Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Autophagy. 2010 Aug;6(6):813-5. doi: 10.1038/cdd.2010.7. Epub 2010 Aug 4.
Three main cell death phenotypes have been identified in mammalian systems: apoptosis, autophagy and programmed necrosis. Currently, the field lacks systems level approaches to assess how the intricate crosstalk and interconnectivity between the different death functional modules affect the cell's final outcome. In order to dissect the cell death network's architecture, we developed a platform that measures the outcome of single and double RNAi-mediated perturbations of different apoptotic and autophagic genes on both the final cell death performance, and the pattern of protein connectivity. We applied this platform on cells exposed to a DNA damaging drug, and identified several levels of connectivity between apoptosis and autophagy. In addition, using computational methods we suggested a novel biochemical pathway providing a connection between ATG5 and caspase-3. Scaling up this platform into hundreds of perturbations will reveal novel principles of the organization of the cell death network, and will provide the basis for future computational modeling.
细胞凋亡、自噬和程序性细胞坏死。目前，该领域缺乏系统水平的方法来评估不同死亡功能模块之间复杂的串扰和相互连接如何影响细胞的最终结果。为了剖析细胞死亡网络的结构，我们开发了一个平台，该平台可测量不同细胞凋亡和自噬基因的单次和双 RNAi 介导的扰动对最终细胞死亡性能和蛋白质连接模式的影响。我们将该平台应用于暴露于 DNA 损伤药物的细胞中，并鉴定出细胞凋亡和自噬之间的几个连通水平。此外，我们使用计算方法提出了一种新的生化途径，该途径为 ATG5 和 caspase-3 之间提供了连接。将该平台扩展到数百个扰动中，将揭示细胞死亡网络组织的新原则，并为未来的计算建模提供基础。
