Porter Lisa A, Cukier I Howard, Lee Jonathan M
Hamilton Regional Cancer Center, Hamilton, ON, Canada.
Blood. 2003 Mar 1;101(5):1928-33. doi: 10.1182/blood-2002-04-1103. Epub 2002 Nov 7.
Some cells undergo apoptosis in response to DNA damage, whereas others do not. To understand the biochemical pathways controlling this differential response, we have studied the intracellular localization of cyclin B1 in cell types sensitive or resistant to apoptosis induced by DNA damage. We found that cyclin B1 protein accumulates in the nucleus of cells that are sensitive to gamma radiation-induced apoptosis (thymocytes, lymphoid cell lines), but remains cytoplasmic in apoptosis-resistant cells (primary and transformed fibroblasts). Treatment of both cell types with leptomycin B, an inhibitor of CRM1-dependent cyclin B1 nuclear export, induces apoptosis. Furthermore, ectopic expression of cyclin B1-5xE, a protein that preferentially localizes to the nucleus, is sufficient to trigger apoptosis. Conversely, expression of cyclin B1-5xA, a predominantly cytoplasmic protein, fails to induce apoptosis. This suggests that nuclear accumulation is necessary for cyclin B1-dependent apoptosis. Our observations are consistent with the idea that localization of cyclin B1 is among the factors determining the cellular decision to undergo apoptosis in response to DNA damage.
一些细胞会因DNA损伤而发生凋亡，而另一些则不会。为了理解控制这种差异反应的生化途径，我们研究了细胞周期蛋白B1在对DNA损伤诱导的凋亡敏感或抗性的细胞类型中的细胞内定位。我们发现，细胞周期蛋白B1蛋白在对γ辐射诱导的凋亡敏感的细胞（胸腺细胞、淋巴细胞系）的细胞核中积累，但在抗凋亡细胞（原代和成纤维细胞系）中仍保留在细胞质中。用CRM1依赖性细胞周期蛋白B1核输出抑制剂莱普霉素B处理这两种细胞类型都会诱导凋亡。此外，优先定位于细胞核的蛋白细胞周期蛋白B1-5xE的异位表达足以触发凋亡。相反，主要位于细胞质中的蛋白细胞周期蛋白B1-5xA的表达未能诱导凋亡。这表明细胞核积累对于细胞周期蛋白B1依赖性凋亡是必要的。我们的观察结果与以下观点一致，即细胞周期蛋白B1的定位是决定细胞对DNA损伤作出凋亡决定的因素之一。
