Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells
Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells
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Erk信号对于小鼠胚胎干细胞的基因组稳定性和自我更新是不可或缺的
DOI：
10.1073/pnas.1516319112
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发表时间：
2015-11-03
影响因子：
11.1
通讯作者：
Chen, Lingyi
中科院分区：
文献类型：
--
作者：
Chen, Haixia;Guo, Renpeng;Chen, Lingyi
胚胎干细胞（embryonic stem cells，ESCs）是胚胎干细胞（embryonic stem cells，ESC）的重要组成部分。通过药理学抑制剂抑制Mek/Erk信号传导促进小鼠ESC的自我更新和多能性维持，支持Erk信号传导对ESC自我更新不利的流行观点。然而，使用诱导型Erk敲除ESC，我们证明了Erk信号传导对于ESC自我更新是至关重要的。ESCs在Erk耗竭后不能维持超过4代，这与多能性基因的表达失调、增殖速率降低、G1细胞周期停滞、凋亡增加、端粒快速缩短和基因组稳定性受损有关。我们进一步证明了Mek的Erk独立功能，这可能解释了Mek抑制和Erk敲除对ESC自我更新的不同影响。药理学Mek抑制剂对Mek/Erk信号传导的抑制促进小鼠胚胎干细胞（ESC）的自我更新和多能性。有趣的是，Erk信号传导对人类ESC自我更新至关重要。在这里，我们证明了Erk信号传导对小鼠ESC自我更新和基因组稳定性至关重要。Erk耗尽的ESC不能维持。缺乏Erk导致快速端粒缩短和基因组不稳定，与多能性基因的表达失调，细胞增殖减少，G1细胞周期停滞和细胞凋亡增加有关。Erk信号传导也是激活分化基因所必需的，但不是ESC分化过程中抑制多能性基因所必需的。此外，我们发现了一个ERK独立的功能的Mek，这可能解释了不同的影响Mek抑制和Erk敲除ESC自我更新。总之，与流行的观点相反，Erk信号传导是端粒维持、基因组稳定性和小鼠ESC自我更新所必需的。
Significance Signaling pathways regulate the self-renewal and differentiation of embryonic stem cells (ESCs). Suppression of Mek/Erk signaling by pharmacological inhibitors promotes self-renewal and pluripotency maintenance of mouse ESCs, supporting the prevailing view that Erk signaling is dispensable for ESC self-renewal. However, using inducible Erk knockout ESCs, we demonstrate that Erk signaling is critical for ESC self-renewal. ESCs cannot be maintained for more than four passages after Erk depletion, associated with misregulated expression of pluripotency genes, reduced proliferation rate, G1 cell-cycle arrest, increased apoptosis, rapid shortening of telomeres, and impaired genomic stability. We further demonstrate an Erk-independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self-renewal. Inhibition of Mek/Erk signaling by pharmacological Mek inhibitors promotes self-renewal and pluripotency of mouse embryonic stem cells (ESCs). Intriguingly, Erk signaling is essential for human ESC self-renewal. Here we demonstrate that Erk signaling is critical for mouse ESC self-renewal and genomic stability. Erk-depleted ESCs cannot be maintained. Lack of Erk leads to rapid telomere shortening and genomic instability, in association with misregulated expression of pluripotency genes, reduced cell proliferation, G1 cell-cycle arrest, and increased apoptosis. Erk signaling is also required for the activation of differentiation genes but not for the repression of pluripotency genes during ESC differentiation. Furthermore, we find an Erk-independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self-renewal. Together, in contrast to the prevailing view, Erk signaling is required for telomere maintenance, genomic stability, and self-renewal of mouse ESCs.