Exendin‐4 induction of Egr‐1 expression in INS‐1 β‐cells: Interaction of SRF, not YY1, with SRE site of rat Egr‐1 promoter

May 1, 2008Journal of cellular biochemistry

Exendin-4 triggers early gene expression in insulin-producing cells through SRF binding at the gene's control site

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Abstract

Exendin-4 (EX-4) significantly increased Egr-1 mRNA and protein levels in INS-1 beta-cells.

Egr-1 expression was upregulated by EX-4 through phosphorylation of the transcription factor CREB.
Inhibition of PKA and ERK1 pathways resulted in a significant reduction of EX-4-induced Egr-1 expression.
Promoter analyses indicated that specific DNA sequences (SRE clusters) are essential for Egr-1 transcription.
EX-4 treatment led to a transient increase in DNA-protein complexes at the SRE site, with binding of SRF and phospho-SRF.
YY1 overexpression did not influence Egr-1 promoter activity or the dynamics of the DNA-protein complex.

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Glucagon-like peptide-1 (GLP-1) induces several immediate early response genes such as c-fos, c-jun, and early growth response-1 (Egr-1), which are involved in cell proliferation and differentiation. We recently reported that exendin-4 (EX-4), a potent GLP-1 agonist, upregulated Egr-1 expression via phosphorylation of CREB, a transcription factor in INS-1 beta-cells. This study was designed to investigate the role of another transcription factors, serum response factor (SRF) and Yin Yang-1 (YY1), in EX-4-induced Egr-1 expression. EX-4 significantly increased Egr-1 mRNA and subsequently its protein level. EX-4-induced Egr-1 expression was inhibited by pretreatment with a PKA inhibitor, H-89, and an MEK inhibitor, PD 98059. The siRNA-mediated inhibition of PKA and ERK1 resulted in significant reduction of EX-4-induced Egr-1 expression. Promoter analyses showed that SRE clusters were essential for Egr-1 transcription, and YY1 overexpression did not affect Egr-1 promoter activity. EMSA results demonstrated that EX-4-induced transient increase in DNA-protein complex on SRE site, and that both SRF and phospho-SRF were bound to this site. Treatment of either YY1 consensus oligonucleotide or YY1 antibody did not effect the change of density or migration of the DNA-protein complex. Collectively, EX-4-induced Egr-1 expression is largely dependent on cAMP-mediated extracellular signal-regulated kinase activation, and EX-4 induces Egr-1 transcription via the interaction of SRF and phospho-SRF to SRE sites.

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Exendin‐4 induction of Egr‐1 expression in INS‐1 β‐cells: Interaction of SRF, not YY1, with SRE site of rat Egr‐1 promoter

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