Glucose and glucoincretin peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic beta(INS-1) cells.
To link glucose signaling to its long-term pleiotropic effects in the pancreatic beta-cell, we have investigated whether glucose regulates immediate-early response genes (IEGs) coding for transcription factors implicated in cell proliferation and differentiation. Glucose causes a coordinated transcriptional activation of the IEGs c-fos, c-jun, JunB, zif-268, and nur-77 in the pancreatic beta-cell line INS-1. This activation is entirely dependent on the presence of the cell-permeant cAMP analog chlorophenylthio-cAMP, which has only a modest effect by itself. The accumulation of c-fos, JunB, and nur-77 mRNA occurs at physiological concentrations of glucose (3 to 11 mM), requires a 1-2 h period, and is mimicked by other nutrient stimuli including mannose, leucine plus glutamine, and pyruvate. Glucose is synergistic with the glucoincretin peptides GLP-1 and PACAP-38, whereas these neurohormonal agents have no effect at low (3 mM) glucose. Mechanistically, the synergy between glucose and the glucoincretins is not based on cAMP alone as glucose does not further increase intracellular cAMP in response to GLP-1 and PACAP-38. A role for Ca2+ signaling is inferred, since the L-type Ca2+ channel blocker nifedipine markedly reduces the induction of c-fos and nur-77 by glucose and GLP-1. The induction of IEGs by glucose and chlorophenylthio-cAMP or GLP-1 and the inhibitory effect of nifedipine are also observed in the betaHC9 cell line. The results indicate that GLP-1 and PACAP-38 act as competence factors for the action of glucose on c-fos, JunB, and nur-77. It is suggested that the synergistic effect of glucose and glucoincretins on IEG expression plays an important role in the adaptive processes of the beta-cell to hyperglycemia.
Susini
S
S
Fondation pour Recherches Médicales, University of Geneva, Switzerland.
Roche
E
E
Prentki
M
M
Schlegel
W
W
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004357:Drug Synergism; D051766:Early Growth Response Protein 1; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017781:Genes, Immediate-Early / Q000187:drug effects; D016762:Genes, fos; D016758:Genes, jun; D005934:Glucagon / Q000494:pharmacology / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011498:Protein Precursors / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D016335:Zinc Fingers
C495401:ADCYAP1 protein, human; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011498:Protein Precursors; D011994:Recombinant Proteins; D013873:Thionucleotides; D014157:Transcription Factors; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D009543:Nifedipine; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate