Apoptosis signal-regulating kinase (ASK)-1 mediates apoptosis through activation of JNK1 following engagement of membrane immunoglobulin
Apoptosis signal-regulating kinase (ASK)-1 mediates apoptosis through activation of JNK1 following engagement of membrane immunoglobulin
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DOI：
10.1016/j.yexcr.2009.09.007
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发表时间：
2009-12-10
影响因子：
3.7
通讯作者：
Mizuguchi, Junichiro
中科院分区：
文献类型：
--
作者：
Furuhata, Masae;Takada, Eiko;Mizuguchi, Junichiro
WEHI-231小鼠B淋巴瘤细胞上的膜免疫球蛋白（mIg）的结合导致在细胞周期的G1期的生长停滞，随后是线粒体膜电位（Δ Psim）的降低和细胞凋亡。WEHI-231细胞在细胞表面表型和对mIg接合的敏感性方面类似于未成熟的B细胞。然而，潜在的分子机制，免疫球蛋白诱导的损失Δ Psim和细胞凋亡尚未建立。在这项研究中，我们发现，凋亡信号调节激酶1（ASK 1）-c-Jun N-末端激酶1（JNK 1）信号通路参与了通过产生活性氧（ROS）的mIg诱导的细胞凋亡。用抗IgM刺激WEHI-231细胞诱导磷酸化和随后的ASK 1活化，导致JNK活化。抗IgM刺激立即（5分钟）诱导过氧化氢（H2 O2）的产生，在随后的时间点（36-48小时）显著增加，伴随着Δ Psi m的损失和亚G1 DNA含量的细胞增加。与单独的对照载体相比，在过表达显性阴性形式的ASK 1的WEHI-231细胞中，抗IgM诱导的晚期H2 O2产生、Δ Psi m的损失和亚G1级分的增加都显著降低，但在过表达组成型活性形式的ASK 1的细胞中显著增强。这些mIg介导的事件也被ROS清除剂N-乙酰基-L-半胱氨酸（NAC）部分消除。综上所述，这些结果表明，mIg接合诱导H2 O2产生，导致ASK 1-JNK 1通路的激活，产生ROS-ASK/JNK的反馈放大环，导致Δ Psi m的丢失和最终的细胞凋亡。(C)2009 Elsevier Inc. All rights reserved.
Engagement of membrane immunoglobulin (mIg) on WEHI-231 mouse B lymphoma cells results in growth arrest at the G1 phase of the cell cycle, followed by a reduction of mitochondrial membrane potential (Delta Psi m) and apoptosis. WEHI-231 cells resemble immature B cells in terms of the cell surface phenotype and sensitivity to mIg engagement. However, the molecular mechanisms underlying mIg-induced loss of Delta Psi m and apoptosis have not yet been established. In this study, we show that apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling pathway participates in mIg-induced apoptosis through the generation of reactive oxygen species (ROS). Stimulation of WEHI-231 cells with anti-IgM induces phosphorylation and subsequent activation of ASK1, leading to JNK activation. Anti-IgM Stimulation immediately (5 min) induces hydrogen peroxide (H2O2) production with a substantial increase during later time points (36-48 h), accompanied by loss of Delta Psi m and an increase in cells with sub-G1 DNA content. The anti-IgM-induced late-phase H2O2 production, loss of Delta Psi m, and increase in the sub-G1 fraction were all reduced substantially in WEHI-231 cells overexpressing a dominant-negative form of ASK1, compared with control vector alone, but enhanced Substantially in cells overexpressing a constitutively active form of ASK1. These mIg-mediated events were also partially abrogated by ROS scavenger N-acetyl-L-cysteine (NAC). Taken together, these results Suggest that mIg engagement induces H2O2 production leading to activation of ASK1-JNK1 pathway, creating a feedback amplification loop of ROS-ASK/JNK that leads to loss of Delta Psi m and finally apoptosis. (C) 2009 Elsevier Inc. All rights reserved.