Induction of early response genes in trypsin inhibitor-induced pancreatic growth

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 292; no. 2; p. G667
• Main Authors: Guo, Lili, Sans, Maria Dolors, Gurda, Grzegorz T, Lee, Sae-Hong, Ernst, Stephen A, Williams, John A
• Format: Journal Article
• Language: English
• Published: United States 01-02-2007
• Subjects: Activating Transcription Factor 2 - metabolism; Activating Transcription Factor 3 - genetics; Activating Transcription Factor 3 - metabolism; Animals; Carbamates - pharmacology; Cholecystokinin - deficiency; Cholecystokinin - genetics; Early Growth Response Transcription Factors - genetics; Early Growth Response Transcription Factors - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Gabexate - analogs & derivatives; Gabexate - pharmacology; Gene Expression - drug effects; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Pancreas - drug effects; Pancreas - growth & development; Pancreas - metabolism; Phosphorylation - drug effects; Protein Binding - drug effects; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Pyrimidinones - pharmacology; Receptors, Cholecystokinin - antagonists & inhibitors; Transcription Factor AP-1 - metabolism; Trypsin Inhibitors - pharmacology
• ISSN: 0193-1857
• DOI: 10.1152/ajpgi.00433.2006

Endogenous CCK release induced by a synthetic trypsin inhibitor, camostat, stimulates pancreatic growth; however, the mechanisms mediating this growth are not well established. Early response genes often couple short-term signals with long-term responses. To study their participation in the pancreatic growth response, mice were fasted for 18 h and refed chow containing 0.1% camostat for 1-24 h. Expression of 18 early response genes were evaluated by quantitative PCR; mRNA for 17 of the 18 increased at 1, 2, 4, or 8 h. Protein expression for c-jun, c-fos, ATF-3, Egr-1, and JunB peaked at 2 h. Nuclear localization was confirmed by immunohistochemistry of c-fos, c-jun, and Egr-1. Refeeding regular chow induced only a small increase of c-jun and none in c-fos expression. JNKs and ERKs were activated 1 h after camostat feeding as was the phosphorylation of c-jun and ATF-2. AP-1 DNA binding evaluated by EMSA showed a significant increase 1-2 h after camostat feeding with participation of c-jun, c-fos, ATF-2, ATF-3, and JunB shown by supershift. The CCK antagonist IQM-95,333 blocked camostat feeding-induced c-jun and c-fos expression by 67 and 84%, respectively, and AP-1 DNA binding was also inhibited. In CCK-deficient mice, the maximal response of c-jun induction and AP-1 DNA binding were reduced by 64 and 70%, respectively. These results indicate that camostat feeding induces a spectrum of early response gene expression and AP-1 DNA binding and that these effects are mainly CCK dependent.