Ionizing radiation-induced apoptosis in ataxia-telangiectasia fibroblasts - Roles of caspase-9 and cellular inhibitor of apoptosis protein-1
Ionizing radiation-induced apoptosis in ataxia-telangiectasia fibroblasts - Roles of caspase-9 and cellular inhibitor of apoptosis protein-1
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DOI：
10.1074/jbc.m010525200
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发表时间：
2001-08-03
影响因子：
4.8
通讯作者：
Jung, M
中科院分区：
文献类型：
--
作者：
Zhang, Y;Dimtchev, A;Jung, M
电离辐射（IR）已被证明在更大程度上诱导细胞凋亡的成纤维细胞系AT 5 BIVA来自一个人共济失调毛细血管扩张症（AT）比对照成纤维细胞。然而，IR诱导AT细胞凋亡的信号通路仍然未知。现在已经在来自不同AT个体的三种AT成纤维细胞系（AT 3BIVA、AT 4 BIVA和AT 5 BIVA）中检查了响应于γ-辐射的细胞凋亡机制。照射后72小时，这些细胞系的凋亡指数分别为12，31和35%，与对照成纤维细胞的2.3%的值相比。免疫印迹分析和荧光分析显示，IR诱导的caspase-3和caspase-9的活化程度在AT 4 BrVA和AT 5 BIVA细胞中明显大于在AT 3BIVA和对照细胞中。此外，与AT 3BIVA和对照细胞相比，AT 4 BIVA和AT 5 BIVA细胞中细胞凋亡抑制剂（细胞凋亡抑制蛋白（c-IAP-1））的基础丰度显著降低。AT 5 BIVA细胞中caspase-9突变体形式或重组c-IAP-1的过表达抑制IR诱导的caspase-3和9的活化，并降低辐射细胞的凋亡指数。这些结果表明，在不同的AT细胞系的IR诱导的细胞凋亡的程度是负相关的c-IAP-1的丰度和直接相关的caspase-3和9的激活程度。
Ionizing radiation (IR) has been shown to induce apoptosis to a greater extent in a fibroblast cell line AT5BIVA derived from an individual with ataxia-telangiectasia (AT) than in control fibroblasts. However, the signaling pathway that underlies IR-induced apoptosis in AT cells has remained unknown. The mechanism of apoptosis in response to gamma -irradiation has now been examined in three AT fibroblast lines (AT3BIVA, AT4BIVA, and AT5BIVA) derived from different individuals with AT. The apoptotic indexes of these cell lines at 72 h after irradiation were 12, 31, and 35%, respectively, compared with a value of 2.3% for control fibroblasts. Immunoblot analysis and fluorometric assays revealed that the extents of IR-induced activation of caspase-3 and caspase-9 were markedly greater in AT4BrVA and AT5BIVA cells than in AT3BIVA and control cells. Furthermore, the basal abundance of the apoptotic inhibitor, a cellular inhibitor of apoptosis proteins (c-IAP-1), was markedly reduced in AT4BIVA and AT5BIVA cells compared with that in AT3BIVA and control cells. The overexpression of either caspase-9 mutant forms or recombinant c-IAP-1 in AT5BIVA cells inhibited the IR-induced activation of caspases-3 and 9 and reduced the apoptotic index of the irradiated cells. These results indicate that the extent of IR-induced apoptosis in different AT cell lines is inversely related to the abundance of c-IAP-1 and directly related to the extent of activation of caspases-3 and 9.