Cadmium-induced germline apoptosis in Caenorhabditis elegans: the roles of HUS1, p53, and MAPK signaling pathways.
Cadmium-induced germline apoptosis in Caenorhabditis elegans: the roles of HUS1, p53, and MAPK signaling pathways.
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DOI：
10.1093/toxsci/kfm220
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发表时间：
2008-04
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影响因子：
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通讯作者：
Shunchang Wang;Minli Tang;Bei Pei;Xiang Xiao;Jun Wang;H. Hang;Lijun Wu
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作者：
Shunchang Wang;Minli Tang;Bei Pei;Xiang Xiao;Jun Wang;H. Hang;Lijun Wu
过渡金属镉（Cd）已被证明可诱导多种细胞系和组织的凋亡。肿瘤抑制基因p53和丝裂原活化蛋白激酶（MAPK）信号级联的Caspase激活已被报道参与cd诱导的细胞凋亡。然而，由于缺乏适当的动物模型，cd诱导细胞凋亡的潜在途径在体内系统中尚未被清楚地阐明。秀丽隐杆线虫已被证明是研究包括细胞凋亡在内的基本生物学过程的良好模型。在这项研究中，我们使用了秀丽隐杆线虫的突变等位基因，这些等位基因与已知的哺乳动物基因同源，参与细胞凋亡的调节。亚致死剂量的Cd暴露增加秀丽隐杆线虫生殖细胞凋亡呈剂量和时间依赖性。DNA损伤反应（DDR）基因HUS1和p53的功能缺失突变在Cd暴露下显着增加了种系细胞凋亡，p53拮抗剂ABL1的缺失显着增强了细胞凋亡。cd诱导的细胞凋亡在c-Jun n -末端激酶（JNK）和p38 MAPK级联的功能丧失等位基因中被阻断，这些等位基因在γ辐照下表现正常。我们的研究结果表明JNK和p38 MAPK级联参与cd诱导的细胞凋亡。总之，本研究结果表明，DDR基因hus1和p53在cd诱导的种系细胞凋亡中起非必要作用，并且凋亡通过ASK1/2-MKK7-JNK和ASK1/2-MKK3/6-p38信号通路以caspase依赖的方式发生。最后，我们的研究表明秀丽隐杆线虫是研究cd诱导细胞凋亡机制的哺乳动物体内替代模型。
The transition metal cadmium (Cd) has been shown to induce apoptosis in a variety of cell lines and tissues. Caspase activation of the tumor suppressor gene p53 and mitogen-activated protein kinase (MAPK) signaling cascades have been reported to be involved in Cd-induced apoptosis. However, the underlying pathways of Cd-induced apoptosis have not been clearly elucidated in the in vivo systems, primarily for the lack of appropriate animal models. The nematode Caenorhabditis elegans has been shown to be a good model to study basic biological processes, including apoptosis. In this study, we used the mutated alleles of C. elegans homologs of known mammalian genes that are involved in regulation of apoptosis. Sublethal doses of Cd exposure increased C. elegans germline apoptosis in a dose- and time-dependent manner. The loss-of-function mutations of DNA damage response (DDR) genes HUS1 and p53 exhibited significant increase in germline apoptosis under Cd exposure, and the depletion of p53 antagonist ABL1 significantly enhanced apoptosis. Cd-induced apoptosis was blocked in the loss-of-function alleles of both c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which behaved normally under gamma-irradiation. Our findings implicate that both JNK and p38 MAPK cascades participate in Cd-induced apoptosis. Together, the results of this study suggest the nonessential roles of the DDR genes hus1 and p53 in Cd-induced germline apoptosis and that the apoptosis occurs through the ASK1/2-MKK7-JNK and ASK1/2-MKK3/6-p38 signaling pathways in a caspase-dependent manner. Finally, our study demonstrates that C. elegans is a mammalian in vivo substitute model to study the mechanisms of Cd-induced apoptosis.