MCB Accepts, published online ahead of print on 12 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00489-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of a novel amino acid response pathway triggering ATF2 phosphorylation in mammals.

Cédric Chaveroux, Céline Jousse, Yoan Cherasse, Anne-Catherine Maurin, Laurent Parry, Valérie Carraro, Benoit Derijard, Alain Bruhat, and Pierre Fafournoux^*

Unité de Nutrition Humaine, UMR 1019, INRA de Theix, 63122 Saint Genès Champanelle, France; Laboratoire de Physiologie Cellulaire et Moléculaire, CNRS UMR 6548, Faculté des Sciences, Université de Nice Sophia Antipolis, 28 Avenue Valrose, 06108 Nice Cedex 2, France

^* To whom correspondence should be addressed. Email: fpierre{at}clermont.inra.fr.

It has been well established that amino acid availability can control gene expression. Previous studies have shown that amino acid depletion induces transcription of the ATF3 gene (Activation Transcription Factor 3), through an Amino Acid Response Element (AARE) located in its promoter. This event requires phosphorylation of Activating Transcription Factor 2 (ATF2), a constitutive AARE bound factor. To identify the signaling cascade leading to phosphorylation of ATF2 in response to amino acid starvation, we used an individual gene knockdown approach by siRNA. We identified the MAPK module MEKK1/MKK7/JNK2 as the pathway responsible for ATF2 phosphorylation on the threonine 69 and 71 (Thr69/71) residues. Then we progressed backwards up the signal transduction pathway and showed that GTPase Rac1/Cdc42 and protein G12 control the MAPK module, ATF2 phosphorylation and AARE dependent transcription. Taken together, our data reveal a new signaling pathway activated by amino acid starvation leading to ATF2 phosphorylation and subsequently positively impacting the transcription of amino acid-regulated genes.