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Nuclear Forkhead Box O1 Controls and Integrates Key Signaling Pathways in Hepatocytes

Institut National de la Santé et de la Recherche Médicale, U145, and Université de Nice-Sophia Antipolis, Faculté de Médecine, Institut de Génétique et Signalisation Moléculaire (IFR50) (M.N., N.G., C.C., E.V.O.), F-06107 Nice, France; Instituto de Investigaciones Biomédicas Alberto Sols Consejo Superior de Investigaciones Científicas C/Arturo Duperier 4 (A.M.V.), 28029 Madrid, Spain; and College of Physicians and Surgeons (D.A.), Columbia University, New York 10032

Address all correspondence and requests for reprints to: Emmanuel Van Obberghen, Institut National de la Santé et de la Recherche Médicale U145, Institut Federatif de Recherche 50, Faculté de Médecine, Avenue de Valombrose, F-06107 Nice, France. E-mail: vanobbeg{at}unice.fr.

Insulin inhibits forkhead O class (FoxO) transcription factors, which down-regulate the expression of genes involved in metabolism, cell cycle arrest, and apoptosis. After being phosphorylated by protein kinase B (PKB) on S253 in its DNA-binding domain, Foxo1 is phosphorylated on T24 and additional sites, which overall triggers its nuclear exclusion. During this process, Foxo1 is thought to retain some transcriptional activity and signaling potential. To evaluate this Foxo1 action, we used a Foxo1-ADA mutant that is constitutively nuclear due to mutation of T24 and S316 to A and harbors a mutation of S253 to D. Adenoviral-mediated expression of Foxo1-ADA in hepatocytes activates PKB and MAPK pathways more than expression of wild-type or of a transactivation domain-deleted mutant (256). PKB activation cannot be accounted for by a Foxo1-mediated increase in upstream signaling components such as insulin receptor substrate 1 or 2 or by Foxo1-mediated down-regulation of Tribbles homolog 3. In contrast, Foxo1-ADA increases p38 activity, and p38 is required for effects of Foxo1 on PKB, at least in part. We propose that Foxo1 turns on a feed-forward loop, relayed by p38 and acting to amplify both PKB activation and Foxo1 inhibition. To conclude, key signaling pathways are activated in hepatocytes through nuclear Foxo1.

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