A novel role for acinus and MCM2 as host-specific signaling enhancers of DNA-damage-induced apoptosis in association with viral protein gp70.
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 C3H-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.
Hasegawa
Maki
M
Department of Comprehensive Pathology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kurata
Morito
M
Yamamoto
Kouhei
K
Yoshida
Kazuko
K
Aizawa
Shirou
S
Kitagawa
Masanobu
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D017209:Apoptosis; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D005622:Friend murine leukemia virus / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D015686:Gene Products, env / Q000096:biosynthesis* / Q000235:genetics; D015316:Genetic Therapy; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D064111:Minichromosome Maintenance Complex Component 2; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D012192:Retroviridae Infections / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D015686:Gene Products, env; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D064111:Minichromosome Maintenance Complex Component 2