CDK1-PDK1-PI3K/Akt 信号通路调节胚胎和诱导的多能性,Cell Death and Differentiation

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CDK1-PDK1-PI3K/Akt 信号通路调节胚胎和诱导的多能性
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2016-09-16 , DOI: 10.1038/cdd.2016.84
Xiao Qi Wang , Chung Mau Lo , Lin Chen , Elly S-W Ngan , Aimin Xu , Randy YC Poon

信号通路如何协调和整合以维持人类胚胎干细胞 (hESCs) 的自我更新和在重编程中获得多能性的机制仍只是部分了解。CDK1 是有丝分裂的关键调节因子。最近，CDK1 已被证明参与调节干细胞的自我更新，尽管 CDK1 如何调节多能性的机制作用尚不清楚。在本报告中，我们旨在了解 CDK1 如何通过将 CDK1 活性降低到对细胞周期进程没有影响的水平来控制多能性。我们证明了高水平的 CDK1 与 hESC 的多能性阶段有关；并且将 CDK1 活性降低到不干扰细胞周期的水平足以诱导分化。CDK1 特异性靶向 PDK1 的磷酸化，从而靶向 PI3K/Akt 及其效应子 ERK 和 GSK3β 的活性。通过抑制 Akt 信号转导效应器逆转无活性 CDK1 介导的分化的证据表明 CDK1-PDK1-PI3K/Akt 激酶级联是 hESC 多能性的功能性信号通路。此外，细胞周期蛋白 B1-CDK1 复合物促进体细胞重编程效率，可能是通过调节诱导多能干细胞 (iPSCs) 的成熟，因为细胞周期蛋白 B1 刺激更高细胞水平的 LIN28A，表明监测 iPSC 因子可能是增强的新途径重编程效率。总之，我们证明了 CDK1-PDK1-PI3K/Akt 激酶信号通路在调节自我更新、分化和体细胞重编程中的重要作用，

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CDK1-PDK1-PI3K/Akt signaling pathway regulates embryonic and induced pluripotency

The mechanisms of how signaling pathways are coordinated and integrated for the maintenance of the self-renewal of human embryonic stem cells (hESCs) and the acquisition of pluripotency in reprogramming are still only partly understood. CDK1 is a key regulator of mitosis. Recently, CDK1 has been shown to be involved in regulating self-renewal of stem cells, even though the mechanistic role of how CDK1 regulates pluripotency is unknown. In this report, we aim to understand how CDK1 can control pluripotency by reducing CDK1 activity to a level that has no effect on cell cycle progression. We demonstrated that high levels of CDK1 is associated with the pluripotency stage of hESCs; and decreased CDK1 activity to a level without perturbing the cell cycle is sufficient to induce differentiation. CDK1 specifically targets the phosphorylation of PDK1 and consequently the activity of PI3K/Akt and its effectors ERK and GSK3β. Evidence of the reversion of inactive CDK1-mediated differentiation by the inhibition of Akt signaling effectors suggests that the CDK1-PDK1-PI3K/Akt kinase cascade is a functional signaling pathway for the pluripotency of hESCs. Moreover, cyclin B1-CDK1 complexes promote somatic reprogramming efficiency, probably by regulating the maturation of induced pluripotent stem cells (iPSCs), as cyclin B1 stimulates a higher cellular level of LIN28A, suggesting that monitoring iPSC factors could be a new path for the enhancement of reprogramming efficiency. Together, we demonstrate an essential role for the CDK1-PDK1-PI3K/Akt kinase signaling pathway in the regulation of self-renewal, differentiation, and somatic reprogramming, which provides a novel kinase cascade mechanism for pluripotency control and acquisition.

更新日期：2016-09-16

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