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1. 发明申请

US20090047742A1 Inhibition of mRNA Interferase-Induced Apoptosis in BAK-Deficient and BAK- and Bax-Deficient Mammalian Cells 审中-公开
标题翻译：抑制BAK缺陷型和BAK-和Bax-缺陷型哺乳动物细胞中mRNA干扰素诱导的细胞凋亡
公开(公告)号：US20090047742A1
公开(公告)日：2009-02-19
申请号：US12064070
申请日：2006-08-22
申请人： Tsutomu Shimazu , Kurt Degenhardt , Eileen White , Masayori Inouye
发明人： Tsutomu Shimazu , Kurt Degenhardt , Eileen White , Masayori Inouye
IPC分类号： C12N15/87 , C12N5/06
CPC分类号： A61K48/0066 , A61K48/00 , C07K14/4747 , C12N9/22 , C12N2800/40
摘要： Ribonucleases, antibiotics, bacterial toxins and viruses inhibit protein synthesis, which results in apoptosis in mammalian cells. How the BCL-2 family of proteins regulates apoptosis in response to shutoff of protein synthesis is not known. According to the present invention, an Escherichia coli toxin MazF inhibited protein synthesis by cleavage of cellular mRNA, and induced apoptosis in mammalian cells. MazF-induced apoptosis required proapoptotic BAK and its upstream regulator, the proapoptotic BH3-only protein NBK/BIK, but not BIM, PUMA or NOXA. Furthermore, NBK/BIK- or BAK-deficient cells were resistant to cell death induced by pharmacologic inhibition of translation and by virus-mediated shutoff of protein synthesis. Thus, the BH3-only protein NBK/BIK is the apical regulator of a BAK-dependent apoptotic pathway in response to shutoff of protein synthesis. Although NBK/BIK is dispensable for development, it is the BH3-only protein targeted for inactivation by viruses, suggesting that it plays a role in pathogen/toxin response through apoptosis activation.
摘要翻译：核糖核酸酶，抗生素，细菌毒素和病毒抑制蛋白质合成，导致哺乳动物细胞凋亡。 BCL-2家族蛋白质如何调节蛋白质合成关闭反应的凋亡是未知的。根据本发明，大肠杆菌毒素MazF通过切割细胞mRNA抑制蛋白质合成，并诱导哺乳动物细胞的细胞凋亡。 MazF诱导的细胞凋亡需要促凋亡BAK及其上游调节因子，即促凋亡BH3蛋白NBK / BIK，而不是BIM，PUMA或NOXA。此外，NBK / BIK-或BAK缺陷细胞对由翻译的药理学抑制和蛋白质合成的病毒介导的切断引起的细胞死亡具有抗性。因此，仅BH3蛋白NBK / BIK是响应于蛋白质合成关闭的BAK依赖性凋亡途径的顶端调节剂。虽然NBK / BIK是不可开发的，但是仅针对通过病毒灭活的BH3蛋白，这表明它通过凋亡激活在病原体/毒素反应中起作用。

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