The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation
The tyrosine kinase Lck is required for CD95-independent caspase-8 activation and apoptosis in response to ionizing radiation
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DOI：
10.1038/sj.onc.1202878
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发表时间：
1999-09-02
期刊：
影响因子：
8
通讯作者：
Bamberg, M
中科院分区：
文献类型：
--
作者：
Belka, C;Marini, P;Bamberg, M
诱导细胞凋亡是细胞抑制剂药物和辐射诱导的人淋巴细胞和淋巴瘤细胞死亡的标志。然而，导致细胞凋亡的机制尚不清楚。我们提供的证据表明，电离辐射诱导caspase-8 （FLICE）的快速激活，随后凋亡独立于CD95配体/受体相互作用。辐射诱导procaspase-8裂解为成熟的caspase-8的模式类似于CD95交联后的模式，并导致促凋亡底物BID的裂解。caspase-8过表达会干扰辐射诱导的细胞凋亡，在src样酪氨酸激酶Lck基因缺陷的细胞中未观察到caspase-8被电离辐射激活，缺乏Lck的细胞对电离辐射诱导的细胞凋亡也表现出明显的抗性。再转染Lck后，caspase-8的激活和对电离辐射的凋亡能力恢复。我们得出结论，辐射通过lck控制的途径激活caspase-8，而不依赖于CD95配体的表达，这是辐射诱导T淋巴瘤细胞凋亡所需的一个新的信号事件。
Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. The radiation induced cleavage pattern of procaspase-8 into mature caspase-8 resembled that following CD95 crosslinking and resulted in cleavage of the proapoptotic substrate BID. Overexpression of dominant-negative caspase-8 interfered with radiation-induced apoptosis, Caspase-8 activation by ionizing radiation was not observed in cells genetically defective for the Src-like tyrosine kinase Lck, Cells lacking Lck also displayed a marked resistance towards apoptosis induction upon ionizing radiation. After retransfection of Lck, caspase-8 activation and the capability to undergo apoptosis in response to ionizing radiation was restored. We conclude that radiation activates caspase-8 via an Lck-controlled pathway independently of CD95 ligand expression, This is a novel signaling event required for radiation induced apoptosis in T lymphoma cells.