Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While Cr (VI)-containing compounds are well established carcinogens, the mechanisms of their action remain to be investigated. In this study we show that Cr (VI) causes increased tyrosine phosphorylation in human lung epithelial A549 cells in a time-dependent manner. N-acetyl-cysteine (NAC), a general antioxidant, inhibited Cr (VI)-induced tyrosine phosphorylation. Catalase, a scavenger of H2O2, sodium formate and aspirin, scavengers of hydroxyl radical (*OH), also inhibited the increased tyrosine phosphorylation induced by Cr (VI). SOD, an inhibitor of superoxide radical (O2*-), caused less inhibition. ESR study shows that incubation of Cr (VI) with the A549 cells generates *OH radical. The generation of radical was decreased by addition of catalase and sodium formate, while SOD did not have any inhibitory effect. Oxygen consumption measurements show that addition of Cr (VI) to A549 cells resulted in enhanced molecular oxygen consumption. These results indicate that Cr (VI) can induce an increase in tyrosine phosphorylation. H2O2 and *OH radicals generated during the process are responsible for the increased tyrosine phosphorylation induced by Cr (VI).
Mol Cell Biochem 2001 Jun
PMID:Cr (VI) increases tyrosine phosphorylation through reactive oxygen species-mediated reactions. 1167 2

Superoxide is a key component of the antibacterial weaponry of phagocytes. Presumably, for this reason, strains of Salmonella typhimurium express a periplasmic superoxide dismutase (SOD) that is essential for full virulence. Because most anions cannot easily penetrate lipid membranes, it is thought that the phagosomal superoxide either damages an unknown target on the bacterial surface or reacts with nitric oxide to form peroxynitrite (HOONO), a toxic oxidant that can freely enter bacteria. However, in this study, we tested whether superoxide itself could penetrate membranes. Superoxide that was generated at high pH (>7.5) very slowly reduced cytochrome c that was encapsulated inside lipid vesicles. It did so much more quickly at lower pH (<7). Under the latter conditions, more superoxide was protonated and uncharged (HO2*), and the penetrance of superoxide was proportional to the concentration of this species. The permeability coefficient of HO2* was determined to be 9 x 10(-4) cm sec(-1), just slightly lower than that of water and far higher than the value of the anionic form (O2-, <10(-7) cm sec(-1). When Escherichia coli mutants that lack periplasmic SOD were exposed to super-oxide at pH 6.5, cytosolic fumarase B was damaged. Damage was minimal at higher pH or in strains that contained periplasmic SOD. Thus, in the acidic phagolysosome, superoxide may be able to penetrate and attack cytosolic targets of captive bacteria. This process may contribute to the potency of the oxidative burst. One role of periplasmic SOD may be to avert this damage. In contrast, periplasmic SOD was ineffective at lowering the extracellular super-oxide concentration and, therefore, may have little impact upon HOONO formation.
Mol Microbiol 2002 Jan
PMID:A potential role for periplasmic superoxide dismutase in blocking the penetration of external superoxide into the cytosol of Gram-negative bacteria. 1184 39

The ras proto-oncogene is frequently mutated in human tumors and functions to constitutively stimulate signal transduction cascades, resulting in unchecked proliferation and malignant transformation. In certain cells, superoxide functions as a signal-transduction messenger, mediating the downstream effects of ras and rac. We demonstrated previously that v-Ha-ras-transfected rat kidney epithelial cells (RECs) overproduced superoxide anion and that this superoxide production was mediated by ras. In the present study, we further demonstrated that v-Ha-ras overexpression transformed immortal nonmalignant RECs into malignant cancer cells; v-Ha-ras-transfected cells formed clones in soft agar, had high plating efficiency, and formed tumors in nude mice. Our data suggest that superoxide radical plays a role in ras-induced transformation; modulation of intracellular superoxide level by overexpression of manganese-containing superoxide dismutase or copper- and zinc-containing superoxide dismutase inhibited ras-induced transformation, as evidenced by in vitro studies of plating efficiency and by in vivo studies of tumor formation in nude mice. Overexpression of catalase (CAT) alone was found to have little effect on tumor cell growth, but overexpression of glutathione peroxidase 1 (GPx1) completely suppressed tumor cell growth in nude mice. This finding suggests that peroxides removed by GPx1, but not by CAT, are also involved in ras-induced transformation.
Mol Carcinog 2002 Apr
PMID:v-Ha-ras mitogenic signaling through superoxide and derived reactive oxygen species. 1193 74

Accumulating data support the view that sepsis is associated with an acquired intrinsic derangement in the ability of cells to consume O(2), a phenomenon that has been termed "cytopathic hypoxia." We sought to use an in vitro "reductionist" model system using cultured cells stimulated with proinflammatory cytokines to test the hypothesis that cytopathic hypoxia is mediated, at least in part, by depletion of intracellular levels of NAD(+)/NADH secondary to activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). We measured O(2) consumption by Caco-2 enterocytes growing on microcarrier beads after cells were incubated for 24 h under control conditions or with cytomix, a mixture of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Immunostimulated cells consumed O(2) at about one-half the rate of control cells, but this effect was largely prevented if any one of the following pharmacological agents was present during the period of incubation with cytomix: 4,5-dihydroxy-1,3-benzene disulfonic acid, a superoxide radical anion scavenger; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a nitric oxide scavenger; 5,10,15,20- tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III], a peroxynitrite (ONOO(-)) decomposition catalyst; urate, an ONOO(-) scavenger; 3-aminobenzamide, a PARP inhibitor; or N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide HCl, a chemically dissimilar and more potent PARP inhibitor. The decrease in O(2) uptake induced by cytomix was associated with decreased cellular levels of NAD(+)/NADH. The decrease in cellular NAD(+)/NADH content and the decrease in O(2) uptake induced by cytomix were completely abrogated if liposome-encapsulated NAD(+) was added to the cultures during immunostimulation. Empty liposomes also increased O(2) uptake by immunostimulated Caco-2 cells, but much less effectively than liposomes containing NAD(+). These data are consistent with the view that enterocytes exposed to proinflammatory cytokines consume less O(2) due to NAD(+)/NADH depletion secondary to activation of PARP by ONOO(-) or other oxidants.
Am J Physiol Lung Cell Mol Physiol 2002 May
PMID:Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. 1194 74

The rotenone-insensitive NADH dehydrogenase isolated from mitochondria of the procyclic form of Trypanosoma brucei has the ability to produce superoxide anions (Biochemistry 41 (2002) 3065). Superoxide production by the purified enzyme was 60% inhibited by diphenyl iodonium (DPI), stimulated significantly by ubiquinone analogues, and unaffected by metal ions. Production of reactive oxygen species (ROS) in intact cells was not affected by addition of rotenone with proline and malate as substrates; however, addition of rotenone inhibited 41% ROS production with succinate as substrate. These results suggest that complex I is not involved in production of ROS and that succinate-linked reversed electron transport occurs in trypanosome mitochondria. Superoxide formation in mitochondria with NADH as substrate was stimulated by antimycin A but was unaffected by myxothiazol plus stigmatellin, indicating that bc(1) complex is not a source of superoxide. DPI and fumarate inhibited by 68 and 36%, respectively, the rate of superoxide production with NADH as substrate. Addition of both fumarate and DPI blocked 70% superoxide production in mitochondria, a total inhibition similar to that observed with DPI addition alone. These results suggest that the rotenone-insensitive NADH dehydrogenase in addition to NADH fumarate reductase is a potential source of superoxide production in procyclic trypanosome mitochondria.
Mol Biochem Parasitol 2002 Aug 28
PMID:Rotenone-insensitive NADH dehydrogenase is a potential source of superoxide in procyclic Trypanosoma brucei mitochondria. 1227 Jun 29

The manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that dismutates a potentially toxic superoxide radical into hydrogen peroxide and dioxygen. To study the regulation of the Schizosaccharomyces pombe MnSOD gene, the 943 bp upstream region was fused into the promoterless beta-galactosidase gene of the shuttle vector YEp357, which resulted in the fusion plasmid pMS14. Restriction mapping and nucleotide sequencing confirmed its construction. The synthesis of beta-galactosidase from the fusion plasmid was induced by aluminum chloride, menadione, cadmium chloride, manganese chloride, and hydrogen peroxide. It was also induced by NO-generating S-nitroso-N-acetylpenicillamine (SNAP). However, cupric chloride and zinc chloride did not affect the synthesis of beta-galactosidase from the fusion plasmid. The beta-galactosidase synthesis appeared to be independent of the Pap1 protein. These results suggest that some metals, oxidative stress, and nitric oxide regulate the S. pombe MnSOD gene.
Mol Cells 2002 Oct 31
PMID:Regulation of the manganese-containing superoxide dismutase gene from fission yeast. 1244 5

The mechanism leading to the high level of radiosensitivity of T lymphocytes has not yet been fully described. In our previous study, we demonstrated that human peripheral T lymphocytes revealed early apoptotic changes (annexin V-positive) and late apoptotic changes (propidium iodide-positive), at 13 and 24 h after irradiation of 5 Gy, respectively. Changes in mitochondrial membrane potential were observed at 10 h after irradiation of 5 Gy. Subsequently, mitochondrial cytochrome c release was confirmed. In order to elucidate the mechanism which occurs prior to the mitochondrial membrane potential changes, we examined in the present study the radiation dose and the timing of oxidative DNA damage induced in human peripheral T lymphocytes following 10 MV X-ray irradiation. As a result, the production of 8-oxoguanine, i.e., the product of oxidative DNA damage, was clearly identified starting at 10, 6, and 3 h, after 2, 5, and 20 Gy of irradiation, respectively. Therefore, we concluded that it remains necessary to evaluate the extent of radiation-induced oxidative DNA damage. Furthermore, it is important to analyze superoxide radical production and scavenging in terms of the variety of radiosensitivities found among various types of normal tissue cells and neoplastic cells.
Int J Mol Med 2003 Jan
PMID:Radiation-induced oxidative DNA damage, 8-oxoguanine, in human peripheral T cells. 1246 13

The actinomycin D (AD)-induced apoptosis in human leukemia CMK-7 cell line is greatly accelerated by microtubule disruption with colcemid (CL). We studied the effect of antioxidants on this apoptosis in order to learn how the universal signal mediators, reactive oxygen species (ROS), are involved. Caspase-3 activation and DNA fragmentation were both suppressed by vitamin E (VE), t-butylhydroxyanisole, and luteolin. The ROS formation in the AD treatment was evidenced by flow cytometry, and further supported by suppression of caspase-3 activation by superoxide radical-forming enzyme inhibitors (TTFA, rotenone, and DPI). The inhibition of apoptosis by VE was completed during the initial 1-h treatment with AD, but it did not appear when VE was added with CL to washed cells after AD treatment. Luteolin, an iron chelator PDTC, and a water-soluble VE analogue, trolox, inhibited the apoptosis when added with CL after the AD treatment. Western blot analysis showed that the proteolytic cleavage of procaspase-9 and procaspase-3 were both inhibited when VE was added with AD or when luteolin was added with CL, and that the cytochrome c liberation was suppressed by both antioxidants. This result implies that the ROS are initially formed in lipophilic environments (e.g. mitochondrial membrane) and then they diffuse into an aqueous environment (i.e. cytoplasm) where they promote the apoptotic process in combination with the cytoskeletal disruption. Thus, the different antioxidants are effective to scavenge ROS for preventing the apoptosis in its different phases.
Mol Cell Biochem 2003 Aug
PMID:Differential effects of vitamin E and three hydrophilic antioxidants on the actinomycin D-induced and colcemid-accelerated apoptosis in human leukemia CMK-7 cell line. 1296 51

Superoxide dismutases (SOD) convert superoxide radicals into less damaging hydrogen peroxide. The opportunistic human pathogen Candida albicans is known to express CuZnSOD (SOD1) and MnSOD (SOD3) in the cytosol and MnSOD (SOD2) in the mitochondria. We identified three additional CuZn-containing superoxide dismutases, SOD4, SOD5, and SOD6, within the sequence of the C. albicans genome. The transcription of SOD5 was up-regulated during the yeast to hyphal transition of C. albicans, and SOD5 was induced when C. albicans cells were challenged with osmotic or with oxidative stresses. SOD5 transcription was also increased when cells were grown on nonfermentable substrates as the only carbon source. The Rim101p transcription factor was required for all inductions observed, whereas the Efg1p transcription factor was specifically needed for serum-modulated expression. Deletion of SOD5 produced a viable mutant strain that showed sensitivity to hydrogen peroxide when cells were grown in nutrient-limited conditions. Sod5p was found to be necessary for the virulence of C. albicans in a mouse model of infection. However, the sod5 mutant strain showed the same resistance to macrophage attack as its parental strain, suggesting that the loss of virulence in not due to an increased sensitivity to macrophage attack.
Mol Biol Cell 2004 Feb
PMID:Superoxide dismutases in Candida albicans: transcriptional regulation and functional characterization of the hyphal-induced SOD5 gene. 1461 19

Previous studies have shown that a constitutively active isoform of Ras is able to produce superoxide radical (O2(-)). The present study investigate the mechanisms by which O2(-) radical mediates signals from Ras protein to the nucleus, leading to cellular responses such as apoptosis in Cr(VI)-stimulated cells. Two human prostate tumor cell lines, Ras(+), which overexpresses Ras, and Ras(-), which has a normal Ras level, were utilized. Compared to Ras(-) cells, Ras(+) cells exhibited higher susceptibility to apoptosis induced by Cr(VI). Catalase, sodium formate, and deferoxamine inhibited Cr(VI)-induced apoptosis. Similar differences were observed in both cellular DNA damage and the activation of p53 protein. The differences in Cr(VI)-induced cell responses in Ras(+) and Ras(-) cells were due to differences in the generation of free radicals between these two cells. ESR spin trapping measurements showed that Ras(+) cells generated more hydroxyl radical ((.)OH), O2(-) radical, and Cr(V) than Ras(-) cells following Cr(VI) stimulation. The generation of the reactive oxygen species (ROS) can be abolished by the addition of superoxide dismutase (SOD) or if the experiment were carried out in an argon atmosphere. Catalase inhibited spin adduct signals but was much less potent than SOD. The mechanism of ROS generation in Cr(VI)-stimulated Ras(+) cells involves the reduction of molecular oxygen to O2(-) radical by a flavoenzyme-containing NADPH oxidase complex as shown by oxygen consumption and diphenylene iodonium (DPI) inhibition. Results shown above support the following conclusions: (a) Ras protein mediates O2(-) radical generation through reduction of molecular oxygen by NADPH oxidase in Cr(VI)-stimulated cells. (b) The O2(-) radical and Cr(VI) produce other reactive species, including H2O2, OH radical, and Cr(V) through O2(-) dismutation and Haber-Weiss type of reactions. (c) Among these reactive species, (.)OH radical is responsible for the further transduction of signals from Ras to the nucleus, leading to various cell responses.
Mol Cell Biochem 2004 Jan
PMID:Role of reactive oxygen species and Cr(VI) in Ras-mediated signal transduction. 1497 53


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