Exendin-4 induction of cyclin D1 expression in INS-1 β-cells: Involvement of cAMP-responsive element

M. J. Kim, J. H. Kang, Y. G. Park, G. R. Ryu, S. H. Ko, I. K. Jeong, K. H. Koh, D. J. Rhie, S. H. Yoon, S. J. Hahn, M. S. Kim, Y. H. Jo

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Abstract

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 β-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 β-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 β-cell proliferation by EX.

Original languageEnglish
Pages (from-to)623-633
Number of pages11
JournalJournal of Endocrinology
Volume188
Issue number3
DOIs
Publication statusPublished - 2006 Mar

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Kim, M. J., Kang, J. H., Park, Y. G., Ryu, G. R., Ko, S. H., Jeong, I. K., Koh, K. H., Rhie, D. J., Yoon, S. H., Hahn, S. J., Kim, M. S., & Jo, Y. H. (2006). Exendin-4 induction of cyclin D1 expression in INS-1 β-cells: Involvement of cAMP-responsive element. Journal of Endocrinology, 188(3), 623-633. https://doi.org/10.1677/joe.1.06480