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Analysis of the genetic network in the host difence system.

宿主差异系统中的遗传网络分析。

基本信息

批准号：
07407010
负责人：
TANIGUCHI Tadatsugu
金额：
$ 19.84万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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.

本研究首先利用IRF家族转录因子IRF-1和p48（ISGF_（3-））缺陷的小鼠研究了IRF家族转录因子IRF-1和p48（ISGF_（3-））的作用<gamma>。发现（i）IRF-1和p48（在ISGF 3复合物的情况下）对于IFN-α/β和IFN-α的抗病毒应答是必需<gamma>的，（ii）这些因子也参与IFN-α/B基因的表达，（iii）IRF-1而不是p48对于诱导Th 1型免疫应答和自然杀伤细胞的发育是必需的。事实上，IRF-1已被证明是IL-12和IL-15基因转录诱导所必需的。此外，我们发现IRF-1作为肿瘤抑制因子发挥作用，并且IRF-1与p53合作，分别在正常成纤维细胞或携带活化癌基因的成纤维细胞中诱导细胞周期停滞和凋亡。IRF-1也被证明是必不可少的诱导DNA损伤诱导的细胞凋亡，增殖的T细胞。在IL-2诱导淋巴细胞增殖的机制中，我们发现了与IL-2受体（IL-2 R）复合物偶联的重要分子--蛋白酪氨酸激酶（PTKs）Jak 1和Jak 3。事实上，我们举出的证据表明，IL-2诱导的活化这些PTKs是必不可少的增殖信号传递。此外，我们确定Pyk 2 PTK是Jak途径的关键下游分子。我们还为IL-2信号转导下游靶基因c-Myc和Bcl-2在促进细胞周期中的协同作用提供了证据，这些结果有助于我们理解宿主防御中细胞反应的分子机制。