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J. Biol. Chem., Vol. 279, Issue 35, 36650-36659, August 27, 2004

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Insulin-response Element-binding Protein 1

A NOVEL Akt SUBSTRATE INVOLVED IN TRANSCRIPTIONAL ACTION OF INSULIN^*

Betty C. Villafuerte, Lawrence S. Phillips¶, Madhavi J. Rane||, and Weidong Zhao¶**

From the Division of Endocrinology and Metabolism, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, the ^¶Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, and the ^||Division of Nephrology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202

Although the cis-acting elements that mediate the actions of insulin on gene transcription have been defined for a significant number of genes, the transcription factors responsible for the transactivation of these target sequences remain unknown. In this report, we identified a novel transcription factor that binds and transactivates the insulin-response elements of the insulin-like growth factor-binding protein-3 and other insulin responsive genes. This factor is a target of insulin signal transduction downstream of the phosphatidylinositol 3'-kinase/protein kinase B (Akt) pathway. Akt phosphorylates this factor in vivo and in vitro. Changes in expression level, phosphorylation, and nuclear translocation modulate the transactivation effects of the factor, and its expression is decreased in conditions of diabetes and insulin deficiency. Identification of a novel target of Akt that appears to mediate signals specific for insulin action should provide further insight into the mechanism of insulin action at the genomic level.

Received for publication, April 20, 2004 , and in revised form, June 9, 2004.

^* This work was supported in part by National Institutes of Health Grant DK52965, grants from EmTech Biotechnology Development Inc., Georgia Institute of Technology FRCP, and the Walter F. and Avis Jacobs Foundation (to B. C. V.). 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.

^** Postdoctoral fellow in the Division of Endocrinology.

To whom correspondence should be addressed. Tel.: 502-852-4048; Fax: 502-852-2492; E-mail: bcvill01{at}louisville.edu.

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