Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Nat Cell Biol. 2011 Jul 31;13(9):1092-9. doi: 10.1038/ncb2293.
Pluripotency of embryonic stem cells (ESCs) is defined by their ability to differentiate into three germ layers and derivative cell types and is established by an interactive network of proteins including OCT4 (also known as POU5F1; ref. 4), NANOG (refs 5, 6), SOX2 (ref. 7) and their binding partners. The forkhead box O (FoxO) transcription factors are evolutionarily conserved regulators of longevity and stress response whose function is inhibited by AKT protein kinase. FoxO proteins are required for the maintenance of somatic and cancer stem cells; however, their function in ESCs is unknown. We show that FOXO1 is essential for the maintenance of human ESC pluripotency, and that an orthologue of FOXO1 (Foxo1) exerts a similar function in mouse ESCs. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters. Finally, AKT is not the predominant regulator of FOXO1 in human ESCs. Together these results indicate that FOXO1 is a component of the circuitry of human ESC pluripotency. These findings have critical implications for stem cell biology, development, longevity and reprogramming, with potentially important ramifications for therapy.
胚胎干细胞（ESCs）的多能性由其分化为三个胚层和衍生细胞类型的能力定义，并由包括 OCT4（也称为 POU5F1；参考文献 4）、NANOG（参考文献 5,6）、SOX2（参考文献 7）及其结合伴侣在内的蛋白质相互作用网络建立。叉头框 O（FoxO）转录因子是长寿和应激反应的进化保守调节剂，其功能受 AKT 蛋白激酶抑制。FoxO 蛋白是维持体干细胞和癌症干细胞所必需的；然而，它们在 ESCs 中的功能尚不清楚。我们表明 FOXO1 对于维持人类 ESC 多能性至关重要，并且 FoxO1 的一个同源物（Foxo1）在小鼠 ESCs 中发挥类似的功能。这种功能可能是通过 FOXO1 通过占据和激活它们各自的启动子来直接控制 OCT4 和 SOX2 基因的表达来介导的。最后，AKT 不是人类 ESCs 中 FOXO1 的主要调节剂。这些结果表明 FOXO1 是人类 ESC 多能性电路的组成部分。这些发现对干细胞生物学、发育、长寿和重编程具有重要意义，并可能对治疗产生重要影响。
