Role of the exchange protein directly activated by cyclic adenosine 5'-monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells.
Endocrinology
; 147(8): 3727-36, 2006 Aug.
Article
em En
| MEDLINE
| ID: mdl-16644915
ABSTRACT
Although proglucagon gene expression and the synthesis of proglucagon encoded peptide hormones could be activated by protein kinase A (PKA) activators such as forskolin/3-isobutyl-1-methylxanthine (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 either not observable or much less potent. Forskolin could activate ERK1/2 phosphorylation and proglucagon gene transcription on its own, whereas forskolin plus IBMX are required to effectively activate the PKA pathway in the proglucagon-producing cells. Exchange protein directly activated by cyclic AMP 2 (Epac2, or cAMP-binding guanine nucleotide exchange factor-2) was found to be expressed in gut and pancreatic proglucagon-producing cell lines, whereas 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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
/
AMP Cíclico
/
Células Enteroendócrinas
/
Fatores de Troca do Nucleotídeo Guanina
/
Proglucagon
Limite:
Animals
Idioma:
En
Revista:
Endocrinology
Ano de publicação:
2006
Tipo de documento:
Article