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J. Biol. Chem., Vol. 283, Issue 28, 19229-19234, July 11, 2008

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Insulin Signaling and the General Amino Acid Control Response

TWO DISTINCT PATHWAYS TO AMINO ACID SYNTHESIS AND UPTAKE^*

From the Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242

ATF4 is a transcription factor that induces a genetic program for amino acid synthesis and amino acid uptake. Previous work demonstrated that ATF4 expression is increased either by insulin or by the general amino acid control (GAAC) response, an evolutionarily ancient pathway that is activated when eukaryotic cells are deprived of amino acids. It is not known whether insulin and the GAAC pathway increase ATF4 expression by the same or different mechanisms. In these studies, we demonstrate that insulin-mediated ATF4 expression occurs as part of a coordinated anabolic program that does not require an essential component of the GAAC pathway, the protein kinase GCN2. Moreover, insulin and the GAAC pathway have an additive effect on expression of ATF4 and downstream mRNAs for amino acid synthesis and uptake. These data suggest that the GAAC pathway may facilitate insulin-mediated anabolism when exogenous amino acids are limiting. We conclude that insulin signaling and the GAAC response comprise two distinct yet complimentary pathways to ATF4 expression, allowing anabolism to be finely tuned to amino acid availability.

Received for publication, February 20, 2008 , and in revised form, May 14, 2008.

^* This work was supported by a Junior Faculty Award from the American Diabetes Association (to C. A.). 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.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.

¹ To whom correspondence should be addressed. Tel.: 319-353-7812; Fax: 319-353-7850; E-mail: christopher-adams{at}uiowa.edu.

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