Regulation of cell death by cell cycling

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Cellular defects that perturb cell cycle progression induce checkpoint-mediated cell cycle arrest, and the defect in this arrest causes cell death. However, checkpoint-independent cell cycle arrest is known to either induce or block cell death. In this study, we addressed mechanisms for cell cycling-mediated regulation of cell death and its biological significance. By using B lymphoma line that undergoes efficient apoptosis upon cell cycle arrest, we established the experimental system in which gene fragments regulating cell cycle arrest-induced apoptosis are enriched We isolated the c-myc gene as a regulator of cell cycle arrestinduced cell death. We further demonstrated that cell cycle arrest induces apoptosis in cells expressing a high level of c-myc, but induces survival in c-myclo cells. This result suggests that cMyc determines whether cell cycling regulates cell death positively or negatively. Further, we isolated genes involved in RNA metabolism such as SMN as regulators of cell cycling-regulated cell death. B lymphocytes undergo cell death upon antigen stimulation, and the antigen-induced cell death is abrogated by CD40 signaling for generating immune responses. We demonstrated that CD40mediated cell survival requires cell cycling, suggesting that regulation of cell death by cell cycling play a crucial role in the immune system. Further, we demonstrated that ROS is generated upon induction of cell death by cell cycle arrest or antigen stimulation, and plays a crucial role in the cell death.