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p53-InducedUp-Regulation ofMnSOD and GPx but notCatalase IncreasesOxidative Stress andApoptosis S. Perwez HussainPaul AmstadPeijun He2004 год

p53-Induced Up-Regulation of MnSOD and GPx but not Catalase Increases Oxidative Stress and Apoptosis
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Аннотация: Abstract 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.
Год издания: 2004
Авторы: S. Perwez Hussain, Paul Amstad, Peijun He, Ana I. Robles, Shawn E. Lupold, Ichiro Kaneko, Masato Ichimiya, Sagar Sengupta, Leah E. Mechanic, Shu Okamura, Lorne J. Hofseth, Matthew M. Moake, Makoto Nagashima, Kathleen Forrester, Curtis C. Harris
Издательство: American Association for Cancer Research
Источник: Cancer Research
Ключевые слова: Cancer-related Molecular Pathways, Cell death mechanisms and regulation, Folate and B Vitamins Research
Другие ссылки: Cancer Research (PDF)
Cancer Research (HTML)
PubMed (HTML)