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Submitted on January 17, 2006
Accepted on April 18, 2006
Div. of Cell and Molecular Biology, Toronto General Research Institute, University Health Network; Institute of Medical Science, University of Toronto; Department of Medicine, University of Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto; Department of Physiology, University of Toronto
* To whom correspondence should be addressed. E-mail: tianru.jin{at}utoronto.ca.
Although proglucagon gene expression and the synthesis of proglucagon encoded peptide hormones could be activated by PKA activators such as Forskolin/IBMX and cholera toxin, whether the activation is entirely attributed to PKA has not been previously examined. We found that Forskolin/IBMX also activate ERK1/2 phosphorylation in intestinal and pancreatic proglucagon producing cell lines. The MEK inhibitors PD98059 and U0126 were found to repress the expression of proglucagon promoter as well as endogenous proglucagon mRNA in two intestinal proglucagon producing cell lines, and to block the stimulatory effect of Forskolin/IBMX on proglucagon mRNA expression. The repressive effect of the PKA specific inhibitors, H-89 and KT-5720, however, was not observable or much less potent. Forskolin could activate ERK1/2 phsophorylation and proglucagon gene transcription on its own, while Forskolin plus IBMX are required to effectively activate the PKA pathway in the proglucagon producing cells. Epac2 (cAMP-GEF-2) was found to be expressed in gut and pancreatic proglucagon producing cell lines, while the Epac-pathway-specific cAMP analog, 8-pMeOPT-2'O-Me-cAMP, effectively stimulated ERK1/2 phosphorylation as well as proglucagon mRNA expression. We, therefore, suggest that cAMP at least partially regulates proglucagon gene expression via the Epac-Ras/Rap-Raf-MEK-ERK signaling pathway.
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