Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because oxidative processes can participate in tumor promotion, it is likely that the cellular antioxidant defense also plays a role. We have compared the levels of the three major antioxidant enzymes, Cu,Zn-superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx), in promotable mouse epidermal JB6 cells clone 41 and nonpromotable cells, clone 30. We found that the constitutive activities of SOD and catalase were approximately twice as high in clone 41 as in clone 30 while the GPx activities were comparable. Correspondingly, catalase protein concentrations were higher in clone 41, according to immunoblots. Northern blot analysis indicated that the steady-state mRNA concentrations for SOD and catalase, but not for GPx, were considerably higher in clone 41 than in clone 30. Southern blot analysis showed no difference between the two clones in their complements of the SOD and catalase genes. Clone 41 also contained slightly higher constitutive levels of glutathione. The higher antioxidant capacity of promotable clone 41 may protect it from excessive toxicity of oxidant promoters and allow growth stimulation. Certain tumor promoters that lack oxidizing properties may generate a cellular prooxidant state by a variety of mechanisms (e.g., it had been reported that the phorbol ester PMA decreases the activities of catalase and SOD in mouse skin). We found for JB6 cells that this loss of enzyme activity was due to a decrease in the steady-state concentrations of catalase and SOD mRNA. No significant changes in the rates of transcription were detected in nuclear run-off experiments. The observed decreases in catalase and SOD can be considered as part of the complex reprogramming of gene expression that is set in motion by phorbol-12-myristate-13-acetate.
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PMID:Constitutive and phorbol-myristate-acetate regulated antioxidant defense of mouse epidermal JB6 cells. 278 90

Cytokines, phorbol esters, radiation and chemotherapeutic drugs up-regulate the expression of MnSOD (manganese superoxide dismutase). Using the VA-13 cell line, we studied the regulation of SOD2 upon treatment with PMA. Pre-treatment with CHX (cycloheximide) followed by PMA led to significantly higher levels of MnSOD mRNA compared with those with either agent alone, suggesting de novo synthesis of an inhibitory protein. PMA treatment modulates redox-sensitive transcription factors, therefore we evaluated the effects of this combination treatment upon AP-1 (activator protein 1) and NF-kappaB (nuclear factor kappaB), two trans-acting factors suggested to play a role in SOD2 regulation. Co-administration of CHX and PMA led to a time-dependent increase in the binding activity of NF-kappaB. Therefore we evaluated IkappaBalpha (inhibitory kappaBalpha) and found that co-administration decreased its steady-state level compared with either agent alone, suggesting that enhanced NF-kappaB activation is due to inhibition of IkappaBalpha synthesis. PMA activates PKC (protein kinase C) enzymes which phosphorylate IkappaBalpha, leading to its degradation, therefore we used GF109203X to inhibit PKC activity. Stable transfection utilizing a PMA-responsive element in the human SOD2 gene, showed a concentration-dependent decrease in luciferase and NF-kappaB-binding activity with GF109203X. Western blot analysis indicated the presence of several PKC isoforms in the VA-13 cell line; however, PMA pre-treatment specifically down-regulated alpha and betaI, suggesting a role for one or more of these proteins in SOD2 induction. Taken together, these results indicate that the PKC pathway leading to SOD2 induction proceeds at least in part through NF-kappaB and that inhibition of IkappaBalpha synthesis might serve as a potential pharmacological approach to up-regulate MnSOD.
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PMID:IkappaBalpha (inhibitory kappaBalpha) identified as labile repressor of MnSOD (manganese superoxide dismutase) expression. 1533 Jul 61

In humans, apoE, which plays a role in repair, is expressed in three isoforms: E2, E3, and E4. E4 is a risk factor for age-related cognitive decline (ACD) and Alzheimer's disease (AD), particularly in women. In contrast, E2 is a protective factor for ACD and AD. E2 and E4 might also differ in their response to cranial 137Cs irradiation, a form of radiation typically used in a clinical setting for the treatment of cancer. This might be mediated by reactive oxygen species (ROS) in an-apoE isoform-dependent fashion. E2 and E4 female mice received sham-irradiation or cranial irradiation at 8 weeks of age and a standard mouse chow or a diet supplemented with the antioxidant alpha-lipoic acid (ALA) starting at 6 weeks of age. Behavioral and cognitive performance of the mice were assessed 12 weeks later. Subsequently, the generation of ROS in hippocampal slices was analyzed. Compared to sham-irradiated E4 mice, irradiated E4 mice showed enhanced spatial memory in the water maze. This was associated with increased hippocampal PMA-induction of ROS. Similar effects were not seen in E2 mice. Irradiation increased endogenous hippocampal ROS levels in E2 mice while decreasing those in E4 mice. NADPH activity and MnSOD levels were higher in sham-irradiated E2 than E4 mice. Irradiation increased NADPH activity and MnSOD levels in hemi brains of E4 mice but not in those of E2 mice. ALA did not affect behavioral and cognitive performance or hippocampal formation of ROS in either genotype. Thus, apoE isoforms modulate the radiation response.
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PMID:Paradoxical effects of 137Cs irradiation on pharmacological stimulation of reactive oxygen species in hippocampal slices from apoE2 and apoE4 mice. 2910 Mar 34