1994 Fiscal Year Final Research Report Summary
The regulation of the cytokine gene expression in cell growth and differentiation
| 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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| Keywords | Interferon / gene network / gene targetting / aniviral / tumor supressor / MDS / leukemia |
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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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Research Products
(13 results)
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[Publications] Harada, H., Kondo, T., Ogawa, S., Tamura, T., Kitagawa, M., Tanaka, N., Lamphier, M.S., Hirai, H., and Taniguchi, T.: "Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia ; leukemia ; a possible mechanism of tumor suppressor inactivation." Oncogene. 9. 3313-3320 (1994)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kimura, T., Nakayama, K., Penninger, J,Kitagawa, M., Harada, H., Matsuyama, T., Tanaka, N., Kamijo, R., Vilcek, J., Mak, T.W., Taniguchi, T: "Involvement of the IRF-1 transcription factor in antiviral responses to interfereons." Science. 264. 1921-1924 (1994)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Tanaka, N., Ishihara, M., Kitagawa, M., Harada, H., Kimura, T., Matsuyama, T., Lamphier, M.S., Aizawa, S., Mak, T.W.and Taniguchi, T.: "Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the ranscription factor IRF-1." Cell. 77. 829-839 (1994)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kamijo, R., Harada, H., Matsuyama, T., Bosland, M., Gerecitano, J., Shapiro, D., Koh, S.I., Kimura, T., Green, J.S., Mak, T.W., Taniguchi, T., Vilcek, J.: "Essential role for the transcription factor IRF-1 in the induction of nitric oxide synthase in macrophages." Science. 263. 1612-1615 (1994)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Harada, H., Takahashi, E., Itoh, S., Harada., K., Hori, T., and Taniguchi, T.: "Structure and regulation of the human interferon regulatory factor 1(IRF-1) and (IRF-2) genes : Implications for a gene network in the interferon system." Mol.Cell.Biol.14. 1500-1509 (1994)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Harada H., Kitagawa, M., Tanaka, N., Yamamoto, H., Harada, K., Ishihara, M., and Taniguchi, T.: "Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2." Science. 259. 971-974 (1993)
Description
「研究成果報告書概要(欧文)」より
