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J. Biol. Chem., Vol. 282, Issue 21, 15851-15861, May 25, 2007

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TRB3 Inhibits the Transcriptional Activation of Stress-regulated Genes by a Negative Feedback on the ATF4 Pathway^*

Céline Jousse¹, Christiane Deval¹, Anne-Catherine Maurin, Laurent Parry, Yoan Chérasse, Cédric Chaveroux, Renaud Lefloch, Philippe Lenormand, Alain Bruhat, and Pierre Fafournoux²

From the UMR 1019, Unité Nutrition Humaine, INRA de Theix, 63122 St Genès Champanelle, France and the Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR 6543, Centre Antoine Lacassagne, 06100 Nice, France

The integrated stress response (ISR) is defined as a highly conserved response to several stresses that converge to the induction of the activating transcription factor 4 (ATF4). Because an uncontrolled response may have deleterious effects, cells have elaborated several negative feedback loops that attenuate the ISR. In the present study, we describe how induction of the human homolog of Drosophila tribbles (TRB3) attenuates the ISR by a negative feedback mechanism. To investigate the role of TRB3 in the control of the ISR, we used the regulation of gene expression by amino acid limitation as a model. The enhanced production of ATF4 upon amino acid starvation results in the induction of a large number of target genes like CHOP (CAAT/enhancer-binding protein-homologous protein), asparagine synthetase (ASNS), or TRB3. We demonstrate that TRB3 overexpression inhibits the transcriptional induction of CHOP and ASNS whereas TRB3 silencing induces the expression of these genes both under normal and stressed conditions. In addition, transcriptional profiling experiments show that TRB3 affects the expression of many ISR-regulated genes. Our results also suggest that TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. Collectively, our data identify TRB3 as a negative feedback regulator of the ATF4-dependent transcription and participates to the fine regulation of the ISR.

Received for publication, December 21, 2006 , and in revised form, March 15, 2007.

^* 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 These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 33-4-73-62-45-62; Fax: 33-4-73-62-47-55; E-mail: fpierre{at}clermont.inra.fr.

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