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This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/E215    most recent 00181.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Kang, J.-H. Articles by Jo, Y.-H. Search for Related Content PubMed PubMed Citation Articles by Kang, J.-H. Articles by Jo, Y.-H.

Proximal cyclic AMP response element is essential for exendin-4 induction of rat EGR-1 gene

¹Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul; ²Department of Food Science and Nutrition, The Catholic University of Korea, Puchon; and ³Department of Family Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea

Submitted 14 April 2006 ; accepted in final form 14 August 2006

Glucagon-like peptide-1 and its potent agonist exendin-4 induce several immediate early response genes (IEGs) that code for transcription factors implicated in cell proliferation, differentiation, and apoptosis. We recently observed that early growth response factor-1 (EGR-1), an IEG product, was required for transcriptional activation of Ccnd1 (cyclin D1) gene by exendin-4. Herein, the regulatory mechanism whereby exendin-4 activates the transcription of EGR-1 gene was investigated in the pancreatic -cell line INS-1. Deletion analysis of rat EGR-1 promoter identified a critical region between –73 and –46 for the activation of EGR-1 in response to exendin-4. Mutation of the proximal putative cAMP response element (CRE, 5'-GTACGTCA-3') located at –69 resulted in a significant decrease in the EGR-1 transcription, whereas the mutation of the distal putative CRE at –139 was without such an effect. In immune supershift assays using exendin-4-treated cells, binding of cAMP response element-binding protein (CREB) phosphorylated on Ser¹³³ to the proximal CRE was increased. Employment of a CREB mutant containing Ala substitution at Ser¹³³ or a dominant negative CREB mutant that inhibits the binding of endogenous CREB to DNA significantly decreased the exendin-4-induced EGR-1 transcription. In experiments using specific protein kinase inhibitors, the effect of H-89 was more prominent than PD-98059, indicating the predominance of the PKA signaling over the MEK/ERK in induction of EGR-1. Therefore, it appears that the proximal CRE site is critical and the binding with CREB phosphorylated on Ser¹³³ is necessary for induction of the EGR-1 transcription by exendin-4.

early growth response factor-1; cyclic adenosine monophosphate response element-binding protein; protein kinase A