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J. Biol. Chem., Vol. 281, Issue 28, 19124-19133, July 14, 2006

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Endoplasmic Reticulum Stress Induction of Insulin-like Growth Factor-binding Protein-1 Involves ATF4^*

Alexandre Marchand¹, Céline Tomkiewicz, Laurent Magne, Robert Barouki, and Michèle Garlatti²

From the INSERM UMR-S 747, Université Paris-Descartes, 45 Rue des Saints-Pères, 75270 Paris, Cedex 06 and Assistance Publique-Hôpitaux de Paris Européen Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France

Endoplasmic reticulum (ER) stress is sensed by cells in different physiopathological conditions in which there is an accumulation of unfolded proteins in the ER. A coordinated adaptive program called the unfolded protein response is triggered and includes translation inhibition, transcriptional activation of a set of genes encoding mostly intracellular proteins, and ultimately apoptosis. Here we show that insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), a secreted protein that modulates IGF bioavailability and has other IGF-independent effects, is potently induced during ER stress in human hepatocytes. Various ER stress-inducing agents were able to increase IGFBP-1 mRNA levels, as well as cellular and secreted IGFBP-1 protein up to 20-fold. A distal regulatory region of the human IGFBP-1 gene (–6682/–6384) containing an activating transcription factor 4 (ATF4) composite site was required for promoter activation upon ER stress. Mutation of the ATF4 composite site led to the loss of IGFBP-1 regulation. Electrophoretic mobility shift assay revealed an ER stress-inducible complex that was displaced by an ATF4 antibody. Knockdown of ATF4 expression using two specific small interfering RNAs impaired up-regulation of IGFBP-1 mRNA, which highlights the relevance of ATF4 in endogenous IGFBP-1 gene induction. In addition to intracellular proteins involved in secretory and metabolic pathways, we conclude that ER stress induces the synthesis of secreted proteins. Increased secretion of IGFBP-1 during hepatic ER stress may thus constitute a signal to modulate cell growth and metabolism and induce a systemic adaptive response.

Received for publication, March 7, 2006 , and in revised form, May 4, 2006.

^* This work was supported in part by INSERM, the University René Descartes (Paris 5), the Ligue Contre Le Cancer, the program Environnement Santé (Ministère de l'Environnement, number EN00DO1), and the Région Ile de France. 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 Recipient of fellowships from the Ministère de la Recherche et de la Technologie and from the Association pour la Recherche Contre le Cancer.

² To whom correspondence should be addressed. Tel.: 33-1-42-86-33-60; Fax: 33-1-42-86-38-68; E-mail: Michele.Garlatti{at}univ-paris5.fr.

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