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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functional Genetic Screening Reveals The Role Of Mitochondrial Cytochrome B As A Mediator Of Fas-induced Apoptosis
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Functional Genetic Screening Reveals The Role Of Mitochondrial Cytochrome B As A Mediator Of Fas-induced Apoptosis

机译：功能基因筛选揭示了线粒体细胞色素B作为Fas诱导的细胞凋亡介体的作用。

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摘要

Functional selection of genetic suppressor elements (GSEs), engineered gene fragments that interfere with the function of a particular gene product, was used to identify regulators of FAS-induced apoptosis. Chicken DF-1 cells expressing human FAS receptor and susceptible to FAS-induced apoptosis were infected with a GSE library consisting of randomly fragmented normalized chicken cDNAs in a replication-competent avian retroviral vector. Virus-producing cells were subjected to several rounds of selection using FAS agonistic antibodies, resulting in isolation of a set of GSEs conferring resistance to FAS-induced apoptosis. Surprisingly, one of the isolated GSEs encoded a 42 amino acid-long polypeptide derived from the C-terminal half of cytochrome b (Cyt b) encoded by the mitochondrial genome. Subsequent experiments showed that caspase 8-dependent cleavage of mitochondrial Cyt b and translocation of its C-terminal half into the cytoplasm occurred during FAS-induced apoptosis in both chicken and human cells. Ectopic cytoplasmic expression of either full-length Cyt b or its C-terminal half in several human cell lines induced apoptosis, which could be suppressed by the isolated GSE, but not by Bcl2 over-expression or Apaf-1 or cytochrome c knock-down. These results reveal a cytochrome c-independent branch of FAS-induced apoptosis involving cleavage and cytoplasmic release of mitochondrial Cyt b.
机译：遗传抑制因子（GSE）的功能选择是干扰特定基因产物功能的工程化基因片段，用于鉴定FAS诱导的细胞凋亡的调控因子。在复制能力强的禽逆转录病毒载体中，用GSE文库感染表达人FAS受体并易受FAS诱导的凋亡的鸡DF-1细胞，该库由随机片段化的标准化鸡cDNA组成。使用FAS激动性抗体对产生病毒的细胞进行数轮选择，从而分离出一组赋予对FAS诱导的细胞凋亡抗性的GSE。令人惊讶地，分离的GSE之一编码由线粒体基因组编码的细胞色素b（Cyt b）的C-末端一半衍生的42个氨基酸长的多肽。随后的实验表明，在鸡和人的细胞中，FAS诱导的细胞凋亡过程中都发生了caspase 8依赖的线粒体Cyt b裂解及其C端一半转移到细胞质中。全长人Cyt b或其C末端一半在某些人细胞系中的异位胞质表达诱导凋亡，该凋亡可被分离的GSE抑制，但不能被Bcl2过表达或Apaf-1或细胞色素c敲低抑制。这些结果揭示了FAS诱导的细胞凋亡的细胞色素c独立分支，涉及线粒体Cyt b的裂解和胞质释放。

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