Erk Signaling is Indispensable for Genomic Stability and Self-renewal of Mouse Embryonic Stem Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Oct 21

PMID 26483458

Citations 57

Authors

Haixia Chen

Renpeng Guo

Qian Zhang

Hongchao Guo

Meng Yang

Zhenfeng Wu

Shan Gao

Lin Liu

Lingyi Chen

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells.

Nai S, Wang M, Yang J, Ling B, Dong Q, Yang X Cell Death Differ. 2024; 31(11):1534-1544.

PMID: 39107495 PMC: 11519497. DOI: 10.1038/s41418-024-01354-x.

A novel chemical genetic approach reveals paralog-specific role of ERK1/2 in mouse embryonic stem cell fate control.

Hu L, Xiao X, Huang W, Zhou T, Chen W, Zhang C Front Cell Dev Biol. 2024; 12:1415621.

PMID: 39071800 PMC: 11272557. DOI: 10.3389/fcell.2024.1415621.

Hallmarks of totipotent and pluripotent stem cell states.

Du P, Wu J Cell Stem Cell. 2024; 31(3):312-333.

PMID: 38382531 PMC: 10939785. DOI: 10.1016/j.stem.2024.01.009.

as potential key regulators of genomic integrity and cellular survival in iPSCs.

Swaidan N, Soliman N, Aboughalia A, Darwish T, Almeshal R, Al-Khulaifi A Front Mol Biosci. 2024; 11:1342011.

PMID: 38375508 PMC: 10875024. DOI: 10.3389/fmolb.2024.1342011.

Navigating the ERK1/2 MAPK Cascade.

Martin-Vega A, Cobb M Biomolecules. 2023; 13(10).

PMID: 37892237 PMC: 10605237. DOI: 10.3390/biom13101555.

References

Yao Y, Li W, Wu J, Germann U, Su M, Kuida K . Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci U S A. 2003; 100(22):12759-64. PMC: 240691. DOI: 10.1073/pnas.2134254100. View

Tang Z, Dai S, He Y, Doty R, Shultz L, Sampson S . MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell. 2015; 160(4):729-744. PMC: 4564124. DOI: 10.1016/j.cell.2015.01.028. View

Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J . Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947-56. PMC: 3006442. DOI: 10.1016/j.cell.2005.08.020. View

Takashima Y, Guo G, Loos R, Nichols J, Ficz G, Krueger F . Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell. 2014; 158(6):1254-1269. PMC: 4162745. DOI: 10.1016/j.cell.2014.08.029. View

Huang J, Wang F, Okuka M, Liu N, Ji G, Ye X . Association of telomere length with authentic pluripotency of ES/iPS cells. Cell Res. 2011; 21(5):779-92. PMC: 3203670. DOI: 10.1038/cr.2011.16. View

Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F . Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science. 1999; 286(5443):1374-7. DOI: 10.1126/science.286.5443.1374. View

Raz R, Lee C, Cannizzaro L, DEustachio P, Levy D . Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A. 1999; 96(6):2846-51. PMC: 15857. DOI: 10.1073/pnas.96.6.2846. View

Stead E, White J, Faast R, Conn S, Goldstone S, Rathjen J . Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities. Oncogene. 2002; 21(54):8320-33. DOI: 10.1038/sj.onc.1206015. View

Shaul Y, Seger R . The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2006; 1773(8):1213-26. DOI: 10.1016/j.bbamcr.2006.10.005. View

10.

Goke J, Chan Y, Yan J, Vingron M, Ng H . Genome-wide kinase-chromatin interactions reveal the regulatory network of ERK signaling in human embryonic stem cells. Mol Cell. 2013; 50(6):844-55. DOI: 10.1016/j.molcel.2013.04.030. View

11.

Theunissen T, Powell B, Wang H, Mitalipova M, Faddah D, Reddy J . Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell. 2014; 15(4):471-487. PMC: 4184977. DOI: 10.1016/j.stem.2014.07.002. View

12.

Levin-Salomon V, Kogan K, Ahn N, Livnah O, Engelberg D . Isolation of intrinsically active (MEK-independent) variants of the ERK family of mitogen-activated protein (MAP) kinases. J Biol Chem. 2008; 283(50):34500-10. PMC: 3259889. DOI: 10.1074/jbc.M806443200. View

13.

Allsopp R, Vaziri H, Patterson C, Goldstein S, Younglai E, Futcher A . Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992; 89(21):10114-8. PMC: 50288. DOI: 10.1073/pnas.89.21.10114. View

14.

Jaenisch R, Young R . Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008; 132(4):567-82. PMC: 4142810. DOI: 10.1016/j.cell.2008.01.015. View

15.

Burdon T, Stracey C, Chambers I, Nichols J, Smith A . Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev Biol. 1999; 210(1):30-43. DOI: 10.1006/dbio.1999.9265. View

16.

Silva J, Nichols J, Theunissen T, Guo G, van Oosten A, Barrandon O . Nanog is the gateway to the pluripotent ground state. Cell. 2009; 138(4):722-37. PMC: 3437554. DOI: 10.1016/j.cell.2009.07.039. View

17.

Weissbein U, Benvenisty N, Ben-David U . Quality control: Genome maintenance in pluripotent stem cells. J Cell Biol. 2014; 204(2):153-63. PMC: 3897183. DOI: 10.1083/jcb.201310135. View

18.

Schneider R, Garrobo I, Foronda M, Palacios J, Marion R, Flores I . TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells. Nat Commun. 2013; 4:1946. DOI: 10.1038/ncomms2946. View

19.

Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

20.

Kim M, Kim S, Cho Y, Nadas J, Jeong C, Yao K . ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4. Nat Struct Mol Biol. 2012; 19(3):283-90. DOI: 10.1038/nsmb.2217. View