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J. Biol. Chem., Vol. 279, Issue 4, 2623-2631, January 23, 2004

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The Transcription Factors HIF-1 and HNF-4 and the Coactivator p300 Are Involved in Insulin-regulated Glucokinase Gene Expression via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway^*

Ulrike Roth, Katja Curth, Terry G. Unterman, and Thomas Kietzmann¶

From the Institut für Biochemie und Molekulare Zellbiologie, Georg-August-Universität, Humboldtallee 23, D-37073 Göttingen, Germany and the Departments of Medicine and Physiology and Biophysics, University of Illinois at Chicago and Veterans Affair Chicago Healthcare System, Chicago, Illinois 60612

Glucokinase plays a key role in the regulation of glucose utilization in liver and its expression is strongly enhanced by insulin and modulated by venous pO₂. In primary rat hepatocytes, pO₂ modulated insulin-dependent glucokinase (GK) gene expression was abolished by wortmannin an inhibitor of phosphatidylinositol 3-kinase (PI3K). Transfection of vectors encoding the p110 catalytic subunit of PI3K or constitutively active proteinkinase B (PKB) stimulated GK mRNA and protein expression. The transfection of GK promoter constructs together with expression vectors for p110 or constitutively active PKB revealed that the GK promoter region –87/–80 mediates the response to PI3K/PKB. Transfection experiments and gel shift assays show that this element is able to bind hypoxia-inducible factor-1 (HIF-1) in a hypoxia- and PKB-dependent manner. The ability of HIF-1 to activate the GK promoter was enhanced by hepatocyte nuclear factor-4 (HNF-4), acting via the sequence –52/–39, and by the coactivator p300. Stimulation of the GK promoter by insulin was dependent on the intact –87/–80 region and maximal stimulation was achieved when HIF-1, HNF-4, and p300 were cotransfected with the –1430 GK promoter Luc construct in primary hepatocytes. Maximal stimulation of GK promoter activity by insulin was inhibited when a p300 vector was used containing a mutation within a PKB phosphorylation site. Thus, a regulatory transcriptional complex consisting of HIF-1, HNF-4, and p300 appears to be involved in insulin-dependent GK gene activation.

Received for publication, July 31, 2003 , and in revised form, October 22, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft Grants SFB 402, TP A1, and GRK335 (to T. K.), National Institutes of Health Grant DKK1430, and by the Department of Veterans Affairs Merrit Review program (to T. G. U.). 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.

This study is dedicated to Kurt Jungermann who died on May 10, 2002.

^¶ To whom correspondence should be addressed: Inst. für Biochemie und Molekulare Zellbiologie, Georg-August-Universität Göttingen, Humboldtallee 23, D-37073 Göttingen, Germany. Tel.: 49-551-395952; Fax: 49-551-395960; E-mail: tkietzm{at}gwdg.de.

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