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Enhancement of radiation-induced apoptosis by retroviral infection : implication for the gene therapy

逆转录病毒感染增强辐射诱导的细胞凋亡：对基因治疗的意义

基本信息

批准号：
14570180
负责人：
KITAGAWA Masanobu
金额：
$ 1.92万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570180/
关键词：
retrovirus DNA damage apoptosis p53 DNA-PK フレンド白血病ウイルス ATM

项目摘要

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.

我们用C3 H小鼠建立了实验系统，表明逆转录病毒感染显着增强辐射诱导的细胞凋亡。Flu感染的C3 H小鼠在低剂量全身照射（3戈伊）后表现出致死性贫血，其原因是骨髓造血细胞凋亡。细胞凋亡的增强是p53依赖性的，并受PI 3激酶、DNA依赖性蛋白激酶（DNA-PK）和共济失调毛细血管扩张突变激酶（ATM）的调节。一般来说，ATM激酶在DNA损伤（如辐射）后p53的活化中起作用。然而，在本研究中，我们可以阐明DNA-PK与FLV衍生的gp 70结合并引入了p53的显著活化（磷酸化）。对于这种DNA-PK的激活，与gp 70相关的宿主基因产物似乎是必不可少的。使用体外细胞系系统，我们证实了FLV感染增强辐射诱导的细胞凋亡。本研究使用从C3 H小鼠的辐射诱导的白血病细胞建立的急性髓性白血病细胞系。这些细胞系具有正常但未突变的p53。通过细胞表面上病毒gp 70的表达证实病毒感染。目前我们正在研究病毒gp 70激活DNA-PK的机制，该模型将有助于建立利用gp 70和低剂量照射特异性诱导癌症等异常细胞凋亡的治疗体系。