Calcineurin-dependent and calcineurin-independent signal transduction pathways activated as part of pancreatic growth.
OBJECTIVE
We have recently reported that pancreatic growth driven by cholecystokinin released endogenously by feeding the synthetic trypsin inhibitor camostat requires the Ca-activated phosphatase calcineurin. In the present study, we evaluated a number of signal transduction pathways for their activation as part of the growth response and whether their activation was dependent on calcineurin.


METHODS
Male ICR mice were fed with either chow or chow plus 1 mg/g of camostat. FK506 was administered at 3 mg/kg. After various times from 12 hours to 10 days, pancreatic samples were prepared and assayed for activity of various signal transduction pathway components.


RESULTS
Camostat feeding increased the activation of extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and phosphorylation of the translation factor eukaryotic initiation factor 4E and activated the mammalian target of rapamycin pathway that leads to phosphorylation of the ribosomal protein S6 and of the eukaryotic initiation factor 4E binding protein but with different time courses. Treatment of mice with the calcineurin inhibitor FK506 totally blocked c-Jun NH2-terminal kinase activation, partially blocked the mammalian target of rapamycin pathway, and had no effect on extracellular signal-regulated kinase activation or the phosphorylation of eukaryotic initiation factor 4E.


CONCLUSIONS
The pancreatic growth response is accompanied by activation of a number of signaling pathways regulating transcription and translation, some of which are dependent on and some independent of calcineurin.
Tashiro
Mitsuo
M
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Dabrowski
Andrzej
A
Guo
Lili
L
Sans
Maria Dolors
MD
Williams
John A
JA
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D004952:Esters; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D016670:Gabexate / Q000031:analogs & derivatives / Q000494:pharmacology; D006146:Guanidines; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010179:Pancreas / Q000254:growth & development*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology
D004952:Esters; D039561:Eukaryotic Initiation Factor-4E; D006146:Guanidines; C034532:camostat; D016670:Gabexate; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin; D016559:Tacrolimus