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

我们用C3H小鼠建立了实验系统，表明逆转录病毒感染显著增强了辐射诱导的细胞凋亡。感染流感的C3H小鼠在低剂量全身照射（3gy）后，出现骨髓造血细胞凋亡引起的致死性贫血。凋亡的增强是p53依赖性的，并受pi3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）的调控。一般来说，ATM激酶在辐照等DNA损伤后p53的激活中起作用。然而，在本研究中，我们可以澄清DNA-PK与flv衍生的gp70结合，并引入p53的显著激活（磷酸化）。对于DNA-PK的激活，宿主基因产物似乎与gp70相关。通过体外细胞系系统，我们证实了FLV感染对辐射诱导的细胞凋亡的增强作用。用辐射诱导的C3H小鼠白血病细胞建立急性髓性白血病细胞系进行研究。这些细胞系的p53是正常的，但没有突变。通过细胞表面病毒gp70的表达证实病毒感染。目前，我们正在研究病毒gp70激活DNA-PK的机制。该模型为利用gp70和低剂量照射特异性诱导肿瘤等异常细胞凋亡的治疗体系的建立提供了理论依据。

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.