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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：
11470036
负责人：
ISHII Shunsuke
金额：
$ 9.22万
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：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470036/
关键词：
C-activator CBP Co-repressor Ski Histone acetylation

项目摘要

The ski gene was originally identified as an oncogene. We have demonstrated that c-ski proto-oncogene product (c-Ski) directly associates with co-repressors N-CoR and mSin3A and forms a complex with histone deacetylase (HDAC). c-Ski acts as a co-repressor, and is required for transcriptional repression mediated by tumor suppressors, Mad and Rb, and nuclear hormone receptors . We have generated the mutant mice lacking the sno (ski-related novel) gene, which encodes the ski-related gene. Sno is essential for blastocyst formation in early development, and the sno-deficient embryos die at an early stage of development. The sno heterozygous mutants appeared to be healthy, but spontaneously arisen tumors were observed in them. Furthermore, they have the increased susceptibility to tumorigenesis when they were treated with the chemical carcinogen DMBA.Similar results were also obtained with the ski heterozygous mutant mice. These results indicate that ski and sno genes act as either oncogene or tumor suppressor depending on the cellular context. We also generated the mutant mice lacking CBP, which is the most famous co-activator containing the histone acetylase activity. The Cbp-deficient embryos died at E12.5-E14.5 due to hemorrhage in the brain. Hemorrhage was caused by impaired formation of blood vessel, indicating the important role of CBP for blood vessel formation. The Cbp-deficient embryos also exhibited the partially impaired hematopoesis in fetal liver. We have found that CBP directly acetylates c-Myb, and acetylation of c-Myb enhances the association between c-Myb and CBP.This is an interesting novel mechanism by which co-activator CBP regulates the activity of transcription factor.

ski基因最初被确定为致癌基因。我们已经证明c-ski原癌基因产物（c-ski）直接与协同抑制因子N-CoR和mSin3A结合，并与组蛋白去乙酰化酶（HDAC）形成复合物。c-Ski作为协同抑制因子，是肿瘤抑制因子Mad和Rb以及核激素受体介导的转录抑制所必需的。我们已经产生了缺乏雪（滑雪相关的新）基因的突变小鼠，该基因编码滑雪相关基因。在胚胎早期发育过程中，一氧化氮对囊胚的形成至关重要，缺乏一氧化氮的胚胎在发育早期死亡。这些杂合突变体看起来是健康的，但在他们身上观察到自发产生的肿瘤。此外，当他们接受化学致癌物DMBA治疗时，他们对肿瘤发生的易感性增加。在ski杂合突变小鼠中也得到了类似的结果。这些结果表明，根据细胞环境的不同，ski和snow基因可以作为致癌基因或肿瘤抑制基因。我们还产生了缺乏CBP的突变小鼠，CBP是最著名的含有组蛋白乙酰化酶活性的共激活剂。由于脑出血，cbp缺陷胚胎在E12.5-E14.5死亡。出血是由血管形成受损引起的，说明CBP在血管形成中的重要作用。cbp缺陷胚胎的肝脏造血功能也出现部分受损。我们发现CBP直接使c-Myb乙酰化，而c-Myb的乙酰化增强了c-Myb与CBP的关联。这是CBP调控转录因子活性的一个有趣的新机制。