1999 Fiscal Year Final Research Report Summary
Analysis of apoptosis signal transduction cascades in optic-nerve system induced by dolichyl monophosphate and bFGF
| Project/Area Number |
10680600
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KANO Kazutaka University of Tokyo, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (70111507)
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| Project Period (FY) |
1998 – 1999
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| Keywords | Apoptosis / Optic nerve cell / Dolichyl Monophosphate / bFGF / Caspasse 3 (DEVDase) / Mitochondria / Respiratory Chain Complex / Cytochrome c release |
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| Research Abstract |
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.
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