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Papers In Press, published online ahead of print March 21, 2006
Dpto. Bioquimica and Instituto de Investigaciones Biomédicas, Universidad Autónoma de Madrid, Madrid, Madrid 28029
Corresponding Author: antonio.cuadrado{at}uam.es
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-3beta (GSK-3
J. Biol. Chem, 10.1074/jbc.M513737200
Submitted on December 27, 2005
Revised on February 21, 2006
Accepted on March 21, 2006
Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusionof the transcription factor NRF2
), 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, while co-expression of active GSK-3 attenuated both phase II gene expression and oxidant protection. These results contribute to clarify the crosstalk 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.
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