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Regulation of IL-3 and GM-CSF genes and their receptors

IL-3 和 GM-CSF 基因及其受体的调节

基本信息

批准号：
04044054
负责人：
ARAI Ken-ichi
金额：
$ 8.26万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04044054/
关键词：
GM-CSF receptor IL-3 receptor Signal transduction Transcription factor Transactivator Tyrosine phosphorylation Gene transfer Early response genes トランスアクチベーター

项目摘要

1.Regulation of cytokine genes in T cells. Using human and mouse T cell clones with TH1, TH2, and TH0 phenotype, we have been working on the coordinate and differential expression of the IL-3, IL-4, IL-5 and GM-CSF genes. The CLE2/GC-box and CLE0 of the mouse GM-CSF promoter are essential for transcriptional activation in response to PMA and Ca ionophore. CLE2 defines a binding site for NF-kappaB.The major GC-box binding activity A1 was purified and was identified as Sp1. We purified a human NF-AT protein from activated Jurkat extract and showed that it strongly bound to the CLE0 within the GM-CSF promoter in association with AP1. We isolated a novel protein with zinc finger motifs which binds to the CT/GC-rich region of the IL-3 promoter. We also identified cis-regulatory elements within IL-5, IL-4 and IL-2 promoters. These works were done in collaboration with Drs.Naoko Arai and de Vries Jan in DNAX.2.Receptor and Signal transduction. We have been working on the structure and function of GM-CSF/IL-3 receptors. There are several signal pathways downstream of the GM-CSF receptor. The membrane proximal region of betac is essential for proliferation, c-myc and pim-1 induction and Jak2 association. The C-terminal region of betac is important for the suppression of apoptosis, Ras, Raf, MAPK activation and c-fos, c-jun induction. We have also shown that bone marrow cells derived from transgenic mice which constitutively express hGM-CSF receptor have the proliferative capacity to induce all the myeloid cell lineages in response to hGM-CSF.Furthermore, we have generated mice carrying a null mutation of betac and betaIL-3. betac mutant mice also showed lung pathology consisting of lymphocytic infiltration and areas resembling alveolar proteinosis. These works were done in collaboration with Dr.Atsushi Miyajima in DNAX and Dr.Ostertag Wolfram in Hamburg University.

1. T细胞中细胞因子基因的调节。使用具有TH 1、TH 2和TH 0表型的人和小鼠T细胞克隆，我们一直致力于IL-3、IL-4、IL-5和GM-CSF基因的协调和差异表达。小鼠GM-CSF启动子的CLE 2/GC-box和CLE 0是响应PMA和Ca离子载体的转录激活所必需的。CLE 2定义了NF-κ B的结合位点。纯化了主要的GC盒结合活性A1，并鉴定为Sp1。我们从活化的Jurkat提取物中纯化了一种人NF-AT蛋白，并表明它与AP 1相关的GM-CSF启动子内的CLE 0强烈结合。我们分离了一种新的蛋白质与锌指基序结合的CT/GC丰富的区域的IL-3启动子。我们还鉴定了IL-5、IL-4和IL-2启动子内的顺式调节元件。这些工作是与Naoko Arai和de弗里斯Jan博士在DNAX.2.受体和信号转导中合作完成的。我们一直在研究GM-CSF/IL-3受体的结构和功能。在GM-CSF受体下游存在几种信号通路。betac的膜近端区域对于增殖、c-myc和pim-1诱导以及Jak 2缔合是必需的。betac的C端区域在抑制细胞凋亡、Ras、Raf、MAPK激活以及c-fos、c-jun诱导中起重要作用。我们还表明，来自组成型表达hGM-CSF受体的转基因小鼠的骨髓细胞具有诱导所有髓系细胞谱系响应hGM-CSF的增殖能力。此外，我们已经产生了携带β c和β IL-3无效突变的小鼠。Betac突变小鼠还显示出由淋巴细胞浸润和类似肺泡蛋白沉积的区域组成的肺病理学。这些工作是与DNAX的宫岛敦博士和汉堡大学的奥斯特塔格·沃尔夫勒姆博士合作完成的。