title: CCK-induced pancreatic growth is not limited by mitogenic capacity in mice.
abstract: In mice fed trypsin inhibitor (camostat) to elevate endogenous CCK, pancreatic growth plateaus by 7 days. It is unknown whether this represents the maximum growth capacity of the pancreas. To test the ability of CCK to drive further growth, mice were fed chow containing camostat (0.1%) for 1 wk, then fed standard chow for 1 wk, and finally returned to the camostat diet for a week. Pancreatic mass increased to 245% of initial value (iv) following 1 wk of camostat feeding, decreased to 147% iv following a 1 wk return to normal chow, and increased to 257% iv with subsequent camostat feeding. Camostat feeding was associated with significant increases in circulating CCK and changes in pancreatic mass were paralleled by changes in protein and DNA content. Moreover, regression of the pancreas following camostat feeding was associated with changes in the expression of the autophagosome marker LC3. Pancreatic protein synthetic rates were 130% of control after 2 days on camostat but were equivalent to control after 7 days. Changes in the phosphorylation of 4E-BP1 and S6, downstream effectors of mammalian target of rapamycin (mTOR), paralleled changes in protein synthetic rates. Cellular content of Akt, an upstream activating kinase of mTOR, decreased after 7 days of camostat feeding whereas expression of the E3 ubiquitin-ligases and the cell cycle inhibitor p21 increased after 2 days. These results indicate that CCK-stimulated growth of the pancreas is not limited by acinar cell mitogenic capacity but is due, at least in part, to inhibition of promitogenic Akt signaling.
authors: Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA. scrozier@umich.edu
authors: Stephen J
authors: SJ
authors: Crozier
authors: Maria Dolors
authors: MD
authors: Sans
authors: Charles H
authors: CH
authors: Lang
authors: Louis G
authors: LG
authors: D'Alecy
authors: Stephen A
authors: SA
authors: Ernst
authors: John A
authors: JA
authors: Williams
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000284:Administration, Oral; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002766:Cholecystokinin / Q000097:blood*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004247:DNA / Q000032:analysis; D004952:Esters; D039642:Eukaryotic Initiation Factors; D016670:Gabexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006146:Guanidines; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499527:Eif4ebp1 protein, mouse; D004952:Esters; D039642:Eukaryotic Initiation Factors; D006146:Guanidines; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D011506:Proteins; C034532:camostat; D016670:Gabexate; D004247:DNA; D002766:Cholecystokinin; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases