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The canonical Wnt pathway is critical for embryonic stem cell (ESC) pluripotency and aberrant control of β-catenin leads to failure of exit from pluripotency and lineage commitments. Hence, maintaining the appropriate level of β-catenin is important for the decision to commit to the appropriate lineage. However, how β-catenin links to core transcription factors in ESCs remains elusive. C-terminal-binding protein (CtBP) in Drosophila is essential for Wnt-mediated target gene expression. In addition, Ctbp acts as an antagonist of β-catenin/TCF activation in mammals. Recently, Ctbp2, a core Oct4-binding protein in ESCs, has been reported to play a key role in ESC pluripotency. However, the significance of the connection between Ctbp2 and β-catenin with regard to ESC pluripotency remains elusive. Here, we demonstrate that C-terminal-binding protein 2 (Ctbp2) associates with major components of the β-catenin destruction complex and limits the accessibility of β-catenin to core transcription factors in undifferentiated ESCs. Ctbp2 knockdown leads to stabilization of β-catenin, which then interacts with core pluripotencymaintaining factors that are occupied by Ctbp2, leading to incomplete exit from pluripotency. These findings suggest a suppressive function for Ctbp2 in reducing the protein level of β-catenin, along with priming its position on core pluripotency genes to hinder β-catenin deposition, which is central to commitment to the appropriate lineage.
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참고문헌 (27)
참고문헌 신청
Aberle H / 1997 / beta-catenin is a target for the ubiquitin-proteasome pathway / EMBO J 16 : 3797 ~ 3804
Bakre MM / 2007 / Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation / J Biol Chem 282 : 31703 ~ 317
Chen X / 2008 / Integration of external signaling pathways with the core transcriptional network in embryonic stem cells / Cell 133 : 1106 ~ 1117
Clevers H / 2006 / Wnt/beta-catenin signaling in development and disease / Cell 127 : 469 ~ 480
Hao J / 2006 / WNT/beta-catenin pathway upregulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells / Dev Biol 290 : 81 ~ 91
Bakre MM / 2007 / Generation of multipotential mesendodermal progenitors from mouse embryonic stem cells via sustained Wnt pathway activation / J Biol Chem 282 : 31703 ~ 317
Chen X / 2008 / Integration of external signaling pathways with the core transcriptional network in embryonic stem cells / Cell 133 : 1106 ~ 1117
Clevers H / 2006 / Wnt/beta-catenin signaling in development and disease / Cell 127 : 469 ~ 480
Hao J / 2006 / WNT/beta-catenin pathway upregulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells / Dev Biol 290 : 81 ~ 91
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