Expression of the transcription factor Egr-1 in pancreatic acinar cells following stimulation of cholecystokinin or Gαq-coupled designer receptors.
BACKGOUND/AIMS: The injection of cerulein, an analogue of the pancreatic secretagogue cholecystokinin (CCK), induces acute pancreatitis in mice that is accompanied by the synthesis of the transcription factor Egr-1. The signaling cascade that connects cerulein stimulation with enhanced Egr-1 biosynthesis was analyzed.


METHODS
AR42J rat pancreatic acinar cells were used as a model system to measure cerulein-induced Egr-1 biosynthesis. For comparison, the signaling cascade induced by activation of Gαq-coupled designer receptors with the designer drug clozapine-N-oxide (CNO) was investigated.


RESULTS
Stimulation of AR42J cells with cerulein induced a robust and transient biosynthesis of Egr-1. The signaling cascade connecting cerulein stimulation with Egr-1 gene expression required elevated levels of cytosolic Ca(2+) and the activation of the protein kinases PKC, Raf and ERK, while expression of MKP-1 prevented Egr-1 biosynthesis in cerulein-stimulated AR42J cells. In addition, ternary complex factors are required to connect cerulein stimulation with enhanced transcription of the Egr-1 gene. Egr-1 biosynthesis induced in CNO-stimulated AR42J pancreatic acinar cells expressing Gαq-coupled designer receptors required identical signaling molecules, although subtle differences were observed in comparison to cerulein/CCK receptor signaling.


CONCLUSIONS
We propose that overstimulation of the canonical Gαq-induced signaling pathway may be crucial for inducing acute pancreatitis.
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, Homburg, Germany.
Anke
A
Kaufmann
Oliver G
OG
Rössler
Gerald
G
Thiel
D061354:Acinar Cells / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002108:Ceruletide / Q000008:administration & dosage / Q000494:pharmacology*; D002766:Cholecystokinin / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D043562:Receptors, G-Protein-Coupled; D002108:Ceruletide; D002766:Cholecystokinin