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Molecular and Cellular Biology, March 2008, p. 1644-1656, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.00325-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Glucose-Dependent Insulinotropic Polypeptide-Mediated Up-Regulation of β-Cell Antiapoptotic Bcl-2 Gene Expression Is Coordinated by Cyclic AMP (cAMP) Response Element Binding Protein (CREB) and cAMP-Responsive CREB Coactivator 2

Department of Cellular and Physiological Sciences and Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada

Received 22 February 2007/ Returned for modification 11 May 2007/ Accepted 11 December 2007

The cyclic AMP (cAMP)/protein kinase A (PKA) cascade plays a central role in β-cell proliferation and apoptosis. Here, we show that the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates expression of the antiapoptotic Bcl-2 gene in pancreatic β cells through a pathway involving AMP-activated protein kinase (AMPK), cAMP-responsive CREB coactivator 2 (TORC2), and cAMP response element binding protein (CREB). Stimulation of β-INS-1 (clone 832/13) cells with GIP resulted in increased Bcl-2 promoter activity. Analysis of the rat Bcl-2 promoter revealed two potential cAMP response elements, one of which (CRE-I [GTGACGTAC]) was shown, using mutagenesis and deletion analysis, to be functional. Subsequent studies established that GIP increased the nuclear localization of TORC2 and phosphorylation of CREB serine 133 through a pathway involving PKA activation and reduced AMPK phosphorylation. At the nuclear level, phospho-CREB and TORC2 were demonstrated to bind to CRE-I of the Bcl-2 promoter, and GIP treatment resulted in increases in their interaction. Furthermore, GIP-mediated cytoprotection was partially reversed by small interfering RNA-mediated reduction in BCL-2 or TORC2/CREB or by pharmacological activation of AMPK. The antiapoptotic effect of GIP in β cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK-dependent regulation of CREB/TORC2 activity.

Published ahead of print on 17 December 2007.

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