Development of novel therapeutic strategy against tumor progression using animal model

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The interaction of viral proteins with host-cellular proteins elicits the activation of cellular signal transduction pathways. Previously, we have clarified that an infection with Friend leukemia virus(FLV) markedly enhanced the IR-induced apoptosis of hematopoietic cells in C3H mice in association with P53, ATM, and DNA-PK. The phenomenon was characterized in vivo by severe anemia when the mice were infected with FLV and then treated with a low dose of total body irradiation(TBI). Viral infection and replication occurred almost cell type-specifically in the hematopoietic cells and thus, the apoptotic enhancement was observed only in the hematopoietic cells. However, p53 knockout mice, Atm knockout mice, and DNA-PK-deficient SCID mice with a C3H background did not exhibit this phenotype. A comparison of apoptotic signals after FLV, TBI, or FLV+TBI treatment of these mice revealed that ATM appeared to be necessary for the general signal transduction of TBI-induced apoptosis, while DNA-PK had a specific role in enhancing p53-dependent apoptosis under FLV infection. The host specificity of this phenomenon was caused by the up-regulated expression of Acinus and minichromosome maintenance(MCM) 2 in C3H mice. We also showed that C3H mouse-derived hematopoietic cells originally expressed higher levels of MCM2 than BALB/c cells and exhibited more frequent apoptosis after DNA-damage by doxorubicin when the cells expressed the Friend leukemia virus envelope protein gp70. Transduction and immunoprecipitation assays using various deletion mutants of