Functional Network of Transcriptional Control Factors Regulated by Multiple Modifications

多重修饰调控的转录控制因子的功能网络

基本信息

批准号：
14206040
负责人：
FUKAMIZU Akiyoshi
金额：
$ 30.04万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Exposure of cells to external signaling causes changes in gene expression for appropriate physiological responses. Once activated on the plasma membrane of cells, the siganals initiate a cascade of signals that are transmitted to the nucleus where they switch on and off the expression of target genes by modifying the activity of transcription factors. Targeted modifications of transcription factors, including acetylation, phosphorylation, methylation, and ubiquitination, for rapid alterations in their activities in response to external and internal stimuli have emerged as an important mechanism in the regulation of transcriptional activation of RNA polymerase II-transcribed genes.In response to insulin, protein kinase B-mediated phosphorylation is shown to modulate the function of the FOXO forkhead transcription family members. The unphosphorylated FOXO factors that localize to the nucleus bind to the insulin response sequence (IRS) within the promoters of the target genes, which control the cell cycle, cell death, oxidative stress, and glucose metabolism. On the other hand, they are phosphorylated by insulin, resulting in promoting their cytoplasmic retention. Although the relevance of FOXO family regulated by multiple modifications to the physiological functions in the transcription-based nuclear action is of significant interest, the fate of FOXO factors in the cells is not yet fully understood. In the present study, we demonstrated the regulatory roles for the FOXO factors by multiple modifications.

细胞暴露于外部信号传导会导致基因表达的变化，以实现适当的生理反应。一旦在细胞的质膜上激活，Siganals就会启动一系列信号，这些信号通过修饰转录因子的活性来传递到核开启和关闭靶基因的表达。针对转录因子的有针对性修饰，包括乙酰化，磷酸化，甲基化和泛素化，以快速改变其活性，以响应外部和内部刺激，作为调节RNA聚合酶II-II转录基因的转录激活的重要机制。对胰岛素的反应，蛋白激酶B介导的磷酸化显示可调节Foxo叉子转录家族成员的功能。靶基因启动子内的胰岛素反应序列（IRS）的未磷酸化FOXO因素与控制细胞周期，细胞死亡，氧化应激和葡萄糖代谢的启动子内结合。另一方面，它们被胰岛素磷酸化，从而促进其细胞质保留率。尽管FOXO家族受多种修饰对基于转录的核作用的生理功能调节的相关性具有重大意义，但细胞中FOXO因素的命运尚未完全了解。在本研究中，我们通过多次修改证明了FOXO因素的调节作用。