Regulation of cell death by cell cycling

扰乱细胞周期进程的细胞缺陷会导致检查点介导的细胞周期停滞，而这种停滞中的缺陷会导致细胞死亡。然而，已知的是，非检查点细胞周期停滞可以诱导或阻止细胞死亡。在这项研究中，我们讨论了细胞周期调节细胞死亡的机制及其生物学意义。我们利用细胞周期停滞后发生有效凋亡的B淋巴瘤细胞系，建立了丰富调控细胞周期停滞诱导细胞凋亡的基因片段的实验体系，分离出了调控细胞周期停滞诱导细胞死亡的c-myc基因。我们进一步证明，细胞周期停滞诱导高表达c-myc的细胞凋亡，但诱导c-myclo细胞存活。这一结果表明，cMyc决定了细胞周期对细胞死亡的调节是积极的还是消极的。此外，我们分离了参与RNA代谢的基因，如SMN，作为细胞周期调节细胞死亡的调节者。B淋巴细胞在抗原刺激下发生细胞死亡，而CD40信号可消除抗原诱导的细胞死亡，从而产生免疫应答。我们证明了CD40介导的细胞存活需要细胞周期，这表明通过细胞周期调节细胞死亡在免疫系统中起着至关重要的作用。此外，我们证明了ROS是在细胞周期停滞或抗原刺激诱导细胞死亡时产生的，在细胞死亡中起着至关重要的作用。

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.