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J. Biol. Chem., Vol. 283, Issue 28, 19201-19210, July 11, 2008

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Wnt Signaling Inhibits Forkhead Box O3a-induced Transcription and Apoptosis through Up-regulation of Serum- and Glucocorticoid-inducible Kinase 1^*

Manuel Dehner, Michel Hadjihannas, Jörg Weiske, Otmar Huber, and Jürgen Behrens¹

From the Department of Experimental Medicine II, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen, Glueckstrasse 6, 91054 Erlangen, Germany and the Department of Laboratory Medicine and Pathobiochemistry, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany

In human cancers, mutations in components of the Wnt signaling pathway lead to β-catenin stabilization and result in augmented gene transcription. HCT116 colon cancer cells carry stabilizing mutations in β-catenin and exhibit an elevated activation of Wnt signaling. To clarify the role of an overactive Wnt signaling, we used DNA microarray analysis to search for genes whose expression is up-regulated after knockdown of the wild type adenomatous polyposis coli (APC) tumor suppressor in HCT116 cells, which further enhances Wnt signaling activation. Serum and glucocorticoid-inducible kinase 1 (SGK1) was among the most up-regulated genes following APC knockdown through small interfering RNA. Up-regulation of SGK1 in response to small interfering RNA against APC was inhibited by concomitant knockdown of β-catenin. Quantitative real time reverse transcription-PCR, Western blot, and chromatin immunoprecipitation analyses confirmed that SGK1 is a direct β-catenin target gene. SGK1 negatively regulates the pro-apoptotic transcription factor Forkhead box O3a (FoxO3a) via phosphorylation and exclusion from the nucleus. We show that Wnt signaling activation results in FoxO3a exclusion from the nucleus and inhibits expression of FoxO3a target genes. Importantly, FoxO3a mutants that fail to be phosphorylated and therefore are regulated by SGK1 are not influenced by activation of Wnt signaling. In line, knockdown of SGK1 relieves the effects of Wnt signaling on FoxO3a localization and FoxO3a-dependent transcription. Finally, we show that induction of Wnt signaling inhibits FoxO3a-induced apoptosis. Collectively our results indicate that evasion of apoptosis is another feature employed by an overactive Wnt signaling.

Received for publication, December 20, 2007 , and in revised form, May 9, 2008.

^* This work was supported by a grant from Nationales Genomforschungsnetz2 (NGFN2) (to J. B.). 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 Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 49-913185-29110; Fax: 49-913185-29111; E-mail: jbehrens{at}molmed.uni-erlangen.de.

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