| Project/Area Number |
17390094
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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 |
Pathological medical chemistry
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| Research Institution | Tokyo Medical and Dental University (2006)
Osaka University (2005) |
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Principal Investigator |
SHIMIZU Shigeomi Tokyo Medical and Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (70271020)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIDA Toshiro Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40263264)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2006: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2005: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | autophagy / cell death / Bcl-2 / ATG5 / 発癌 / Beclin1 / アポトーシス / Bax / Bak |
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| Research Abstract |
Programmed cell death is a crucial process in the normal development and physiology of metazoans : it can be divided in several categories including type I (apoptosis) and type II (autophagic death). The BcI-2 family of proteins are well-characterized regulators of apoptosis, and multidomain pro-apoptotic members of this family, such as Bax and Bak, function as a mitochondrial gateway on which a variety of apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak double knock-out (DKO) mice are resistant to apoptosis, we have found that these cells still died in a non-apoptotic fashion with autophagic features after death stimulation. Furthermore, we have also shown that the non-apoptotic death of DKO cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, and was dependent on an autophagy protein APG5 as well as Beclin 1.
We have extended these studies to analyze molecular mechanism of the autophagic death, and found that activation of JNK played a crucial role in autophagic cell death. This conclusion was supported by the facts that (1) JNK activation was observed during etoposide-induced autophagic death of DKO cells, (2) this form, of cell death was suppressed by addition of JNK inhibitors or expression of a dominant-negative mutant of JNK. However, amino acid depletion-induced death of DKO cells was not dependent on JNK. These results indicated that JNK activation is crucial for the autophagic death of DKO cells.
We also produced ATG5/Bax/Bak (TKO) mice embryo, and found that apoptosis and autophagic cell death compensated each other. Furthermore, we also discovered that some of the cancer cells had mutations in the autophagy-related gene.
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