Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsDe Jaime-Soguero, Anchel
Del Sol, Antonio
Cosma, Maria Pia
MetadataShow full item record
AbstractUnderstanding the mechanisms regulating cell cycle, proliferation and potency of pluripotent stem cells guarantees their safe use in the clinic. Embryonic stem cells (ESCs) present a fast cell cycle with a short G1 phase. This is due to the lack of expression of cell cycle inhibitors, which ultimately determines naïve pluripotency by holding back differentiation. The canonical Wnt/β-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/β-catenin controls the cell cycle of mESCs remains unknown. Here we show that the Wnt-effector Tcf1 is recruited to and triggers transcription of the Ink4/Arf tumor suppressor locus. Thereby, the activation of the Wnt pathway, a known mitogenic pathway in somatic tissues, restores G1 phase and drastically reduces proliferation of mESCs without perturbing pluripotency. Tcf1, but not Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of β-catenin or Tcf1 expression impairs Wnt-dependent cell cycle regulation. All together, here we showed that Wnt signaling controls mESC pluripotency and proliferation through non-overlapping functions of distinct Tcf factors.
CitationWnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. 2017, 13 (3):e1006682 PLoS Genet.
AffiliationTwinCore, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- β-Catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors.
- Authors: Grumolato L, Liu G, Haremaki T, Mungamuri SK, Mong P, Akiri G, Lopez-Bergami P, Arita A, Anouar Y, Mlodzik M, Ronai ZA, Brody J, Weinstein DC, Aaronson SA
- Issue date: 2013
- Inhibition of β-catenin-TCF1 interaction delays differentiation of mouse embryonic stem cells.
- Authors: Chatterjee SS, Saj A, Gocha T, Murphy M, Gonsalves FC, Zhang X, Hayward P, Akgöl Oksuz B, Shen SS, Madar A, Martinez Arias A, DasGupta R
- Issue date: 2015 Oct 12
- Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal.
- Authors: Yi F, Pereira L, Hoffman JA, Shy BR, Yuen CM, Liu DR, Merrill BJ
- Issue date: 2011 Jun 19
- Retinoic acid suppresses the canonical Wnt signaling pathway in embryonic stem cells and activates the noncanonical Wnt signaling pathway.
- Authors: Osei-Sarfo K, Gudas LJ
- Issue date: 2014 Aug
- Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer.
- Authors: Gamell C, Gulati T, Levav-Cohen Y, Young RJ, Do H, Pilling P, Takano E, Watkins N, Fox SB, Russell P, Ginsberg D, Monahan BJ, Wright G, Dobrovic A, Haupt S, Solomon B, Haupt Y
- Issue date: 2017 Jan 10