Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic beta-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism.
Endocrinology
; 142(5): 1820-7, 2001 May.
Article
em En
| MEDLINE
| ID: mdl-11316746
ABSTRACT
Glucagon-like peptide-1 (GLP-1) enhances insulin secretion and synthesis. It also regulates the insulin, glucokinase, and GLUT2 genes. It mediates increases in glucose-stimulated insulin secretion by activating adenylyl cyclase and elevating free cytosolic calcium levels in the beta-cell. In addition, GLP-1 has been shown, both in vitro and in vivo, to be involved in regulation of the transcription factor, pancreatic duodenal homeobox-1 protein (PDX-1), by increasing its total protein levels, its translocation to the nucleus and its binding and resultant increase in activity of the insulin gene promoter in beta-cells of the pancreas. Here we have investigated the role of protein kinase A (PKA) in these processes in RIN 1046-38 cells. Three separate inhibitors of PKA, and a cAMP antagonist, inhibited the effects of GLP-1 on PDX-1. Furthermore, forskolin, (which stimulates adenylyl cyclase and insulin secretion), and 8-Bromo-cAMP, (an analog of cAMP which also stimulates insulin secretion), mimicked the effects of GLP-1 on PDX-1. These effects were also prevented by PKA inhibitors. Glucose-mediated increases in nuclear translocation of PDX-1 were not prevented by PKA inhibitors. Our results suggest that regulation of PDX-1 by GLP-1 occurs through activation of adenylyl cyclase and the resultant increase in intracellular cAMP, in turn, activates PKA, which ultimately leads to increases in PDX-1 protein levels and translocation of the protein to the nuclei of beta-cells.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Precursores de Proteínas
/
Sulfonamidas
/
Glucagon
/
Transativadores
/
Núcleo Celular
/
Proteínas Quinases Dependentes de AMP Cíclico
/
AMP Cíclico
/
Proteínas de Homeodomínio
/
Citoplasma
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2001
Tipo de documento:
Article