p53-Induced Up-Regulation of MnSOD and GPx but not Catalase Increases Oxidative Stress and Apoptosis
| Autor: | Makoto Nagashima, Paul Amstad, Leah E. Mechanic, Shawn E. Lupold, Masato Ichimiya, Kathleen Forrester, S. Perwez Hussain, Curtis C. Harris, Ana I. Robles, Lorne J. Hofseth, Ichiro Kaneko, Matthew Moake, Sagar Sengupta, Peijun He, Shu Okamura |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
GPX1 animal diseases Apoptosis Biology Mitochondrion medicine.disease_cause Gene Expression Regulation Enzymologic Cell Line medicine Humans RNA Messenger chemistry.chemical_classification Glutathione Peroxidase Reactive oxygen species Superoxide Dismutase Lymphoblast Cytochrome c fungi Cytochromes c Fibroblasts Catalase Molecular biology Mitochondria Up-Regulation Oxidative Stress enzymes and coenzymes (carbohydrates) Oncology chemistry Doxorubicin Enzyme Induction biology.protein Calcium Tumor Suppressor Protein p53 Reactive Oxygen Species Oxidative stress |
| Zdroj: | Cancer Research. 64:2350-2356 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | p53-mediated apoptosis may involve the induction of redox-controlling genes, resulting in the production of reactive oxygen species. Microarray expression analysis of doxorubicin exposed, related human lymphoblasts, p53 wild-type (WT) Tk6, and p53 mutant WTK1 identified the p53-dependent up-regulation of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx). Consensus p53 binding sequences were identified in human MnSOD and GPx promoter regions. A 3-fold increase in the MnSOD promoter activity was observed after the induction of p53 in Li-Fraumeni syndrome (LFS) fibroblast, TR9-7, expressing p53 under the control of a tetracycline-regulated promoter. An increased protein expression of endogenous MnSOD and GPx also positively correlated with the level of p53 induction in TR9-7 cells. However, catalase (CAT) protein expression remained unaltered after p53 induction. We also examined the expression of MnSOD, GPx, and CAT in a panel of normal or LFS fibroblasts, containing either WT or mutant p53. We found increased MnSOD enzymatic activity, MnSOD mRNA expression, and MnSOD and GPx protein in LFS fibroblasts carrying a WT p53 allele when compared with homozygous mutant p53 isogenic cells. The CAT protein level was unchanged in these cells. We observed both the release of cytochrome C and Ca2+ from the mitochondria into the cytoplasm and an increased frequency of apoptotic cells after p53 induction in the TR9-7 cells that coincided with an increased expression of MnSOD and GPx, and the level of reactive oxygen species. The increase in apoptosis was reduced by the antioxidant N-acetylcysteine. These results identify a novel mechanism of p53-dependent apoptosis in which p53-mediated up-regulation of MnSOD and GPx, but not CAT, produces an imbalance in antioxidant enzymes and oxidative stress. |
| Databáze: | OpenAIRE |
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