title: DNA damage-induced apoptosis and genetic background of the host: host-specific signaling enhancers of apoptosis.
abstract: Radiation therapy, inducing DNA damage, is one of the most effective tools for treatments of human cancers, but the effectiveness of the therapy is largely depending on the host specific conditions. Recently genetic constitution has proven to be important for apoptosis-induction responding to DNA damage. Regarding the host-specific manner of responses against DNA-damage in animal model, we have reported that infection with Friend leukemia virus (FLV) enhances the DNA damage-induced apoptosis in hematopoietic cells derived from C3H but DBA/2 mice. Furthermore, p53 or ATM knockout mice of C3H background and DNA-PK-deficient C3H SCID mice did not show the enhanced apoptosis by FLV. Recently, we could show that this host-specific apoptosis was mediated by the kinase activity of DNA-PK in association with FLV env-coding protein, gp70. Interestingly, two host proteins, acinus and MCM2, were also associated with DNA-PK and gp70 and were host-specifically overexpressed in C3H-derived cells. Our data suggest 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. By introducing gp70/acinus/MCM2-associated pathways into tumor cells, cancer therapy with DNA damage-inducing agents might become much more effective. Our aim is to develop a novel form of targeted therapy that can be combined with other treatment modalities, such as radiotherapy and chemotherapy, using the host-specific regulatory mechanisms of apoptotic enhancement.
authors.affiliation: Department of Comprehensive Pathology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Morito
authors.initials: M
authors.lastname: Kurata
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.forename: Shiho
authors.initials: S
authors.lastname: Suzuki
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Iichiro
authors.initials: I
authors.lastname: Ohnishi
authors.forename: Maki
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D051747:DNA-Activated Protein Kinase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005622:Friend murine leukemia virus / Q000235:genetics; D015686:Gene Products, env / Q000235:genetics; D006801:Humans; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016513:Mice, SCID; D064111:Minichromosome Maintenance Complex Component 2 / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D015686:Gene Products, env; C576318:Mcm2 protein, mouse; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D064111:Minichromosome Maintenance Complex Component 2