CCK, bombesin, and carbachol stimulate c-fos, c-jun, and c-myc oncogene expression in rat pancreatic acini.
To identify possible nuclear signals mediating long-term regulation of the pancreas by gastrointestinal hormones, the expression of c-fos, c-jun, and c-myc was investigated in rat pancreatic acini. Stimulation of the acini with cholecystokinin octapeptide (CCK-8, 100 pM), bombesin (10 nM), or carbachol (10 microM), but not gastrin (100 nM), secretin (100 nM), or vasoactive intestinal peptide (10 nM) induced an increase in oncogene mRNA expression. The percent increases of c-fos, c-jun, and c-myc mRNA were 207 +/- 40, 171 +/- 26, and 46 +/- 19 (n = 5) for CCK-8; 223 +/- 71, 159 +/- 31, and 43 +/- 21 (n = 5) for bombesin; and 125 +/- 51, 123 +/- 58, and 67 +/- 19 (n = 5) for carbachol, respectively. CCK-induced increases in oncogene mRNA were rapid and transient. c-fos and c-jun mRNA levels were increased after 30 min stimulation, peaked at 1 h, and returned to basal level in 2 h. Activation of c-myc was more prolonged with levels remaining elevated for at least 3 h. The effects of CCK-8 were concentration dependent. Detectable stimulation was seen at 10 pM; maximal stimulation occurred at 10 nM and was not affected by further increase in the concentration of CCK-8. JMV-180, a high-affinity site CCK receptor agonist and low-affinity site antagonist, alone did not stimulate c-fos mRNA expression but inhibited c-fos mRNA expression induced by CCK-8. These results suggest that the interaction between CCK and the low-affinity state of the CCK receptor is responsible for oncogene activation.
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Department of Physiology, University of Michigan, Ann Arbor 48109-0622.
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D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos; D016758:Genes, jun; D016259:Genes, myc; D009857:Oncogenes; D010179:Pancreas / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000378:metabolism / Q000502:physiology; D012844:Sincalide / Q000494:pharmacology*
D012333:RNA, Messenger; D011949:Receptors, Cholecystokinin; D002217:Carbachol; D012844:Sincalide; D001839:Bombesin