DNA-dependent protein kinase enhances DNA damage-induced apoptosis in association with Friend gp70.
Friend leukemia virus (FLV) infection strongly enhances gamma-irradiation-induced apoptosis of hematopoietic cells of C3H hosts leading to a lethal anemia. Experiments using p53 knockout mice with the C3H background have clarified that the apoptosis is p53-dependent and would not be associated with changes of cell populations caused by the infection with FLV. In bone marrow cells of FLV + total body irradiation (TBI)-treated C3H mice, the p53 protein was prominently activated to overexpress p21 and bax suggesting that apoptosis-enhancing mechanisms lay upstream of p53 protein in the signaling pathway. Neither of DNA-dependent protein kinase (DNA-PK)-deficient SCID mice nor ataxia telangiectasia mutated (ATM) gene knockout mice with the C3H background exhibited a remarkable enhancement of apoptosis or p53 activation on FLV + TBI-treatment indicating that DNA-PK and ATM were both essential. ATM appeared necessary for introducing DNA damage-induced apoptosis, while DNA-PK enhanced p53-dependent apoptosis under FLV-infection. Surprisingly, viral envelope protein, gp70, was co-precipitated with DNA-PK but not with ATM in FLV + TBI-treated C3H mice. These results indicated that FLV-infection enhances DNA damage-induced apoptosis via p53 activation and that DNA-PK, in association with gp70, might play critical roles in modulating the signaling pathway.
Yamaguchi
Shuichi
S
Department of Comprehensive Pathology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Hasegawa
Maki
M
Aizawa
Shiro
S
Tanaka
Kaoru
K
Yoshida
Kazuko
K
Noda
Yuko
Y
Tatsumi
Kouichi
K
Hirokawa
Katsuiku
K
Kitagawa
Masanobu
M
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007942:Leukemia, Experimental / Q000201:enzymology / Q000821:virology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012192:Retroviridae Infections / Q000532:radiotherapy; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014412:Tumor Virus Infections / Q000532:radiotherapy; D014759:Viral Envelope Proteins / Q000502:physiology*; D014916:Whole-Body Irradiation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D015682:Retroviridae Proteins, Oncogenic; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014759:Viral Envelope Proteins; C073723:glycoprotein gp70, Feline leukemia virus; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases