Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells.
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.
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China;
Haixia
H
Chen
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China;
Renpeng
R
Guo
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China;
Qian
Q
Zhang
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China;
Hongchao
H
Guo
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China;
Meng
M
Yang
College of Mathematics, Nankai University, Tianjin 300071, China;
Zhenfeng
Z
Wu
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China;
Shan
S
Gao
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China; liulin@nankai.edu.cn lingyichen@nankai.edu.cn.
Lin
L
Liu
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China liulin@nankai.edu.cn lingyichen@nankai.edu.cn.
Lingyi
L
Chen
D000818:Animals; D002453:Cell Cycle; D016923:Cell Death; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D042822:Genomic Instability; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000071317:Nanog Homeobox Protein; D015398:Signal Transduction; D016615:Telomere
D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases
Erk; Mek; embryonic stem cells; genomic stability; self-renewal