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Analysis of the signal transduction pathway of the transcription factor NF-κB activated by cytokines

细胞因子激活转录因子NF-κB信号转导通路分析

基本信息

批准号：
13660083
负责人：
KATAOKA Takao
金额：
$ 2.18万
依托单位：
Tokyo Institute of Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13660083/
关键词：
E-73 Cycloheximide TNF receptor NF-κB Apoptosis Mitochondria Penicillic acid Caspase-8 JNK caspase-8 サイトカイン p38 MAPキナーゼ

项目摘要

Acetoxycycloheximide (E-73) inhibits induction of the transcription factor NF-κB by TNF in the lung carcinoma A549 cells. Although E-73 failed to affect the expression of the adaptor proteins TRADD, RIP, and TRAF2, which are essential for activation of the NF-κB signaling pathway, the agent induced the downregulation of the cell-surface TNF receptor 1 via activation of p38 MAP kinase. By contrast, E-73 selectively induced caspase-dependent apoptosis and cytochrome c release from mitochondria in the human leukemia HL-60 and Jurkat T cells. E-73-induced cytochrome c release was blocked by the Bcl-2 family member Bcl-x_L and the JNK inhibitor SP600125, but was unaffected by the caspase inhibitor z-VAD-fmk and the p38 MAP kinase inhibitor SB203580. Thus, these data suggest that E-73 induces cytochrome c release from mitochondria through the JNK activation, thereby triggering the caspase cascade.The mycotoxin penicillic acid inhibited apoptosis by preventing activation of caspase-8, but not recruitment of caspase-8 into the Fas-FADD complex upon stimulation with Fas ligand (FasL). Penicillic acid inhibited the enzymatic activities of caspase-3, caspase-8, and casoase-9. However, penicillic acid weakly inhibited activation of caspase-3 and casoase-9 in staurosporine-treated cells, but did inhibit caspase-8 activation in FasL-treated cells, suggesting that penicillic acid selectively targets caspase-8 at the cellular level. Glutathione and cysteine suppressed the inhibitory effect of penicillic acid on caspase-8, and penicillic acid directly bound to the active center cysteine of caspase-8. These results demonstrate that penicillic acid inhibits FasL-induced apoptosis by blocking the self-processing of caspase-8.

Acetoxycycloheximide （E-73）抑制TNF对肺癌A549细胞转录因子NF-κB的诱导作用。虽然E-73不能影响NF-κB信号通路激活所必需的接头蛋白TRADD、RIP和TRAF2的表达，但该药物通过激活p38 MAP激酶诱导细胞表面TNF受体1的下调。相比之下，E-73选择性诱导人白血病HL-60和Jurkat T细胞的caspase依赖性凋亡和线粒体细胞色素c释放。e -73诱导的细胞色素c释放被Bcl-2家族成员Bcl-x_L和JNK抑制剂SP600125阻断，但不受caspase抑制剂z-VAD-fmk和p38 MAP激酶抑制剂SB203580的影响。因此，这些数据表明E-73通过JNK激活诱导线粒体释放细胞色素c，从而触发caspase级联反应。霉菌毒素青霉素酸通过阻止caspase-8的激活来抑制细胞凋亡，但在Fas配体（FasL）刺激下，caspase-8不被募集到Fas- fadd复合体中。青霉素酸抑制caspase-3、caspase-8和cascasase -9的酶活性。然而，在staurosporine处理的细胞中，青霉素酸弱抑制caspase-3和cascasase -9的激活，但在fasl处理的细胞中却抑制caspase-8的激活，这表明青霉素酸在细胞水平上选择性地靶向caspase-8。谷胱甘肽和半胱氨酸抑制了青霉酸对caspase-8的抑制作用，青霉酸直接与caspase-8的活性中心半胱氨酸结合。这些结果表明，青霉素酸通过阻断caspase-8的自我加工来抑制fasl诱导的细胞凋亡。