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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会引起基因表达的变化，以产生适当的生理反应。一旦在细胞的质膜上被激活，信号传导体就启动一系列信号，这些信号被传递到细胞核，在细胞核中它们通过改变转录因子的活性来开启和关闭靶基因的表达。转录因子的靶向修饰，包括乙酰化、磷酸化、甲基化和泛素化，以响应外部和内部刺激而快速改变其活性，已成为RNA聚合酶II转录基因转录激活调节的重要机制。蛋白激酶B介导的磷酸化显示调节FOXO叉头转录家族成员的功能。定位于细胞核的未磷酸化FOXO因子与靶基因启动子内的胰岛素应答序列（IRS）结合，所述靶基因控制细胞周期、细胞死亡、氧化应激和葡萄糖代谢。另一方面，它们被胰岛素磷酸化，导致促进其细胞质滞留。尽管FOXO家族在基于转录的核作用中受多种修饰调节的生理功能的相关性是重要的兴趣，但FOXO因子在细胞中的命运尚未完全了解。在本研究中，我们通过多种修饰证明了FOXO因子的调节作用。