ASK1 mediates apoptotic cell death induced by genotoxic stress
ASK1 mediates apoptotic cell death induced by genotoxic stress
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DOI：
10.1038/sj.onc.1202276
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发表时间：
1999-01-07
期刊：
影响因子：
8
通讯作者：
Tsuruo, T
中科院分区：
文献类型：
--
作者：
Chen, ZH;Seimiya, H;Tsuruo, T
遗传毒性应激诱导的细胞凋亡是由caspase家族蛋白酶介导的，如由其他刺激触发的。在这项研究中，我们发现DNA损伤剂顺铂（cDDP）激活MAP激酶ASK 1和随后的MAP激酶激酶下游亚组，SEK 1（或MKK 4）和MKK 3/MKK 6，进而激活c-Jun N-末端激酶1/应激激活蛋白激酶在人卵巢癌（OVCAR-3）和人肾（293 T）细胞中，JNK 1/SAPK和p38 MAP激酶在半胱天冬酶家族蛋白酶活化和凋亡开始之前的表达。如前所述，苄氧基羰基-Asp-CH 2 OC（O）-2，6-二氯苯（Z-Asp），一种caspase家族蛋白酶的优先抑制剂，阻断了由遗传毒性应激cDDP诱导的OVCAR-3细胞凋亡。然而，Z-Asp并不抑制ASK 1活化和随后的激酶级联反应。过表达激酶阴性的ASK 1（K709 R）可抑制ASK 1的活化和下游的MKK 3-p38和MKK 4-JNK 1通路，也可抑制cDDP诱导的caspase蛋白酶活化和细胞凋亡。这些结果表明，ASK 1途径参与遗传毒性应激诱导的细胞凋亡，并介导凋亡的一个步骤上游的半胱天冬酶蛋白酶激活。
Genotoxic stress-induced apoptosis is mediated by caspase family proteases as triggered by other stimuli. In this study, we found that the DNA-damaging agent cisplatin (cDDP) activated MAP kinase kinase kinase ASK1 and subsequent downstream subgroups of MAP kinase kinase, SEK1 (or MKK4) and MKK3/MKK6, which in turn activated c-Jun N-terminal kinase 1/stress-activated protein kinase (JNK1/SAPK) and p38 MAP kinase prior to caspase family protease activation and the onset of apoptosis in human ovarian carcinoma (OVCAR-3) and human kidney (293T) cells. As reported previously, benzyloxy carbonyl-Asp-CH2OC(O)-2, 6-dichlorobenzene (Z-Asp), a preferential inhibitor of caspase family proteases, blocked the apoptosis of OVCAR-3 cells induced by the genotoxic stress cDDP. Z-Asp, however, did not inhibit ASK1 activation and the subsequent kinase cascades. Overexpression of kinase-negative ASK1 (K709R), which inhibited ASK1 activation and the downstream MKK3-p38 and MKK4-JNK1 pathways, also suppressed the caspase protease activation and apoptosis induced by cDDP. These results indicate that the ASK1 pathway is involved in genotoxic stress-induced apoptosis and mediates apoptosis at a step upstream of caspase protease activation.