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J. Biol. Chem., Vol. 280, Issue 8, 7369-7376, February 25, 2005

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Protein Kinase B Activity Is Sufficient to Mimic the Effect of Insulin on Glucagon Gene Transcription^*

Sven Schinner, Andreas Barthel¶, Claudia Dellas, Rafal Grzeskowiak, Sanjeev K. Sharma, Elke Oetjen, Roland Blume, and Willhart Knepel||

From the Department of Molecular Pharmacology, University of Göttingen, 37099 Göttingen, Germany and the ^¶Department of Endocrinology, Diabetes, and Rheumatology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany

Insulin inhibits glucagon gene transcription, and insulin deficiency is associated with hyperglucagonemia that contributes to hyperglycemia in diabetes mellitus. However, the insulin signaling pathway to the glucagon gene is unknown. Protein kinase B (PKB) is a key regulator of insulin signaling and glucose homeostasis. Impaired PKB function leads to insulin resistance and diabetes mellitus. Therefore, the role of PKB in the regulation of glucagon gene transcription was investigated. After transient transfections of glucagon promoter-reporter genes into a glucagon-producing islet cell line, the use of kinase inhibitors indicated that the inhibition of glucagon gene transcription by insulin depends on phosphatidylinositol (PI) 3-kinase. Furthermore, insulin caused a PI 3-kinase-dependent phosphorylation and activation of PKB in this cell line as revealed by phospho-immunoblotting and kinase assays. Overexpression of constitutively active PKB mimicked the effect of insulin on glucagon gene transcription. Both insulin and PKB responsiveness of the glucagon promoter were abolished when the binding sites for the transcription factor Pax6 within the G1 and G3 promoter elements were mutated. Recruitment of Pax6 or its potential coactivator, the CREB-binding protein (CBP), to G1 and G3 by using the GAL4 system restored both insulin and PKB responsiveness. These data suggest that insulin inhibits glucagon gene transcription by signaling via PI 3-kinase and PKB, with the transcription factor Pax6 and its potential coactivator CBP being critical components of the targeted promoter-specific nucleoprotein complex. The present data emphasize the importance of PKB in insulin signaling and glucose homeostasis by defining the glucagon gene as a novel target gene for PKB.

Received for publication, July 28, 2004 , and in revised form, November 12, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants GRK 335 and SFB402/A3. 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.

Present address: Dept. of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.

^|| To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Georg-August-Universität, Robert-Koch-Str. 40, 37099 Göttingen, Germany. Tel.: 49-551-395787; Fax: 49-551-395699; E-mail: wknepel{at}med.uni-goettingen.de.

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