UNIPROT:P04179 - FACTA Search

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Query: UNIPROT:P04179 (MnSOD)
2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide dismutases (SODs) are vital components in the resistance of aerobic organisms to the toxicity of oxygen. Escherichia coli contains two highly homologous cytoplasmic SODs, a manganese- and an iron-containing enzyme (MnSOD, FeSOD). We previously demonstrated that MnSOD and FeSOD have different physiological functions and that MnSOD is more effective in preventing oxidative damage to DNA. In this report, purified E. coli MnSOD was shown to bind nonspecifically to DNA by electrophoretic mobility shift assay and nitrocellulose-filter binding methodologies. From electrophoretic mobility shift assay, the equilibrium dissociation constants for interaction with a variety of double-stranded and single-stranded oligonucleotides ranged from 1.5 +/- 0.2 to 8.4 +/- 1.3 microM at 20 degrees C. This range of concentrations corresponds to MnSOD concentrations in aerobically grown E. coli. In vivo binding of MnSOD to DNA was supported by colocalization of MnSOD and the E. coli nucleoid in immunoelectron microscopy. Both MnSOD and DNA were inhomogeneously distributed in the cytosol, the concentration of each being higher in the center of the cell and relatively low near the inner membrane. In contrast, there was no evidence for physiologically relevant interaction of FeSOD with DNA. Binding to DNA in vitro was weak, Kd > 40-220 microM, concentrations 7-40 times higher than found in vivo. In addition, the cytoplasmic distribution of FeSOD did not correlate with DNA. FeSOD concentration was higher near the inner membrane and lower in the center of the cytosol. These results demonstrate that E. coli MnSOD associates with DNA in vitro and in vivo. Combined with prior data demonstrating that MnSOD preferentially protects DNA in vivo while an equal enzymatic activity of FeSOD does not (Hopkin, K. A., Papazian, M. A., and Steinman, H. M. (1992) J. Biol. Chem. 267, 24253-24258), our data suggest that E. coli MnSOD acts as a "tethered antioxidant"; association of MnSOD with DNA localizes dismutase activity near a target of oxidative stress and increases protection of DNA from oxidative damage. This model has implications for the therapeutic use of SODs as antioxidants.
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PMID:The manganese superoxide dismutase of Escherichia coli K-12 associates with DNA. 796 11

Cultured rat glomerular mesangial and epithelial cells and bovine glomerular endothelial cells were exposed to various concentrations of hydrogen peroxide (H2O2). Mesangial cells treated with 10 to 100 microM H2O2 for 24 hours showed a two- to ninefold increase in Mn-SOD mRNA expression associated with significantly (P < 0.005) increased Mn-SOD activity (22.2 +/- 1.2 and 12.2 +/- 0.7 mu/mg protein for H2O2 100 microM treated and untreated cells, respectively). In contrast, expression of Cu-Zn SOD and beta-actin mRNA was not affected by H2O2. Induction of Mn-SOD mRNA by H2O2 was inhibited by actinomycin-D (4 microM) treatment. Glomerular endothelial cells also showed an increase in Mn-SOD mRNA expression following 100 microM H2O2 treatment, as did glomerular epithelial cells following treatment with 500 and 1000 microM H2O2 but not with 100 microM. Transcriptional activity of the Mn-SOD gene was assessed with a fusion reporter gene consisting of a luciferase gene (pGL2P) and a 1.2 kb fragment from the rat Mn-SOD genomic DNA (-806 to +408 bp of the transcription initiation site, -806:+408). The construct was transfected into rat glomerular mesangial and epithelial cells. Mesangial and epithelial cells transfected with pGL2P (-806:+408) and treated with H2O2 (100 microM and 1 mM for mesangial and epithelial cells, respectively) demonstrated some threefold increase in luciferase activity, whereas cells transfected with pGL2P lacking the Mn-SOD fragment did not show changes in luciferase activity following H2O2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidants induce transcriptional activation of manganese superoxide dismutase in glomerular cells. 796 52

A genomic clone encoding manganese-containing superoxide dismutase (SOD; EC 1.15.1.1) was isolated from a Hevea brasiliensis genomic library made in lambda phage EMBL3 by using a heterologous cDNA probe of MnSOD from Nicotiana plumbaginifolia. The nucleotide sequence of 4968 bp from the genomic clone was determined. Based on the putative translation initiation codon and stop codon, PCR primers were designed and utilized for cloning the full-length cDNA from total mRNA. Of the two distinct cDNAs of MnSOD isolated, MnSOD-A has a perfect match with exons of the nuclear gene, while MnSOD-B has a 90.2% homology and is 6 nucleotides longer than MnSOD-A in the putative transit peptide region. The nuclear gene comprises 6 exons and 5 introns, giving a total length of 3211 bp. The sequences of 1400 bp upstream of the initiation codon and 320 bp downstream of the stop codon were also determined. Southern analysis of genomic DNA from Hevea probed with a genomic fragment indicated there are at least two genes of MnSOD in Hevea. Northern blot analysis showed that MnSOD transcripts were present in all tissues examined (leaf, petiole, root, latex, callus) with young leaves showing the highest levels in intact plants. The transcript level in embryogenic callus was nearly 50-fold higher than in mature leaves. In addition, transcripts of MnSOD could be induced 3- to 5-fold in response to sucrose, ethephon and Murashige-Skoog salts.
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PMID:Molecular cloning, characterization and expression of Mn-superoxide dismutase from the rubber tree (Hevea brasiliensis). 821 64

Previous studies using an in vivo rabbit model in which lung tissue hypoxia/hypoperfusion was created by unilateral lung collapse for 7 days demonstrated a decrease in MnSOD activity in previously hypoxic/hypoperfused lungs. In the present study, we determined whether tissue hypoxia/hypoperfusion decreased MnSOD protein concentration or mRNA expression in the lung as well, changes that would suggest pretranslational regulation of enzyme activity. Expression of MnSOD may be critical in determining the degree of tissue injury during re-oxygenation because the mitochondrial electron transport system produces reactive oxygen species (ROS) both during hypoxia and re-oxygenation. We purified MnSOD protein from rabbit livers to a specific activity of approximately 3,500 U/mg protein and found the amino terminal sequence nearly identical to those of the rat and human MnSOD proteins. Lung MnSOD protein content was quantitated by immunoassay, and MnSOD mRNA content was determined by slot blotting. Results from five control and six experimental rabbits, the right lungs of which had been hypoxic/hypoperfused because of collapse for 7 days, demonstrated a 32% decrease (P < 0.03) in MnSOD protein content (42 +/- 8 micrograms/mg DNA in hypoxic lungs compared with 61 +/- 3 micrograms/mg DNA in contralateral lungs) that was not due to decreased numbers of mitochondria. Lung succinate dehydrogenase activity, a mitochondrial marker, did not change in hypoxic/hypoperfused lungs. The mRNA for MnSOD did not change relative to B-actin mRNA in lungs that had been hypoxic and hypoperfused for 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:MnSOD protein content changes in hypoxic/hypoperfused lung tissue. 825 93

A broad array of oxidative stresses modulates gene expression in a variety of mammalian cells. One goal of this review was to characterize cellular responses to oxidative injury, how these processes are regulated, and the outcome for a particular cell or tissue. Many genes induced in response to specific oxidant stresses have been identified and include transcription factors, replication proteins, proteases, protease inhibitors, proteins affecting cell proliferation and various antioxidants, i.e. heme oxygenase, MT, and MnSOD. The latter enzyme is induced after a number of cytokines and oxidant stresses including hyperoxia and mineral dusts causing inflammation. Moreover, increases in mRNA levels of TNF and IL-1, cytokines inducing MnSOD, are observed after exposure to UV and ionizing radiation. Since increased electron flow could lead to generation of more AOS within mitochondria, increased levels of MnSOD might be necessary to maintain normal functioning of the mitochondria after oxidative stress. Alterations in cell growth are intrinsically related to the pathogenesis of many diseases. Paradoxically, some of the responses of cells to oxidative stress reflect cytotoxicity and cytostasis, whereas others result in increased cell proliferation. For example, induction of gadd genes observed after oxidative stress is related to growth arrest of cells, a response which might enable the cell to repair oxidative damage prior to replication. This phenomenon might prevent fixation of mutations associated with oxidative DNA damage. On the other hand, increased mRNA expression and activity of ODC, observed after exposure of cells to UV or asbestos is associated with increased cell proliferation. In addition, increased mRNA expression of cellular proto-oncogenes observed after exposure to oxidants could also be related to increased DNA synthesis or proliferation. Figure 5 provides a general scheme of cell responses to oxidative stress and possible ramifications. AOS can react with a number of target molecules including proteins, lipids, and DNA. These interactions elicit a number of signals including activation of gene regulatory factors (transcription factors) which in turn activate oxidative stress-responsive genes or regulons. Consequently, a number of proteins are produced with distinctive functions including DNA repair enzymes, antioxidants, proteases inhibitors, cytokines and proteins affecting cell proliferation. These cellular responses to AOS can lead to restoration of normal cellular function and adaptation to oxidative stress, cell death or aberrant proliferation. It is the latter two responses which can lead to a variety of disease states including cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cell and tissue responses to oxidative damage. 837 69

Bradyrhizobium sp. (Parasponia) strain ANU289 expresses a single Mn-SOD in both the vegetative and symbiotic states. A 500 bp sod-homologous sequence was amplified from genomic DNA of strain ANU289 using PCR. A 1.3 kb SalI fragment was subsequently cloned which contained an ORF, sodA, encoding a 23 Kd protein. This putative SOD shares considerable homology with other Mn-SODs and analysis of the sodA sequence predicts that it is expressed. A lacZ-sodA fusion complemented the SOD-deficiency of E. coli QC779 and resulted in the expression of SOD activity in both mutant and wild type E. coli. We conclude that sodA encodes the Mn-SOD of strain ANU289.
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PMID:The isolation and characterisation of a gene encoding superoxide dismutase from Bradyrhizobium sp. (Parasponia) strain ANU289. 859 79

Cu/Zn-superoxide dismutase (SOD)-accelerated oxidation of the benzene metabolite 1,4-hydroquinone (HQ) results in the enhanced formation of semiquinone anion radicals, electrophilic 1,4-benzoquinone (BQ), and H202. We selected bone marrow stromal cells and phiX-174 double stranded plasmid DNA as model systems to investigate the cytotoxicity and DNA cleaving activity of the Cu/Zn-SOD-mediated activation of HQ. The addition of either Cu/Zn-SOD or Min-SOD to the primary bone marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity, which could be completely prevented by adding reduced glutathione (GSH) or dithiothreitol but not be adding catalase. Incubation of the plasmid DNA with the HQ/Cu/Zn-SOD system resulted in the induction of single- as well as double-strand breaks, which could be inhibited by catalase and the Cu(I) chelators, bathocuproinedisulfonic acid (BCS) and GSH. Although Mn-SOD could enhance HQ-induced cytotoxicity to stromal cells, the activation of HQ by Mn-SOD did not contribute to the induction of DNA strand breaks. Similar to the HQ/Cu(II) and H202/Cu(II) systems, the DNA strand breaks mediated by HQ/Cu/Zn-SOD could not be effectively inhibited by the hydroxyl radical scavengers, including dimethylsulfoxide, mannitol, and 5,5-dimethyl-1-pyrroline N-oxide, but could be protected by sodium azide. Low-temperature electron spin resonance experiments showed that incubation of Cu/Znu-SOD with HQ resulted in the release of copper from the Cu/Zn-SOD, which could be prevented by catalase. Alpha-(4-Pyridyl-1-oxide)-N-tert-butylnitrone (POBN)/spin-trapping studies demonstrated that the interaction of HQ with Cu/Zn-SOD, but not with Mn-SOD, resulted in the significant formation of POBN-CH3 adduct in the presence of dimethylsulfoxide, suggesting the production of hydroxyl radical or its equivalent from this enzyme/xenobiotic interaction. The formation of the POBN-CH3 adduct from the HQ/Cu/Zn-SOD could be inhibited by catalase, BCS or GSH, indicating the important role for H202 and Cu(I) in the production of reactive oxygen species. Addition of human myeloperoxidase to the HQ/Cu/Zn-SOD synergistically enhanced the formation of BQ from HQ. This enhancement could be abolished by catalase. Taken together, these results demonstrate that activation of HQ by either Cu/Zn-SOD or Mn-SOD results in cytotoxicity to primary bone marrow stromal cells through the formation of electrophilic BQ. Interaction of HQ with Cu/Zn-SOD causes oxidative damage to Cu/Zn-SOD, leading to the release of copper from the enzyme. The further reaction between the released copper and H202 generates reactive oxygen species that participate in the induction of strand breaks in plasmid DNA. The H202 generated from the Cu/Zn-SOD-accelerated oxidation of HQ can also be utilized by myeloperoxidase resulting in additional conversion of HQ to BQ.
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PMID:Role of Cu/Zn-superoxide dismutase in xenobiotic activation. II. Biological effects resulting from the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone. 864 80

To estimate the oxidative damage to skeletal muscle DNA in mitochondrial encephalomyopathies, we studied the amount of 8-hydroxy-deoxyguanosine (8-OH-dG) and the localization of superoxide dismutase (SOD) in the skeletal muscles of patients with progressive external ophthalmoplegia (PEO) or Kearns-Sayre syndrome (KSS). The molar ratio of 8-OH-dG/deoxyguanosine in skeletal muscle from PEO or KSS patients was significantly higher than the control value. The ratio from patients with polymyositis or Duchenne's muscular dystrophy was not significantly elevated. Immunohistochemical staining for both Mn-SOD and Cu,Zn-SOD showed pronounced staining in the subsarcolemmal and intermyofibrillar regions of cytochrome-oxidase-negative ragged red fibers of KSS or PEO muscles. Our findings suggest that overproduction of 8-OH-dG and mitochondrial dysfunction with gene deletions are associated with each other in muscle cells of patients with PEO or KSS, and that free radicals may play an important role in the pathophysiology of mitochondrial encephalomyopathies.
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PMID:Oxidative damage to skeletal muscle DNA from patients with mitochondrial encephalomyopathies. 883 81

Copper/zinc (Cu/ZnSOD) and manganese (MnSOD) superoxide dismutases which catalyze the dismutation of toxic superoxide anion, O(2-)-, to O2 and H2O2, play a major role in protecting cells from toxicity of oxidative stress. However, cells overexpressing either form of the enzyme show signs of toxicity, suggesting that too much SOD may be injurious to the cell. To elucidate the possible mechanism of this cytotoxicity, the effect of SOD on DNA and RNA strand scission was studied. High purity preparations of Cu/ZnSOD and MnSOD were tested in an in vitro assay in which DNA cleavage was measured by conversion of phage phi X174 supercoiled double-stranded DNA to open circular and linear forms. Both types of SOD were able to induce DNA strand scission generating single- and double-strand breaks in a process that required oxygen and the presence of fully active enzyme. The DNA strand scission could be prevented by specific anti-SOD antibodies added directly or used for immunodepletion of SOD. Requirement for oxygen and the effect of Fe(II) and Fe(III) ions suggest that cleavage of DNA may be in part mediated by hydroxyl radicals formed in Fenton-type reactions where enzyme-bound transition metals serve as a catalyst by first being reduced by superoxide and then oxidized by H2O2. Another mechanism was probably operative in this system, since in the presence of magnesium DNA cleavage by SOD was oxygen independent and not affected by sodium cyanide. It is postulated that SOD, by having a similar structure to the active center of zinc-containing nucleases, is capable of exhibiting non-specific nuclease activity causing hydrolysis of the phosphodiester bonds of DNA and RNA. Both types of SOD were shown to effectively cleave RNA. These findings may help explain the origin of pathology of certain hereditary diseases genetically linked to Cu/ZnSOD gene.
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PMID:DNA and RNA strand scission by copper, zinc and manganese superoxide dismutases. 883 54

(-)-Deprenyl stereospecifically reduces neuronal death even after neurons have sustained seemingly lethal damage at concentrations too small to cause monoamine oxidase-B (MAO-B) inhibition. (-)-Deprenyl can also influence the process growth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with the earlier work of others, we showed that (-)-deprenyl alters the expression of a number mRNAs or proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial ATP production depends on mitochondrial membrane potential (MMP) and mitochondrial failure has been shown to be one of the earliest events in apoptosis, we used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl are accompanied by a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and to decrease cytoplasmic oxidative radical levels and thereby to reduce apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may contribute to the development of new therapies for neurodegenerative diseases.
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PMID:(-)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. 898 61

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