| Co-Investigator(Kenkyū-buntansha) |
MIYAZAKI Tadaaki University of Tokyo Graduate School of Medicine, Department of Immunology, Assis, 大学院・医学系研究科, 助手 (60272431)
TAKI Shinsuke University of Tokyo Graduate School of Medicine, Department of Immunology, Lectu, 大学院・医学系研究科, 講師 (50262027)
TANAKA Nobuyuki University of Tokyo Graduate School of Medicine, Department of Immunology, Assoc, 大学院・医学系研究科, 助教授 (80222115)
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| Research Abstract |
The present study has been focused on the elucidation of the molecular mechanisms underlying requlation of host defense, including the regulation of the immune system and oncogenesis.
First, we studied the roles of the IRF family transcription factors, i.e.IRF-1 and p48 (ISGF3_<gamma>), using mice deficient in these factors. It was found that (i) both IRF-1 and p48 (in the context of the ISGF3 complex) are essential for the antiviral response of IFN-alpha/beta and IFN-_<gamma>, (ii) 9 these factors are also involved in the expression of the IFN-a/B genes, (iii) IRF-1, but not p48, is essential for the induction of the Th1 type immune response and development of natural killer cells. In fact, IRF-1 has been shown to be essential for the transcriptional induction of IL-12 and IL-15 genes. In addition, we discovered that IRF-1 functions as atumor suppressor, and that IRF-1 cooperates with p53 to induce cell cycle arrest and apoptosis in normal fibroblasts or fibroblasts carrying an activated oncogene, respectively. IRF-1 was also shown to be essential for the induction of apoptosis of DNA damage-induced, proliferating T cells. We aldo discovered anovel anti-viral function of IFN-alpha/beta, i.e.selective induction of apoptosis in virally infected cells.
Regarding to the mechanisms of the IL-2-induced lymphocyte proliferation, we identified Jak1 and Jak3 protein tyrosine kinases (PTKs) as the crucial molecules coupling with the IL-2 receptor (IL-2R) somplex. Indeed, we adduced evidence that the IL-2-induced activation of these PTKs is essential for proliferative signal transmission. Furthermore, we identified Pyk2 PTK as a crucial downstream molecule of the Jak pathway. We also provided evidence for cooperation of the downstream target genes of the IL-2 signaling, i.e.c-Myc and Bcl-2, in promotion of the cell cycle.
These results in to contribute to our understanding of the molecular mechanisms of cellular responses in the host defense.
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