Hahn Peter J, Lai Zhi-Wei, Nevaldine Barbara, Schiff Ninel, Fiore Nancy C, Silverstone Allen E
Departments of Radiation Oncology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Radiat Res. 2003 Nov;160(5):559-67. doi: 10.1667/rr3058.
We have quantified the emergence of early chromatin breaks during the signal transduction phase of apoptosis in mouse thymocytes after treatment with either ionizing radiation or dexamethasone. Dexamethasone at 1 microM can induce significant levels of DNA breaks (equivalent to the amount induced directly by 7.5 Gy ionizing radiation) within 0.5 h of treatment. The execution phase of apoptosis was not observed until 4-6 h after the same treatment. The presence of the Bcl2 transgene under the control of the p56lck promoter almost completely inhibited apoptosis up to 24 h after treatment, but it had virtually no effect on the early chromatin cleavage occurring in the first 6 h. Ionizing radiation induced chromatin cleavage both directly by damaging DNA and indirectly with kinetics similar to the induction of chromatin cleavage by dexamethasone. The presence of the Bcl2 transgene had no effect on the direct or indirect radiation-induced cleavage in the first 6 h, but after the first 6 h, the Bcl2 gene inhibited further radiation-induced chromatin cleavage. These results suggest that endonucleases are activated within minutes of treatment with either dexamethasone or ionizing radiation as part of the very early signal transduction phase of apoptosis, and prior to the irreversible commitment to cell death.
我们已经对经电离辐射或地塞米松处理后的小鼠胸腺细胞凋亡信号转导阶段早期染色质断裂的出现情况进行了量化。1微摩尔的地塞米松在处理后0.5小时内可诱导显著水平的DNA断裂（相当于7.5 Gy电离辐射直接诱导的量）。直到相同处理后4 - 6小时才观察到凋亡的执行阶段。在p56lck启动子控制下的Bcl2转基因的存在在处理后长达24小时几乎完全抑制了凋亡，但对最初6小时内发生的早期染色质切割几乎没有影响。电离辐射既通过损伤DNA直接诱导染色质切割，也通过与地塞米松诱导染色质切割相似的动力学间接诱导。Bcl2转基因的存在在最初6小时对直接或间接辐射诱导的切割没有影响，但在最初6小时后，Bcl2基因抑制了进一步的辐射诱导的染色质切割。这些结果表明，作为凋亡非常早期信号转导阶段的一部分，在用糖皮质激素或电离辐射处理后的几分钟内核酸内切酶被激活，且早于对细胞死亡的不可逆承诺。
