A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis.
A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis.
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DOI：
10.1158/0008-5472.203.65.1
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Takamasa Ishii;K. Yasuda;A. Akatsuka;O. Hino;P. Hartman;N. Ishii
中科院分区：
文献类型：
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作者：
Takamasa Ishii;K. Yasuda;A. Akatsuka;O. Hino;P. Hartman;N. Ishii
线粒体细胞内氧化应激被认为在癌变和肿瘤发生中起重要作用，但直接的实验证据有限。本研究构建了一株SDHC基因（电子传递链中复合体II的亚基）突变的转基因小鼠细胞系（SDHC E69）来验证这一问题。SDHC E69细胞从线粒体中过量产生超氧阴离子(O(2)(-))，胞质羰基蛋白和DNA中8- oh脱氧鸟嘌呤含量升高，突变频率明显高于野生型。观察到caspase 3活性升高，线粒体膜电位降低，线粒体结构改变，提示该细胞系凋亡细胞较多。此外，一些逃脱凋亡的细胞发生了转化，在裸鼠上皮下注射SDHC E69细胞可导致良性肿瘤。这些结果强调了线粒体产生的氧化应激可能导致核DNA损伤、突变，并最终导致肿瘤发生的概念。
Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O(2)(-)) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.