S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biochemistry & Molecular Biology (생화학교실) Journal Papers (저널논문_생화학교실)
DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress
- Jin, S M; Cho, H J; Jung, E S; Shim, M-Y; Mook-Jung, I
- Issue Date
- Nature Publishing Group
- Cell Death Differ. 2008; 15(9): 1375-1384
- Amyloid Precursor Protein Secretases/*metabolism; Amyloid beta-Protein/*metabolism/pharmacology; Animals; *Apoptosis; CHO Cells; Camptothecin/toxicity; Cricetinae; Cricetulus; Cytochromes c/metabolism; *DNA Damage; Enzyme Activation; Etoposide/toxicity; Glutathione/metabolism; Humans; Mice; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins/antagonists & inhibitors; *Oxidative Stress; Reactive Oxygen Species/metabolism
- According to the amyloid cascade hypothesis, Alzheimer's disease is the consequence of neuronal cell death induced by beta-amyloid (Abeta), which accumulates by abnormal clearance or production. On the other hand, recent studies have shown cell death-induced alteration in amyloid precursor protein (APP) processing, suggesting potential mutual interactions between APP processing and cell death. We have shown previously that the cell death caused by DNA damage-inducing agents (DDIAs) facilitated gamma-secretase activity and Abeta generation in a Bax/Bcl-2-dependent, but caspase-independent manner. Here, we attempted to elucidate the downstream mechanism that modulates gamma-secretase activity in DDIA-treated cells. N-acetyl cysteine, a potent antioxidant, attenuated DDIA-induced enhancement of gamma-secretase activity but failed to rescue cell death. Overexpression of heat shock protein 70, which blocks cytochrome c release from mitochondria, also reduced gamma-secretase activity. Moreover, glutathione depletion significantly facilitated gamma-secretase activity and Abeta generation by enhancing the formation of higher molecular weight gamma-secretase complex before signs of cell death developed. Finally, Abeta treatment, a known inducer of oxidative stress, also increased gamma-secretase activity. Taken together, these results indicate that DDIA-induced gamma-secretase activation is dependent on augmented oxidative stress, and that Abeta and gamma-secretase may activate each other. On the basis of these results, we propose a feed-back loop between oxidative stress and Abeta generation mediated by gamma-secretase activation.
- 1350-9047 (Print)
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