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J. Biol. Chem., Vol. 282, Issue 9, 6265-6273, March 2, 2007

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Regulation of Nanog Expression by Phosphoinositide 3-Kinase-dependent Signaling in Murine Embryonic Stem Cells^*

Mike P. Storm, Heather K. Bone, Craig G. Beck, Pierre-Yves Bourillot, Valerie Schreiber, Teresa Damiano^¶, Adam Nelson^¶, Pierre Savatier^||, and Melanie J. Welham¹

From the Department of Pharmacy and Pharmacology and Centre for Regenerative Medicine, The University of Bath, Bath BA2 7AY, United Kingdom, INSERM U846, Stem Cell and Brain Research, 18 Avenue du Doyen Lépine, 69500 Bron, France, ^||Université de Lyon, F-69003 Lyon, France, and ^¶School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom

Embryonic stem (ES) cell pluripotency is regulated by a combination of extrinsic and intrinsic factors. Previously we have demonstrated that phosphoinositide 3-kinase (PI3K)-dependent signaling is required for efficient self-renewal of murine ES cells. In the study presented here, we have investigated the downstream molecular mechanisms that contribute to the ability of PI3Ks to regulate pluripotency. We show that inhibition of PI3K activity with either pharmacological or genetic tools results in decreased expression of RNA for the homeodomain transcription factor Nanog and decreased Nanog protein levels. Inhibition of glycogen synthase kinase 3 (GSK-3) activity by PI3Ks plays a key role in regulation of Nanog expression, because blockade of GSK-3 activity effectively reversed the effects of PI3K inhibition on Nanog RNA, and protein expression and self-renewal under these circumstances were restored. Furthermore, GSK-3 mutants mimicked the effects of PI3K or GSK-3 inhibition on Nanog expression. Importantly, expression of an inducible form of Nanog prevented the loss of self-renewal observed upon inhibition of PI3Ks, supporting a functional relationship between PI3Ks and Nanog expression. In addition, expression of a number of putative Nanog target genes was sensitive to PI3K inhibition. Thus, the new evidence provided in this study shows that PI3K-dependent regulation of ES cell self-renewal is mediated, at least in part, by the ability of PI3K signaling to maintain Nanog expression. Regulation of GSK-3 activity by PI3Ks appears to play a key role in this process.

Received for publication, November 27, 2006

^* This work was supported by European Community FP6 integrated project FunGenES Grant LSHG-CT 2003-503494 (to M. J. W. and P. S.), by the Wellcome Trust and Biotechnology and Biological Sciences Research Council (BBSRC) (to M. J. W.), by the INSERM AVENIR program (to P. S.), and by the BBSRC and an Engineering and Physical Sciences Research Council (EPSRC) fellowship (to A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2, Table S1, and supplemental data.

¹ To whom correspondence should be addressed. Tel.: 44-1225-386428; Fax: 44-1225-386114; E-mail: M.J.Welham{at}bath.ac.uk.

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