Induction of early response genes in trypsin inhibitor-induced pancreatic growth.
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.
Guo
Lili
L
Dept of Molecular and Integrative Physiology, Univ of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Sans
Maria Dolors
MD
Gurda
Grzegorz T
GT
Lee
Sae-Hong
SH
Ernst
Stephen A
SA
Williams
John A
JA
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D002766:Cholecystokinin / Q000172:deficiency / Q000235:genetics; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000378:metabolism; D004952:Esters; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016670:Gabexate / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006146:Guanidines; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; C497106:Atf2 protein, mouse; C103002:Atf3 protein, mouse; D002219:Carbamates; D051765:Early Growth Response Transcription Factors; D004952:Esters; D006146:Guanidines; C108038:IQM 95333; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011744:Pyrimidinones; D011949:Receptors, Cholecystokinin; D018808:Transcription Factor AP-1; D014361:Trypsin Inhibitors; C034532:camostat; D016670:Gabexate; D002766:Cholecystokinin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases