Li Jian, Wang Guangwen, Wang Chengyan, Zhao Yang, Zhang Hong, Tan Zhijia, Song Zhihua, Ding Mingxiao, Deng Hongkui
Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education, College of Life Sciences, Peking University, Beijing, 100871, China.
Differentiation. 2007 Apr;75(4):299-307. doi: 10.1111/j.1432-0436.2006.00143.x. Epub 2007 Feb 5.
MEK/ERK signaling plays a crucial role in a diverse set of cellular functions including cell proliferation, differentiation and survival, and recently has been reported to negatively regulate mouse embryonic stem cell (mESC) self-renewal by antagonizing STAT3 activity. However, its role in human ESCs (hESCs) remains unclear. Here we investigated the functions of MEK/ERK in controlling hESC activity. We demonstrated that MEK/ERK kinases were targets of fibroblast growth factor (FGF) pathway in hESCs. Surprisingly, we found that, in contrast to mESCs, high basal MEK/ERK activity was required for maintaining hESCs in an undifferentiated state. Inhibition of MEK/ERK activity by specific MEK inhibitors PD98059 and U0126, or by RNA interference, rapidly caused the loss of self-renewal capacity. We also showed that MEK/ERK signaling cooperated with phosphoinositide 3-kinase (PI3K)/AKT signaling in maintaining hESC pluripotency. However, MEK/ERK signaling had little or no effect on regulating hESC proliferation and survival, in contrast to PI3K/AKT signaling. Taken together, these findings reveal the unique and crucial role of MEK/ERK signaling in the determination of hESC cell fate and expand our understanding of the molecular mechanisms behind the FGF pathway maintenance of hESC pluripotency. Importantly, these data make evident the striking differences in the control of self-renewal between hESCs and mESCs.
MEK/ERK信号传导在包括细胞增殖、分化和存活在内的多种细胞功能中起着关键作用，最近有报道称它通过拮抗STAT3活性对小鼠胚胎干细胞（mESC）的自我更新起负调控作用。然而，其在人类胚胎干细胞（hESC）中的作用仍不清楚。在此，我们研究了MEK/ERK在控制hESC活性方面的功能。我们证明MEK/ERK激酶是hESC中纤维母细胞生长因子（FGF）信号通路的靶点。令人惊讶的是，我们发现，与mESC相反，hESC维持未分化状态需要较高的基础MEK/ERK活性。用特异性MEK抑制剂PD98059和U0126或通过RNA干扰抑制MEK/ERK活性，会迅速导致自我更新能力丧失。我们还表明，MEK/ERK信号传导在维持hESC多能性方面与磷酸肌醇3激酶（PI3K）/AKT信号传导协同作用。然而，与PI3K/AKT信号传导相反，MEK/ERK信号传导对调节hESC增殖和存活几乎没有影响。综上所述，这些发现揭示了MEK/ERK信号传导在决定hESC细胞命运中的独特关键作用，并扩展了我们对FGF信号通路维持hESC多能性背后分子机制的理解。重要的是，这些数据凸显了hESC和mESC在自我更新控制方面的显著差异。
