GST and alpha-BHC, gamma-BHC. These results show that free-radical mediated oxidative stress is, at least partly, associated with some of these OCP residues in human breast tumors.
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PMID:The organochlorine pesticide residues and antioxidant enzyme activities in human breast tumors: is there any association? 1203 8

Thioredoxin reductase (TrxR) is the first selenoenzyme containing selenocysteine in the active center and FAD as a second prosthetic group. TrxR catalyses the NADPH-dependent reduction of thioredoxin and of many other physiologically important substrates. TrxR exhibits a many-fold increase in the activity in tumor cells and stimulates their proliferation as well the phenotype changes. Some gold compounds and a number of other clinically and experimentally tested drugs have been shown to inhibit TrxR. The involvement of TrxR/Trx/NADPH system in a broad spectrum of cellular processes renders it a potential target for therapeutic approaches.
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PMID:[Thioredoxin reductase--a new target for molecular medical investigations]. 1210 60

Thioredoxin reductase 2 (TrxR2), thioredoxin II (Trx II) and peroxiredoxin III (Prx III) are specifically localized in mitochondria and believed to play important roles in the regulation of cellular redox status by serving as a primary line of defense against H2O2 produced during respiration. Substantial evidence indicates that the alteration of cellular redox status is a critical factor involved in cell growth and death and results in tumorigenesis. We therefore investigated the expression of TrxR2 and Prx III in 58 paraffin-embedded hepatocellular carcinoma tissues by immunohistochemistry. The labeling indices of TrxR2 and Prx III were significantly higher in tumor tissues than in the corresponding adjacent normal tissues. In 39 (67.2%) out of 58 samples, the levels of TrxR2 expression were higher in tumor tissues than in corresponding adjacent normal tissues, while 11 samples (19.0%) showed lower expression in tumor tissues. Prx III expression was increased in tumor tissues of 23 samples (39.7%) compared to adjacent normal tissues and were decreased in 18 samples (31.0%). These results suggest that alterations in cellular redox status by enhanced expression of TrxR2 and/or Prx III might be associated with the formation and development of hepatocellular carcinomas.
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PMID:Overexpression of mitochondrial thioredoxin reductase and peroxiredoxin III in hepatocellular carcinomas. 1253 83

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