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¹ Departments of Physiology and
³ Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
² Department of Biochemistry, College of Medicine, Korea University, Seoul 136-701, Korea
⁴ Department of Internal Medicine, School of Medicine, Hallym University, Seoul 150-030, Korea
⁵ Department of Food Science and Nutrition, The Catholic University of Korea, Puchon City 420-743, Korea

(Requests for offprints should be addressed to Y-H Jo; Email: yhjo{at}catholic.ac.kr)

^* (M-J Kim and J-H Kang contributed equally to this study)

Glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (EX) have been considered as a growth factor implicated in pancreatic islet mass increase and ß-cell proliferation. This study aimed to investigate the effect of EX on cyclin D1 expression, a key regulator of the cell cycle, in the pancreatic ß-cell line INS-1. We demonstrated that EX significantly increased cyclin D1 mRNA and subsequently its protein levels. Although EX induced phosphorylation of Raf-1 and extracellular-signal-regulated kinase (ERK), both PD98059 and exogenous ERK1 had no effect on the cyclin D1 induction by EX. Instead, the cAMP-elevating agent forskolin induced cyclin D1 expression remarkably and this response was inhibited by pretreatment with H-89, a protein kinase A (PKA) inhibitor. Promoter analyses revealed that the cAMP-responsive element (CRE) site (at position –48; 5'-TAACGTCA-3') of cyclin D1 gene was required for both basal and EX-induced activation of the cyclin D1 promoter, which was confirmed by site-directed mutagenesis study. For EX to activate the cyclin D1 promoter effectively, CRE-binding protein (CREB) should be phosphorylated and bound to the putative CRE site, according to the results of electrophoretic mobility shift and chromatin immunoprecipitation assays. Lastly, a transfection assay employing constitutively active or dominant-negative CREB expression plasmids clearly demonstrated that CREB was largely involved in both basal and EX-induced cyclin D1 promoter activities. Taken together, EX-induced cyclin D1 expression is largely dependent on the cAMP/PKA signaling pathway, and EX increases the level of phosphorylated CREB and more potently trans-activates cyclin D1 gene through binding of the CREB to the putative CRE site, implicating a potential mechanism underlying ß-cell proliferation by EX.

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