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Published online January 12, 2009
doi:10.1083/jcb.200801009
The Journal of Cell Biology, Vol. 184, No. 1, 67-82
The Rockefeller University Press, 0021-9525 $30.00
© 2009 Zhang et al.
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Article

A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A



Xin Zhang1,2, Irina Neganova1,2, Stefan Przyborski1,3, Chunbo Yang1,2, Michael Cooke1,3, Stuart P. Atkinson1,2, George Anyfantis1,2, Stefan Fenyk1,3, W. Nicol Keith4, Stacey F. Hoare4, Owen Hughes1,2, Tom Strachan1,2, Miodrag Stojkovic1, Philip W. Hinds5, Lyle Armstrong1,2, and Majlinda Lako1,2

1 NorthEast England Stem Cell Institute and 2 Institute of Human Genetics, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, England, UK
3 School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, England, UK
4 Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, Scotland, UK
5 Molecular Oncology Research Institute, Tufts Medical Center, Tufts University, Boston, MA 02111

Correspondence to Majlinda Lako: Majlinda.Lako{at}ncl.ac.uk

In this study, we show that NANOG, a master transcription factor, regulates S-phase entry in human embryonic stem cells (hESCs) via transcriptional regulation of cell cycle regulatory components. Chromatin immunoprecipitation combined with reporter-based transfection assays show that the C-terminal region of NANOG binds to the regulatory regions of CDK6 and CDC25A genes under normal physiological conditions. Decreased CDK6 and CDC25A expression in hESCs suggest that both CDK6 and CDC25A are involved in S-phase regulation. The effects of NANOG overexpression on S-phase regulation are mitigated by the down-regulation of CDK6 or CDC25A alone. Overexpression of CDK6 or CDC25A alone can rescue the impact of NANOG down-regulation on S-phase entry, suggesting that CDK6 and CDC25A are downstream cell cycle effectors of NANOG during the G1 to S transition.

M. Stojkovic's present address is Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.

Abbreviations used in this paper: AFP, {alpha}-fetoprotein; ChIP, chromatin immunoprecipitation; EB, embryoid body; ESC, embryonic stem cell; FDP, fluorescein diphosphate; GAPDH; glyceraldehyde 3-phosphate dehydrogenase; hESC, human ESC; PGA, protein G–agarose; SCID, severe combined immunodeficient; SMA, smooth muscle actin.

© 2009 Zhang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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