Delineation of the cell-extrinsic apoptosis pathway in the zebrafish
Delineation of the cell-extrinsic apoptosis pathway in the zebrafish
复制标题
DOI：
10.1038/sj.cdd.4402015
复制
发表时间：
2006-10-01
影响因子：
12.4
通讯作者：
Ashkenazi, A.
中科院分区：
文献类型：
--
作者：
Eimon, P. M.;Kratz, E.;Ashkenazi, A.
哺乳动物外源性细胞凋亡通路由Fas配体(FasL)和APO2配体/肿瘤坏死因子(TNF)相关的凋亡诱导配体(Apo2L/TRAIL)触发。与同源受体的配基结合直接激活死亡诱导信号复合体中的启动子caspase。在果蝇中，肿瘤坏死因子配体结合通过JNK间接激活启动子caspase。我们描述了斑马鱼的外在途径，以确定它在非哺乳动物脊椎动物中是如何运作的。我们鉴定了FasL和Apo2L/TRAIL的同源物、它们的受体以及细胞死亡机制的其他组件。对三个Apo2L/TRAIL同源物的研究表明，它们与受体zHDR(以前与造血有关)和卵巢TNFR(ZOTR)结合。这些配体在胚胎发育过程中的异位表达诱导了红细胞和脊索细胞的凋亡。抑制zHDR、zOTR、接头zFADD或类似caspase-8的蛋白水解酶可以阻断配体诱导的细胞凋亡，抗细胞凋亡的Bcl2家族成员也是如此。因此，斑马鱼的外源性凋亡途径与哺乳动物的凋亡途径非常相似，并与内在途径协同作用，在胚胎发生过程中响应异位Apo2L/TRAIL的表达而触发组织特异性的细胞凋亡。
The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression.