| Project/Area Number |
11470194
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | SAPPORO MEDICAL UNIVERSITY |
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Principal Investigator |
HAREYAMA Masato School of Medicine, SAPPORO MEDICAL UNIVERSITY Professor, 医学部, 教授 (10173098)
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| Co-Investigator(Kenkyū-buntansha) |
SAKATA Ko-ichi School of Medicine, SAPPORO MEDICAL UNIVERSITY Associate Professor, 医学部, 助教授 (10235153)
IMAI Kozo School of Medicine, SAPPORO MEDICAL UNIVERSITY Professor, 医学部, 教授 (60117603)
ADACHI Masaaki School of Medicine, SAPPORO MEDICAL UNIVERSITY Associate Professor, 医学部, 助教授 (70240926)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | radiation-induced apoptosis / radiosensitivity / MEK / ERK signal / mitochondrial membrame potential / caspase activation / ウイルスベクター / Caspase8 |
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| Research Abstract |
Ionizing radiation activates caspases and induces apoptosis in different cell types. However, how ionizing radiation activates caspases and subsequently induces cell death remains to be definitively elucidated. Here we provide evidence that ionizing radiation activates caspase-8 and Bid and disrupts mitochondrial membrane potential (ΔΨm) by two distinct pathways in lymphocytic leukemia cells. Radiation-induced cleavage of caspase-8, -3 and Bid, and subsequent DNA fragmentation were substantially blocked by pre-treatment with the tetrapeptide z-IETD-FMK, however it could not suppress the breakdown of ΔΨm, indicating that the ΔΨm loss occurred independently of the caspase activation. Moreover, suppression of caspase activation alone was insufficient to prevent the radiation-induced cell death. In contrast, 12-O-tetradecanoylphorbol-3-acetate (TPA) substantially inhibited the radiation-induced cell death through blockage of both caspase-8/Bid activation and the ΔΨm loss. TPA-mediated anti-apoptotic activity was abrogated by a MEK inhibitor PD98059, but not by a PKC inhibitor 19-27 pseudosubstrate, which rather augmented the anti-apoptotic activity. These data strongly suggest that there are at least two distinct pathways to facilitate radiation-induced apoptosis, i.e., caspase activation and caspase-independent ΔΨm reakdown, the latter being a crucial process in the apoptosis. These two pathways are negatively regulated by the MEK/ERK-mediated signal, signifying that its activation is a possible mechanism for radioresistance.
These studies demonstrate that the new approach using radiation-induced apoptosis modulates the radiosensitivity as new radiosensitizers.
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