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.

本研究一直集中在阐明宿主防御重新排出的分子机制上，包括对免疫系统的调节和发病。首先，我们研究了IRF家族转录因子的作用，即I..IRF-1和p48（ISGF3_ <gamma>）（使用这些因子中的鼠标）。发现（i）IRF-1和p48（在ISGF3复合物的背景下）对于IFN-Alpha/beta和IFN-__ <gamma>的抗病毒药反应至关重要，（ii）9这些因素也与IFN-A/B基因（III）IRF-1的IFN-A/B基因（III）IRF-1的响应及其响应的启动和启动及其定期的响应以及THEN的启动和THENS的开发及其及其the and the Innune and The and the Is the and the Is the and the Is the and the and the and the and and and and and and ins of。实际上，IRF-1已被证明对于IL-12和IL-15基因的转录诱导至关重要。此外，我们发现IRF-1充当Atumor抑制剂，IRF-1与p53合作，分别诱导正常成纤维细胞或携带激活癌基的成纤维细胞中的细胞周期停滞和凋亡。 IRF-1也被证明对于诱导DNA损伤诱导的增殖T细胞的凋亡至关重要。我们Aldo发现了IFN-Alpha/beta的无铜病毒功能，即病毒感染细胞中凋亡的凋亡诱导。对IL-2淋巴细胞增殖的机制进行了验证，我们确定了JAK1和JAK3蛋白质激酶（PTKS）crecials cocules（Cou）cor-cou cou cou cou cou cou cou cou cou cou （IL-2R）Somplex。确实，我们提出了证据表明，IL-2诱导的这些PTK的激活对于增殖信号传递至关重要。此外，我们将PYK2 PTK鉴定为JAK途径的至关重要的下游分子。我们还为促进细胞周期的IL-2信号传导（即C-Myc和Bcl-2）的下游靶基因的合作提供了证据。这些导致我们对宿主防御中细胞反应的分子机制的理解有助于。