Feng Yongdong, Wu Jianhong, Feng Xiaolan, Tao Deding, Hu Junbo, Qin Jichao, Li Xiaolan, Xiao Wei, Gardner Kevin, Judge Susan I V, Li Qingdi Q, Gong Jianping
Cancer Center, Tongji Hospital, Tongji Medical College, Central China University of Science and Technology, Wuhan 430030, PR China.
Oncol Rep. 2007 Jun;17(6):1437-44.
Apoptosis results in cell death within 10 min after initiation by Bcl-2 family proteins and mitochondria; however, cells enter the apoptotic pathway at different elapsed times after being triggered. Intrinsic factors related to chemical or physical cell damage can initiate apoptosis at a specific cell cycle phase; it is not clear whether cells insulted via an extrinsic pathway also die at a specific cell cycle phase, or how apoptosis is related to cell cycle progression in cells. To illustrate the kinetic changes of apoptosis during cell cycle progression, we examined both intrinsically and extrinsically induced apoptosis in MOLT-4 and Jurkat lymphocytic leukemia cells and in cultured peripheral blood lymphocytes (PBLs) using a recently modified annexin V and propidium iodide method, which detects cell cycle-specific apoptosis. Apoptosis predominantly occurred at a specific cell cycle phase. Leukemia cells were sensitive to induction by both intrinsic (X-rays, UV light, camptothecin, arsenic trioxide, and the traditional Chinese medicine Jinke, which is an extract of Auricularia auricula) and extrinsic factors (via Fas and TNF receptor pathways). The phase at which leukemia cells entered apoptosis depended on the nature of the insult (X-ray or UV, G1-phase; camptothecin, S-phase; arsenic, G1/S phases; Jinke, G1/S phases; and TNF or Fas ligand, G1/S phases), whereas PBLs did not exhibit such insult-dependent differences. PHA-stimulated PBLs entered apoptosis, and additional cells were recruited following additional insults. Unstimulated PBLs remained unresponsive to apoptosis, and proliferating cells became insensitive to the insults after the cell cycle checkpoint was abolished by caffeine. Confluent or starving PBLs were also unresponsive to apoptotic triggers. Thus, apoptotic cell death is a cell cycle event with most, if not all, apoptosis being initiated during a particular cell cycle phase, and changes in the cell cycle result in changes in the apoptotic pattern and schedule. The coordination of apoptosis and proliferation in cells offers a mechanism for the integration of both cell cycle and apoptotic signals.
细胞凋亡是由Bcl-2家族蛋白和线粒体引发的，在启动后10分钟内导致细胞死亡；然而，细胞在被触发后不同的时间进入凋亡途径。与化学或物理性细胞损伤相关的内在因素可在特定细胞周期阶段引发细胞凋亡；目前尚不清楚通过外在途径受到损伤的细胞是否也在特定细胞周期阶段死亡，或者细胞凋亡与细胞周期进程之间是如何关联的。为了阐明细胞周期进程中细胞凋亡的动力学变化，我们使用最近改良的膜联蛋白V和碘化丙啶方法，检测细胞周期特异性凋亡，研究了MOLT-4和Jurkat淋巴细胞白血病细胞以及培养的外周血淋巴细胞（PBL）中内在和外在诱导的细胞凋亡。细胞凋亡主要发生在特定的细胞周期阶段。白血病细胞对内在因素（X射线、紫外线、喜树碱、三氧化二砷以及中药金科，即黑木耳提取物）和外在因素（通过Fas和TNF受体途径）的诱导均敏感。白血病细胞进入凋亡的阶段取决于损伤的性质（X射线或紫外线，G1期；喜树碱，S期；砷，G1/S期；金科，G1/S期；TNF或Fas配体，G1/S期），而PBL没有表现出这种损伤依赖性差异。PHA刺激的PBL进入凋亡，额外的损伤会导致更多细胞被招募。未刺激的PBL对凋亡无反应，在咖啡因消除细胞周期检查点后，增殖细胞对损伤变得不敏感。汇合或饥饿的PBL对凋亡触发因素也无反应。因此，凋亡性细胞死亡是一个细胞周期事件，大多数（如果不是全部）细胞凋亡在特定细胞周期阶段启动，细胞周期的变化导致凋亡模式和时间表的改变。细胞凋亡与增殖的协调为整合细胞周期和凋亡信号提供了一种机制。
