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Research on Gene Expression Network via histone acetylation

组蛋白乙酰化基因表达网络研究

基本信息

批准号：
12557018
负责人：
ISHII Shunsuke
金额：
$ 8.32万
依托单位：
THE INSTITUTE OF PHYSICAL AND CHEMICAL RESEARCH (RIKEN)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

We have generated and analysed the mutant mice lacking transcription factor Shn-2. Shn-2 was originally identified by our group as a factor that binds to the NF-KB site, and a large protein of 270 kD with two metal-finger structures. Since Drosophila homologue of Shn acts in the dpp signaling pathway, vertebrate Shn is thought to act in the BMP/TGFβ/activin signaling pathway. Shn-2-deficient mice seems to be healthy, but have a defects of T-cell development. In the thimi of Shn-2 mutant mice, almost no single-positive T cells were observed. A series of analyses indicated that Shn-2 is essential for the positive selection of T ceils. These results suggest that the BMP/TGFβ/activin signaling pathway plays some role in the T cell development.We have also analysed the physiological role of Ski by using the Ski-deficient mice. We treated the Ski heterozygous mutant mice with chemical carcinogen DMBA. No tumors were generated in wild-type mice, whereas significant numbers of Ski heterozygotes developed the tumors such as T- and B-cell lymphomas. Further, the mouse fibroblasts prepared from the Ski-deficient embryos had increased proliferative capacity compared to wild-type cells. In addition, the introduction of activated Ki-ras into Ski-deficient mouse embryonic fibroblasts resulted in neoplastic transformation. These finding demonsrrate that Ski acts as a tumor suppressor in some types of cells.

我们产生并分析了缺乏转录因子sh -2的突变小鼠。我们的研究小组最初发现，Shn-2是一种结合NF-KB位点的因子，是一种270 kD的大蛋白，具有两个金属指结构。由于果蝇的Shn同源物在dpp信号通路中起作用，脊椎动物的Shn被认为在BMP/TGFβ/激活素信号通路中起作用。缺乏shn -2的小鼠似乎是健康的，但有t细胞发育缺陷。在sh -2突变小鼠的胸腺中，几乎没有观察到单阳性T细胞。一系列分析表明，sh -2对T细胞的阳性选择至关重要。这些结果提示BMP/TGFβ/激活素信号通路在T细胞发育中起一定作用。我们还通过使用Ski缺陷小鼠分析了Ski的生理作用。我们用化学致癌物DMBA治疗Ski杂合突变小鼠。野生型小鼠未产生肿瘤，而大量Ski杂合子产生肿瘤，如T细胞淋巴瘤和b细胞淋巴瘤。此外，与野生型细胞相比，从缺乏ski的胚胎制备的小鼠成纤维细胞具有更高的增殖能力。此外，将活化的Ki-ras引入ski缺陷小鼠胚胎成纤维细胞导致肿瘤转化。这些发现表明Ski在某些类型的细胞中起肿瘤抑制作用。