S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
Human 8-oxoguanine DNA glycosylase suppresses the oxidative stress induced apoptosis through a p53-mediated signaling pathway in human fibroblasts
- Youn, Cha-Hyung.; Song, Peter I.; Kim, Mi-Hwa; Kim, Jin Sook; Hyun, Jin-Won; Choi, Sang-Joon; Yoon, Sang Pil; Chung, Myung Hee; Chang, In-Youb; You, Ho Jin
- Issue Date
- American Association for Cancer Research
- Mol Cancer Res. 2007 Oct;5(10):1083-98.
- *Apoptosis/genetics; Caspase 3/metabolism; Caspase 7/metabolism; Cell Line, Tumor; Cell Survival; DNA Damage/genetics; DNA Glycosylases/genetics/*physiology; Fibroblasts/enzymology; Humans; Hydrogen Peroxide/toxicity; *Oxidative Stress/genetics; RNA, Small Interfering/pharmacology; Signal Transduction; Tumor Suppressor Protein p53/antagonists & inhibitors/genetics/*metabolism
- Human 8-oxoguanine DNA glycosylase (hOGG1) is the main defense enzyme against mutagenic effects of cellular 7,8-dihydro-8-oxoguanine. In this study, we investigated the biological role of hOGG1 in DNA damage-related apoptosis induced by hydrogen peroxide (H(2)O(2))-derived oxidative stress. The down-regulated expression of hOGG1 by its small interfering RNA prominently triggers the H(2)O(2)-induced apoptosis in human fibroblasts GM00637 and human lung carcinoma H1299 cells via the p53-mediated apoptotic pathway. However, the apoptotic responses were specifically inhibited by hOGG1 overexpression. The p53-small interfering RNA transfection into the hOGG1-deficient GM00637 markedly inhibited the H(2)O(2)-induced activation of p53-downstream target proteins such as p21, Noxa, and caspase-3/7, which eventually resulted in the increased cell viability. Although the cell viability of hOGG1-knockdown H1299 p53 null cells was similar to that of the hOGG1 wild-type H1299, after the overexpression of p53 the hOGG1-knockdown H1299 showed the significantly decreased cell viability compared with that of the hOGG1 wild-type H1299 at the same experimental condition. Moreover, the array comparative genome hybridization analyses revealed that the hOGG1-deficient GM00637 showed more significant changes in the copy number of large regions of their chromosomes in response to H(2)O(2) treatment. Therefore, we suggest that although p53 is a major modulator of apoptosis, hOGG1 also plays a pivotal role in protecting cells against the H(2)O(2)-induced apoptosis at the upstream of the p53-dependent pathway to confer a survival advantage to human fibroblasts and human lung carcinomas through maintaining their genomic stability.
- 1541-7786 (Print)
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