2004 Fiscal Year Final Research Report Summary
Enhancement of radiation-induced apoptosis by retroviral infection : implication for the gene therapy
| Project/Area Number |
14570180
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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 |
Experimental pathology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KITAGAWA Masanobu Tokyo Medical and Dental University, Graduate School, Department of Comprehensive Pathology, Associate Professor, 大学院・医歯学総合研究科, 助教授 (10177834)
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| Project Period (FY) |
2002 – 2004
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| Keywords | retrovirus / DNA damage / apoptosis / p53 / DNA-PK |
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| Research Abstract |
We established the experimental system using C3H mice indicating that retroviral infection remarkably enhanced the radiation-induced apoptosis. FLU-infected C3H mice exhibited lethal anemia after low dose total body irradiation (3 Gy) caused by apoptosis of hematopoietic cells of the bone marrow. The enhancement of apoptosis was p53-dependent and regulated by PI3-kinases, DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutation kinase (ATM). In general, ATM kinase plays a role in the activation of p53 after DNA damage like irradiation. However, in this study, we could clarify that the DNA-PK bound with the FLV-derived gp70 and introduced marked activation (phosphorylation) of p53. For this activation of DNA-PK, a host gene product seemed essential in association with gp70.
Using in vitro cell line systems, we confirmed the enhancement of radiation-induced apoptosis by infection with FLV. Acute myelogenous leukemia cell lines established from radiation-induced leukemia cells of C3H mice were used for the study. These cell lines had normal but not mutated p53. Viral infection was confirmed by the expression of viral gp70 on the cell surface. Now we are investigating about the mechanisms of DNA-PK activation by viral gp70.
This model would be useful for establishing the therapeutic system by the specific induction of apoptosis to abnormal cells such as cancers by using gp70 and low dose irradiation.
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