A novel role for acinus and MCM2 as host-specific signaling enhancers of DNA-damage-induced apoptosis in association with viral protein gp70
A novel role for acinus and MCM2 as host-specific signaling enhancers of DNA-damage-induced apoptosis in association with viral protein gp70
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DOI：
10.1016/j.leukres.2008.10.025
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发表时间：
2009-08-01
影响因子：
2.7
通讯作者：
Kitagawa, Masanobu
中科院分区：
文献类型：
--
作者：
Hasegawa, Maki;Kurata, Morito;Kitagawa, Masanobu
病毒蛋白质与宿主细胞蛋白质的相互作用激活了许多可能导致病毒致病的细胞信号转导途径。我们以前证明，感染Friend白血病病毒（FLV）通过C3 H宿主中的p53依赖性凋亡途径使小鼠造血细胞放射增敏。在这里，我们表明，朋友鼠白血病病毒（F-MuLV）的env基因（gp 70）的转导敏化C3 H衍生的髓系白血病细胞的DNA损伤（电离辐射以及阿霉素）诱导的细胞凋亡，通过激活的DNA依赖性蛋白激酶（DNA-PK）和P53。通过siRNA敲低DNA-PK可抑制gp 70诱导的放射增敏作用。与gp 70和DNA-PK相关，腺泡和MCM 2蛋白在GH衍生细胞中宿主特异性过表达。总之，这些数据表明，gp 70增强与宿主特异性细胞蛋白（包括腺泡和MCM 2）相关的细胞DNA损伤诱导的信号传导，导致DNA-PK活化以磷酸化P53。该体外研究清楚地表明，gp 70对DNA损伤诱导的细胞凋亡的增强不是由宿主的骨髓环境引起的，而是由造血细胞中修饰的信号传导引起的。病毒蛋白调节细胞基因表达的能力所涉及的机制可以为操纵细胞促凋亡信号传导和开发新的治疗策略提供宝贵的见解。(C)2008爱思唯尔有限公司保留所有权利。
The interaction of viral proteins with host-cellular proteins elicits the activation of numerous cellular signal transduction pathways possibly leading to the viral pathogenesis. We previously demonstrated that infection with Friend leukemia virus (FLV) radiosensitizes murine hematopoietic cells via a p53-dependent apoptotic pathway in C3H hosts. Here, we show that the transduction of the env-gene (gp70) of Friend murine leukemia virus (F-MuLV) sensitized C3H-derived myeloid leukemia cells to DNA-damage (ionizing radiation as well as doxorubicin)-induced apoptosis through the activation of DNA-dependent protein kinase (DNA-PK) and P53. Knockdown of DNA-PK by siRNA inhibited the radiosensitization induced by gp70. In association with gp70 and DNA-PK, the acinus and MCM2 proteins were host-specifically overexpressed in GH-derived cells. Taken together, these data suggested that gp70 enhances cellular DNA-damage-induced signaling in association with host-specific cellular proteins including acinus and MCM2 resulting in the activation of DNA-PK to phosphorylate P53. This in vitro study clearly indicates that the enhancement of DNA-damage-induced apoptosis by gp70 is not caused by the bone marrow environment of the host but is introduced by modified signaling in hematopoietic cells. The mechanisms involved in the ability of a viral protein to regulate cellular gene expression could provide invaluable insight into the manipulation of cellular pro-apoptotic signaling and the development of novel therapeutic strategies. (C) 2008 Elsevier Ltd. All rights reserved.