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J. Biol. Chem., Vol. 281, Issue 26, 17929-17940, June 30, 2006

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Amino Acid Starvation Induces the SNAT2 Neutral Amino Acid Transporter by a Mechanism That Involves Eukaryotic Initiation Factor 2 Phosphorylation and cap-independent Translation^*

Francesca Gaccioliy, Charlie C. Huang, Chuanping Wang, Elena Bevilacqua, Renata Franchi-Gazzola, Gian Carlo Gazzola, Ovidio Bussolati, Martin D. Snider^¶, and Maria Hatzoglou¹

From the Departments of Nutrition and ^¶Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and Unit of General and Clinical Pathology, Department of Experimental Medicine, University of Parma, 43100 Parma, Italy

Nutritional stress caused by amino acid starvation involves a coordinated cellular response that includes the global decrease of protein synthesis and the increased production of cell defense proteins. Part of this response is the induction of transport system A for neutral amino acids that leads to the recovery of cell volume and amino acid levels once extracellular amino acid availability is restored. Hypertonic stress also increases system A activity as a mechanism to promote a rapid recovery of cell volume. Both a starvation-dependent and a hypertonic increase of system A transport activity are due to the induction of SNAT2, the ubiquitous member of SLC38 family. The molecular mechanisms underlying SNAT2 induction were investigated in tissue culture cells. We show that the increase in system A transport activity and SNAT2 mRNA levels upon amino acid starvation were blunted in cells with a mutant eIF2 that cannot be phosphorylated. In contrast, the induction of system A activity and SNAT2 mRNA levels by hypertonic stress were independent of eIF2 phosphorylation. The translational control of the SNAT2 mRNA during amino acid starvation was also investigated. It is shown that the 5'-untranslated region contains an internal ribosome entry site that is constitutively active in amino acid-fed and -deficient cells and in a cell-free system. We also show that amino acid starvation caused a 2.5-fold increase in mRNA and protein expression from a reporter construct containing both the SNAT2 intronic amino acid response element and the SNAT2-untranslated region. We conclude that the adaptive response of system A activity to amino acid starvation requires eukaryotic initiation factor 2 phosphorylation, increased gene transcription, and internal ribosome entry site-mediated translation. In contrast, the response to hypertonic stress does not involve eukaryotic initiation factor 2 phosphorylation, suggesting that SNAT2 expression can be modulated by specific signaling pathways in response to different stresses.

Received for publication, January 12, 2006 , and in revised form, March 17, 2006.

^* This work was supported by National Institutes of Health Grants RO1-DK60596 and RO1-DK53307 (to M. H.) and by Local Interest Fund-University of Parma (to R. F.-G.) and O. B. 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 To whom correspondence should be addressed: Dept. of Nutrition, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4906. Tel.: 216-368-3012; Fax: 216-368-6644; E-mail: mxh8{at}po.cwru.edu.

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