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J. Biol. Chem., Vol. 281, Issue 21, 14841-14851, May 26, 2006

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Glycogen Synthase Kinase-3 Inhibits the Xenobiotic and Antioxidant Cell Response by Direct Phosphorylation and Nuclear Exclusion of the Transcription Factor Nrf2^*

From the Instituto de Investigaciones Biomédicas and Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain

The transcription factor Nrf2 (nuclear factor E2-related factor 2) regulates the expression of antioxidant phase II genes and contributes to preserve redox homeostasis and cell viability in response to oxidant insults. Nrf2 should be coordinated with the canonical cell survival pathway represented by phosphatidylinositol 3-kinase (PI3K) and the Ser/Thr kinase Akt but so far the mechanistic connections remain undefined. Here we identify glycogen synthase kinase-3 (GSK-3), which is inhibited by Akt-mediated phosphorylation, as the link between both processes. Using heme oxygenase-1 (HO-1) as a model phase II gene, we found that both PI3K and Akt increased mRNA and protein levels of this enzyme. Pharmacological inhibitors (LiCl and PDZD-8) and genetic variants of GSK-3 (constitutively active and dominant negative mutants) indicated that PI3K/Akt activates and GSK-3 inhibits the antioxidant response elements of the ho1 promoter and pointed Nrf2 as directly involved in this process. Indeed, GSK-3 phosphorylated Nrf2 in vitro and in vivo. Immunocytochemistry and subcellular fractionation analyses demonstrated that the effect of GSK-3-mediated phosphorylation of Nrf2 is to exclude this transcription factor from the nucleus. Nrf2 up-regulated the expression of HO-1, glutathione peroxidase, glutathione S-transferase A1, NAD(P)H: quinone oxidoreductase and glutamate-cysteine ligase and protected against hydrogen peroxide-induced glutathione depletion and cell death, whereas co-expression of active GSK-3 attenuated both phase II gene expression and oxidant protection. These results contribute to clarify the cross-talk between the survival signal elicited by PI3K/Akt and the antioxidant phase II cell response, and introduce GSK-3 as the key mediator of this regulation mechanism.

Received for publication, December 27, 2005 , and in revised form, February 21, 2006.

^* This work was supported by Grant SAF2004-02039 from Spanish Ministry of Education (MEC), GR/SAL/0198/2004 from the Community of Madrid, and RSMN (03/08) from the Health Institute Carlos III. 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.

¹ Recipients of "Formacion de Profesorado Universitario" fellowships from MEC.

² To whom correspondence should be addressed: Departamento de Bioquímica, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain. Tel.: 3491-497-5327; Fax: 3491-585-4401; E-mail: antonio.cuadrado{at}uam.es.

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