Functional Network of Transcriptional Control Factors Regulated by Multiple Modifications

细胞暴露在外界信号下会引起基因表达的变化，从而做出适当的生理反应。一旦在细胞质膜上被激活，信号就会启动一系列信号，这些信号被传递到细胞核，在那里它们通过改变转录因子的活性来开启和关闭目标基因的表达。转录因子的靶向性修饰，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迅速改变其活性，已成为调节RNA聚合酶II转录基因转录激活的重要机制。在对胰岛素的响应中，蛋白激酶B介导的磷酸化调节FOXO叉头转录家族成员的功能。定位于细胞核的非磷酸化FOXO因子与靶基因启动子内的胰岛素反应序列(IRS)结合，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，导致促进它们的细胞质保留。尽管FOXO家族在基于转录的核作用中受多重修饰调控与生理功能的相关性很有意义，但FOXO因子在细胞中的命运尚不完全清楚。在本研究中，我们通过多重修饰来证明FOXO因子的调节作用。

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.