| Project/Area Number |
04670288
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Immunology
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| Research Institution | Osaka University |
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Principal Investigator |
HARADA Hisashi Research Associates, Institute for Molecular and Cellular Biology Osaka University, 細胞生体工学センター, 助手 (10222233)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Nobuyuki Assistant Professor Institute for Molecular and Cellular Biology Osaka Universit, 細胞生体工学センター, 講師 (80222115)
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1993: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1992: ¥700,000 (Direct Cost: ¥700,000)
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| Keywords | Interferon / gene network / gene targetting / aniviral / tumor supressor / MDS / leukemia / IRF‐2 / 転写因子 / IRF / 細胞増殖 / 癌化 / 白血病 / MDS / ノックアウトマウス |
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| Research Abstract |
Two structurally related transcription factors, IRF-1 and IRF-2 were originally identified as regulators of the interferon (IFN) system. It has been shown that IRF-1 functions as an activator for the type I IFN genes and some IFN-inducible genes, whereas IRF-2 represses the effect of IRF-1 by competing for binding to the same DNA sequence elements (IRF-E_8). We demonstrated a role for IRF-1 as a tumor suppressor ; overexpression of the repressor IRF-2 in NIH3T3 cells causes cell transformation and this cell transformation is suppressed by concomitant overexpression of the activator IRF-1. To examine further the role of IRF-1 and IRF-2 in vivo, we genereted mice with a null mutation in the IRF-1 gene or IRF-2 gene by gene targetting. We demonstrate that (i) infection with BCG was more severe in IRF-1^<-/-> mice than in wild-type mice ; (ii) the inhibition of encephalimyocarditis virus (EMCV) replication by IFN was impared in cells from IRF-1^<-/-> mice and these mice were less resistant than wild-type mice to EMCV infection ; (iii) primary embryonic fibroblasts (EFs) with a null mutation in the IRF-1 gene (IRF-1^<-/-> mice) are susceptible to transformation by an activated form of c-Ha-ras, a property also seen in the EFs from p53^<-/-> mice, but not in wild-type EFs. Thus, IRF-1 contributes to antibacterial, antiviral, and antitumor functions. The human IRF-1 gene has been mapped to 5q31.1. It has been demonstrated that one or both human IRF-1 alleles were deleted in MDS and leukemia chracterrized by 5q abberations. We also found that the accelerated exon skipping of human IRF-1 gene may cause the inactivation of IRF-1 and thereby contribute to the development of human hematopoietic malignancies.
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