JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways
JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways
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DOI：
10.1038/sj.cdd.4401353
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发表时间：
2004-03-01
影响因子：
12.4
通讯作者：
Kallunki, T
中科院分区：
文献类型：
--
作者：
Dietrich, N;Thastrup, J;Kallunki, T
最近的研究强烈表明，c-Jun n -末端激酶（JNK）信号通路积极参与肿瘤坏死因子（TNF）诱导的细胞凋亡。关于JNK及其同工异构体作用的直接证据一直缺失，JNK实际上如何促进这一过程的机制仍不清楚。在这项研究中，我们发现与相应的野生型和Jnk1-/- pmef相比，Jnk2-/-原代小鼠胚胎成纤维细胞（pmef）对tnf诱导的细胞凋亡表现出抗性。JNK2缺陷的pmef可以通过四种不同的JNK2剪接变体中的任何一种的逆转录病毒转导对TNF重新敏感。Jnk2-/- pMEFs表现出效应caspase激活缺陷和延迟，以及胞质半胱氨酸组织蛋白酶活性受损：这两个过程都是tnf诱导pMEFs有效凋亡所必需的。我们的研究表明，JNK在促进tnf诱导的pmef细胞凋亡中起核心作用，并且JNK2亚型可以调节这些细胞的线粒体和溶酶体死亡途径。
Recent studies strongly suggest an active involvement of the c-Jun N-terminal kinase (JNK) signaling pathway in tumor necrosis factor (TNF)-induced apoptosis. The direct evidence for the role of JNK and its isoforms has been missing and the mechanism of how JNK actually could facilitate this process has remained unclear. In this study, we show that Jnk2-/- primary mouse embryonic fibroblasts (pMEFs) exhibit resistance towards TNF-induced apoptosis as compared to corresponding wild-type and Jnk1-/- pMEFs. JNK2-deficient pMEFs could be resensitized to TNF via retroviral transduction of any of the four different JNK2 splicing variants. Jnk2-/- pMEFs displayed deficient and delayed effector caspase activation as well as impaired cytosolic cystein cathepsin activity: processes that both were needed for efficient TNF-induced apoptosis in pMEFs. Our work demonstrates that JNK has a central role in the promotion of TNF-induced apoptosis in pMEFs, and that the JNK2 isoform can regulate both mitochondrial and lysosomal death pathways in these cells.