ERK1/2 control phosphorylation and protein level of cAMP-responsive element-binding protein: a key role in glucose-mediated pancreatic beta-cell survival. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Diabetes Année : 2006

ERK1/2 control phosphorylation and protein level of cAMP-responsive element-binding protein: a key role in glucose-mediated pancreatic beta-cell survival.

Safia Costes
  • Fonction : Auteur
Christophe Broca
  • Fonction : Auteur
Gyslaine Bertrand
  • Fonction : Auteur
Joel Bockaert
Stéphane Dalle

Résumé

cAMP-responsive element-binding protein (CREB) is required for beta-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 micromol/l) and reduced by 50% with the extracellular signal-regulated kinase (ERK)1/2 inhibitor PD98059 (20 micromol/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 beta-cell survival.

Dates et versions

hal-00201283 , version 1 (27-12-2007)

Identifiants

Citer

Safia Costes, Christophe Broca, Gyslaine Bertrand, Anne-Dominique Lajoix, Dominique Bataille, et al.. ERK1/2 control phosphorylation and protein level of cAMP-responsive element-binding protein: a key role in glucose-mediated pancreatic beta-cell survival.. Diabetes, 2006, 55 (8), pp.2220-30. ⟨10.2337/db05-1618⟩. ⟨hal-00201283⟩
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