Resistance against Friend leukemia virus-induced leukemogenesis in DNA-dependent protein kinase (DNA-PK)-deficient scid mice associated with defective viral integration at the Spi-1 and Fli-1 site.
Retroviral DNA integration is mediated by the viral protein integrase. However, elements of the host DNA repair machinery such as the phosphatidylinositol 3-kinase (PI-3K)-related protein kinase family system would play a role in the integration of viral DNA into the host DNA. Here, we show that a host PI-3K-related protein kinase, DNA-dependent protein kinase (DNA-PK), plays a role in the specific integration of retroviral DNA and induction of retroviral diseases in vivo. DNA-PK-deficient scid mice inoculated with Friend leukemia virus (FLV) exhibited a random integration into their genomic DNA and expressed the viral envelope protein gp70. However, the specific integration of FLV at Spi-1 or Fli-1 sites did not occur in association with the significant resistance of scid mice to FLV-induced leukemogenesis. In contrast, the knockout of another member of the PI-3K-related protein kinase family, encoded by the ataxia telangiectasia mutated (ATM) gene, resulted in mice as sensitive to FLV-induced leukemogenesis as the wild type mice. FLV was specifically integrated into the DNA at Spi-1 and Fli-1 sites with significant expression of these transcription factors. These findings indicated that DNA-PK would be essential for controlling the in vivo integration of FLV at specific sites as well as the susceptibility to FLV-induced leukemogenesis.
Department of Comprehensive Pathology, Aging and Developmental Sciences, Tokyo Medical and Dental University, Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 13-8519, Japan.
Maki
M
Hasegawa
Shuichi
S
Yamaguchi
Shiro
S
Aizawa
Hidetoshi
H
Ikeda
Kouichi
K
Tatsumi
Yuko
Y
Noda
Katsuiku
K
Hirokawa
Masanobu
M
Kitagawa
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation; D004279:DNA, Viral / Q000235:genetics*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral; D005622:Friend murine leukemia virus / Q000235:genetics* / Q000276:immunology; D016158:Genes, p53 / Q000276:immunology; D007942:Leukemia, Experimental / Q000235:genetics* / Q000276:immunology / Q000821:virology; D008214:Lymphocytes / Q000276:immunology* / Q000821:virology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012192:Retroviridae Infections / Q000235:genetics; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000737:chemistry / Q000276:immunology / Q000821:virology; D016019:Survival Analysis; D015534:Trans-Activators / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D016662:Virus Integration
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D014759:Viral Envelope Proteins; C073723:glycoprotein gp70, Feline leukemia virus; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases