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1 Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
2 Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA
3 Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: mdsansg{at}umich.edu.
Acute pancreatitis (AP) has been shown in some studies to inhibit total protein synthesis in the pancreas while in other studies protein synthesis was not affected. Previous in vitro work has shown that high concentrations of cholecystokinin both inhibit protein synthesis and inhibit the activity of the guanine nucleotide exchange factor eIF2B by increasing the phosphorylation of the eukaryotic initiation factor 2
. We therefore evaluated in C57Bl6 mice the effects of caerulein-induced AP on pancreatic protein synthesis, eIF2B activity and other protein translation regulatory mechanisms. Repetitive hourly injections of caerulein were administered IP at 50 µg/kg. Pancreatic protein synthesis was reduced 10 min after the initial caerulein administration and further inhibited after 3 and 5 hourly injections. Caerulein inhibited the two major regulatory points of translation initiation: the activity of the guanine nucleotide exchange factor eIF2B (with an increase of eIF2 phosphorylation), and the formation of the eIF4F complex due, in part, to degradation of eIF4G. This inhibition was not accounted for by changes in the upstream stimulatory pathway, since caerulein activated Akt as well as the downstream effectors of mTOR, 4E-BP1 and ribosomal protein S6. Caerulein also decreased the phosphorylation of the eukaryotic elongation factor 2 (eEF2), implying that this translation factor was not inhibited in AP. Thus, the inhibition of pancreatic protein synthesis in this model of AP most likely results from the inhibition of translation initiation as a result of increased eIF2 phosphorylation, reduction of eIF2B activity, and the inhibition of eIF4F complex formation.
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