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ERK1/2 Control Phosphorylation and Protein Level of cAMP-Responsive Element–Binding Protein

A Key Role in Glucose-Mediated Pancreatic ß-Cell Survival

¹ INSERM U661, Equipe Avenir, Institut de Génomique Fonctionnelle, CNRS 5203, Université Montpellier I, Université Montpellier II, Montpellier, France
² CNRS UMR 5160, Faculté de Pharmacie, Montpellier, France

Address correspondence and reprint requests to Stéphane Dalle, INSERM, U661, Equipe Avenir, Institut de Génomique Fonctionnelle, 141, rue de la cardonille, 34094 Montpellier Cedex 5, France. E-mail: stephane.dalle{at}igf.cnrs.fr

Abbreviations: CREB, cAMP-responsive element–binding protein; DMEM, Dulbecco’s modified Eagle’s medium; ERK, extracellular signal–regulated kinase; GLP-1, glucagon-like peptide-1; PKA, protein kinase A; siRNA, small interfering RNA

cAMP-responsive element–binding protein (CREB) is required for ß-cell survival by regulating expression of crucial genes such as bcl-2 and IRS-2. Using MIN6 cells and isolated rat pancreatic islets, we investigated the signaling pathway that controls phosphorylation and protein level of CREB. We observed that 10 mmol/l glucose–induced CREB phosphorylation was totally inhibited by the protein kinase A (PKA) inhibitor H89 (2 µmol/l) and reduced by 50% with the extracellular signal–regulated kinase (ERK)1/2 inhibitor PD98059 (20 µmol/l). This indicates that ERK1/2, reported to be located downstream of PKA, participates in the PKA-mediated CREB phosphorylation elicited by glucose. In ERK1/2-downregulated MIN6 cells by siRNA, glucose-stimulated CREB phosphorylation was highly reduced and CREB protein content was decreased by 60%. In MIN6 cells and islets cultured for 24–48 h in optimal glucose concentration (10 mmol/l), which promotes survival, blockade of ERK1/2 activity with PD98059 caused a significant decrease in CREB protein level, whereas CREB mRNA remained unaffected (measured by real-time quantitative PCR). This was associated with loss of bcl-2 mRNA and protein contents, caspase-3 activation, and emergence of ultrastructural apoptotic features detected by electron microscopy. Our results indicate that ERK1 and -2 control the phosphorylation and protein level of CREB and play a key role in glucose-mediated pancreatic ß-cell survival.

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