| Project/Area Number |
16591443
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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 |
Cerebral neurosurgery
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| Research Institution | The University of Tokushima |
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Principal Investigator |
MATSUZAKI Kazuhito The University of Tokushima, Institute of Health Biosciences, Assistant, 大学院・ヘルスバイオサイエンス研究部, 助手 (90363168)
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| Co-Investigator(Kenkyū-buntansha) |
KAGEJI Teruyoshi The University of Tokushima, Tokushima University Hospital, Assistant Professor, 医学部・歯学部附属病院, 講師 (70294684)
NAGAHIRO Shinji The University of Tokushima, Institute of Health Biosciences, Professor, 大学院・ヘルスバイオサイエンス研究部, 教授 (60145315)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Akt / PKB / PML / glioma / 悪性神経膠腫 |
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| Research Abstract |
1.There are three isoforms of Akt/PKB : Akt1, Akt2 and Akt3. We investigated whether endogenous Akt contributes to resistance to ionizing irradiation and which isoforms of Akt are responsible for GBM biology.
(Materials and methods) U251MG, U87MG and GB1 cells were used. Synthetic siRNA against each Akt isoform was introduced into these cells for specific knockdown. Protein expression was examined with immunoblotting analysis. Cell cycle profiles were determined by Flow cytometric analysis. Apoptotic cells were verified with TUNEL assays. (Results) We found that Akt1 and Akt2 highly expressed in U251 MG, U87 MG, and GB1 cells and the expression level of Akt3 was much lower than that of Akt1 and Akt2. The introduction of short interference RNA against Akt1 (siAkt1) and siAkt2 specifically decreased Akt1 and Akt2, respectively. Introduction of either siAkt1 or siAkt2 alone did not significantly increase susceptibility to apoptosis. However, cointroduction of siAkt1 and siAkt2 remarkably e
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nhanced radiation-induced apoptosis, concomitantly with reduction of phosphorylated forms of Akt and Bad. (Conclusions) Knockdown of Akt1 and Akt2 inhibits Akt-mediated survival signals by reducing phosphorylated forms of Akt and Bad, leading to augment of radiosesitivity. Akt isoforms highly expressing play a crucial role in resistance to apoptosis of glioblastoma cells. Akt is highlighted as an important therapeutic target. It remains to be elucidated which downstream molecules in Akt signaling pathways could contribute the survival of glioblastoma cells.
2.PML (promyelocytic leukemia) is suggested to act as a tumor suppressor. We investigated the expression of PML gene and PML protein in glioma samples collected at the time of surgical resection with written informed consent.
(Method) Gene and protein expression was evaluated with semiquantitative reverse transcript PCR and immunohistochemical analysis, respectively. (Results) PML gene and PML protein expression was significantly reduced in glioblastomas, as compared with low grade astrocytomas. (Conclusions) Reduction of PML expression associated with tumor grade, suggesting contribution to tumor progression or malignant transformation.
These results described above are in preparation for the submission of manuscripts. Less
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