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Analysis of apoptosis signal transduction cascades in optic-nerve system induced by dolichyl monophosphate and bFGF

单磷酸多萜酯和bFGF诱导视神经系统凋亡信号转导级联分析

基本信息

批准号：
10680600
负责人：
KANO Kazutaka
金额：
$ 0.7万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680600/
关键词：
Apoptosis Optic nerve cell Dolichyl Monophosphate bFGF Caspasse 3 (DEVDase)Mitochondria Respiratory Chain Complex Cytochrome c release 細胞死 U937細胞チトクロームc 情報伝達

项目摘要

We reported previously that dolichyl phosphate (Dol-p) activated caspase-3 (DEVDase), a key executioner to induce apoptosis in human premonocytic leukemia U937 cells . However, the mechanism of apoptosis caused by this lipid is unclear. In this study, we demonstrated that mitochondrial change such as swelling, and loss of the transmembrane potential, and reactive oxygen species (ROS) production occurred by treatment of Dol-p. Further studies using isolated mitochondria showed that the activities of respiratory chain complex I, II and III were inhibited by Dol-p in a dose dependent manner. Dol-p also induced the release of cytochrome c from the isolated mitochondria. Dol-p-induced DEDase activity was inhibited by artificial electron carriers, 6 , 6-dichlorophenolindophenol and N, N, N1, N1, tetramethyl p-phenylenediamine, and an antioxidant, pyrrolidine dithocarbamate. This also suggests that a role of mitochondrial electron flow alterations in Dol-p-induced DEVDase activation. DEVDase activity increased by co-treatment of rotenone and TTFA (specific complex I and 11 inhibitors) at the concentration that themselves had no influence. These results shows that direct block of respiratory chain at CI, CII and CIII by Dol-P raise cytochrome c release from mitochondria followed an executioner caspase (DEVDase) activation.

我们之前报道了dolp激活了caspase-3 (DEVDase)，这是诱导人单核细胞白血病U937细胞凋亡的关键刽子手。然而，这种脂质引起细胞凋亡的机制尚不清楚。在这项研究中，我们证明了dolp处理会导致线粒体发生变化，如肿胀、跨膜电位丧失和活性氧（ROS）的产生。对分离线粒体的进一步研究表明，dolp对呼吸链复合体I、II和III的活性具有剂量依赖性。dolp还诱导离体线粒体释放细胞色素c。人工电子载体6,6 -二氯苯酚和N， N, N1, N1，四甲基对苯二胺以及抗氧化剂吡咯烷二硫代氨基甲酸酯抑制了dolp诱导的dedease活性。这也表明线粒体电子流改变在dolp诱导的DEVDase激活中的作用。鱼藤酮和TTFA（特异性复合物I和11抑制剂）在其本身没有影响的浓度下共同处理可以增加DEVDase的活性。这些结果表明，dolp直接阻断CI、CII和CIII呼吸链，增加了线粒体细胞色素c的释放，并激活了刽子手半胱天冬酶（executioner caspase, DEVDase）。