Dynamic FoxO transcription factors
Dynamic FoxO transcription factors
复制标题
DOI：
10.1242/jcs.001222
复制
发表时间：
2007-08-01
影响因子：
4
通讯作者：
Tindall, Donald J.
中科院分区：
文献类型：
--
作者：
Huang, Haojie;Tindall, Donald J.
叉头盒O（Forkhead box O，FoxO）转录因子FoxO 1、FoxO 3a、FoxO 4和FoxO 6是秀丽隐杆线虫（Caeidhabditis elegans）的哺乳动物直系同源物，是一类重要的蛋白质家族，它们调节细胞凋亡、细胞周期、DNA损伤修复、氧化应激、细胞分化、葡萄糖代谢等细胞功能相关基因的表达。FoxO蛋白受多种机制调控。它们通过蛋白激酶如Akt、SGK、IKK和CDK 2响应于外部和内部刺激而进行抑制性磷酸化。相反，它们在应激条件下被上游调节因子如JNK和MST 1激活。它们的活性被乙酰化酶CBP和p300以及脱乙酰化酶SIRT 1抵消。此外，尽管FoxO 1和FoxO 3a的多泛素化导致它们被蛋白酶体降解，但FoxO 4的单泛素化促进其核定位并增强其转录活性。因此，FoxO蛋白的有效功能在生理条件下受到复杂信号通路的严格控制;这些蛋白的失调可能最终导致疾病，如癌症。
Forkhead box O ( FoxO) transcription factors FoxO1, FoxO3a, FoxO4 and FoxO6, the mammalian orthologs of Caenorhabditis elegans DAF-16, are emerging as an important family of proteins that modulate the expression of genes involved in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism and other cellular functions. FoxO proteins are regulated by multiple mechanisms. They undergo inhibitory phosphorylation by protein kinases such as Akt, SGK, IKK and CDK2 in response to external and internal stimuli. By contrast, they are activated by upstream regulators such as JNK and MST1 under stress conditions. Their activities are counterbalanced by the acetylases CBP and p300 and the deacetylase SIRT1. Also, whereas polyubiquitylation of FoxO1 and FoxO3a leads to their degradation by the proteasome, monoubiquitylation of FoxO4 facilitates its nuclear localization and augments its transcriptional activity. Thus, the potent functions of FoxO proteins are tightly controlled by complex signaling pathways under physiological conditions; dysregulation of these proteins may ultimately lead to disease such as cancer.