Arsenite-induced germline apoptosis through a MAPK-dependent, p53-independent pathway in Caenorhabditis elegans.
Arsenite-induced germline apoptosis through a MAPK-dependent, p53-independent pathway in Caenorhabditis elegans.
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DOI：
10.1021/tx800074e
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发表时间：
2008-07
影响因子：
4.1
通讯作者：
Bei Pei;Shunchang Wang;Xiaoying Guo;Jun Wang;Gen Yang;H. Hang;Lijun Wu
中科院分区：
文献类型：
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作者：
Bei Pei;Shunchang Wang;Xiaoying Guo;Jun Wang;Gen Yang;H. Hang;Lijun Wu
许多研究表明，亚砷酸盐在细胞和组织中都是一种有效的细胞凋亡诱导剂。然而，缺乏合适的体内动物模型来研究亚砷酸盐诱导细胞凋亡的潜在机制。秀丽隐杆线虫是研究许多生物过程的良好模式生物。我们之前已经证明秀丽隐杆线虫可以作为体内系统来研究亚砷酸盐的遗传毒性效应。为了阐明体内亚砷酸盐诱导细胞凋亡的潜在机制，在本研究中，我们使用了已知的参与细胞凋亡调控的哺乳动物基因的秀丽隐杆线虫同源突变等位基因。我们的研究结果表明，在亚砷酸盐暴露下，p53/ cap -1和DNA损伤反应（DDR）基因hus-1、clk-2和egl-1的功能丧失突变显著增加了生殖细胞凋亡，而亚砷酸盐诱导的生殖细胞凋亡在细胞外信号调节激酶（ERK） （lin-45 （ku51）、mek-2 （n1989）和mpk-1 (ku1)）、c-Jun n末端激酶（JNK） （jkk-1 （km2）、mek-1 （ks54）、JNK -1 （gk7）、mkk-4 (ju91)）和p38 (nsy1 （ag3）的功能丧失等位基因中被阻断。sek-1 （ag1）和pmk-1 (km25)) MAPK级联。这些结果表明，砷酸盐诱导的细胞凋亡独立于p53/ cep-1和DNA损伤反应（DDR）基因hus-1、clk-2和egl-1发生，秀丽隐杆线虫caspase基因ced-3、Apaf-1同源基因ced-4和MAPK信号通路对生殖细胞凋亡至关重要。此外，我们的研究表明秀丽隐杆线虫可以作为哺乳动物体内研究细胞凋亡机制的替代模型。
Many studies have shown that arsenite is a potent inducer of apoptosis both in cells and tissues. However, there is a lack of appropriate in vivo animal models to study the underlying mechanisms of arsenite-induced apoptosis. Caenorhabditis elegans is an excellent model organism for studying many biological processes. We showed previously that C. elegans could be used as an in vivo system to investigate the genotoxic effects of arsenite. In order to elucidate the underlying mechanisms of arsenite-induced apoptosis in vivo, in the present study, we used the mutated alleles of the C. elegans homologue of known mammalian genes that are involved in the regulation of apoptosis. Our results showed that the loss-of-function mutations of p53/ cep-1 and DNA damage response (DDR) genes hus-1, clk-2, and egl-1 exhibited significant increase in germline apoptosis under arsenite exposure, whereas arsenite-induced germline apoptosis was blocked in loss-of-function alleles of extracellular signal-regulated kinase (ERK) (lin-45 (ku51), mek-2 (n1989), and mpk-1 (ku1)), c-Jun N-terminal kinase (JNK) (jkk-1 (km2), mek-1 (ks54), jnk-1 (gk7), mkk-4 (ju91)), and p38 ( nsy-1 (ag3), sek-1 (ag1), and pmk-1 (km25)) MAPK cascades. These results suggest that arsenite-induced apoptosis occurs independently of p53/ cep-1 and the DNA damage response (DDR) genes hus-1, clk-2, and egl-1 and that the C. elegans caspase gene ced-3, Apaf-1 homologue ced-4, and the MAPK signaling pathways are essential for germline apoptosis. Moreover, our study demonstrates that C. elegans could be a mammalian in vivo substitute model to study the mechanisms of apoptosis.