The road not taken: a systems level strategy for analyzing the cell death network.
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.
Zalckvar
Einat
E
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Bialik
Shani
S
Kimchi
Adi
A
D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology
D005047:Etoposide