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  Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation

Wray, J., Kalkan, T., Gomez-Lopez, S., Eckardt, D., Cook, A., Kemler, R., et al. (2011). Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nature Cell Biology, 13, 838-845.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-8DD2-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-9897-F
Genre: Journal Article

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 Creators:
Wray, Jason, Author
Kalkan, Tüzer, Author
Gomez-Lopez, Sandra, Author
Eckardt, Dominik1, Author              
Cook, Andrew, Author
Kemler, Rolf2, Author              
Smith, Austin, Author
Affiliations:
1Department of Molecular Embryology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243651              
2Emeritus Group: Molecular Embryology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243656              

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 Abstract: Self-renewal of rodent embryonic stem cells is enhanced by partial inhibition of glycogen synthase kinase-3 (Gsk3; refs 1, 2). This effect has variously been attributed to stimulation of Wnt signalling by β-catenin, stabilization of Myc protein and global de-inhibition of anabolic processes. Here we demonstrate that β-catenin is not necessary for embryonic stem cell identity or expansion, but its absence eliminates the self-renewal response to Gsk3 inhibition. Responsiveness is fully restored by truncated β-catenin lacking the carboxy-terminal trans-activation domain. However, requirement for Gsk3 inhibition is dictated by expression of T-cell factor 3 (Tcf3) and mediated by direct interaction with β-catenin. Tcf3 local-izes to many pluripotency genes in embryonic stem cells. Our findings confirm that Tcf3 acts as a transcriptional repressor and reveal that β-catenin directly abrogates Tcf3 function. We conclude that Gsk3 inhibition stabilizes the embryonic stem cell state primarily by reducing repressive influence on the core pluripotency network.

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Language(s): eng - English
 Dates: 2011-07
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 578906
 Degree: -

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Title: Nature Cell Biology
  Alternative Title : Nat. Cell Biol.
Source Genre: Journal
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Pages: - Volume / Issue: 13 Sequence Number: - Start / End Page: 838 - 845 Identifier: -