title: ERK activation is required for CCK-mediated pancreatic adaptive growth in mice.
abstract: High levels of cholecystokinin (CCK) can stimulate pancreatic adaptive growth in which mature acinar cells divide, leading to enhanced pancreatic mass with parallel increases in protein, DNA, RNA, and digestive enzyme content. Prolonged release of CCK can be induced by feeding trypsin inhibitor (TI) to disrupt normal feedback control. This leads to exocrine growth in a CCK-dependent manner. The extracellular signal-related kinase (ERK) pathway regulates many proliferative processes in various tissues and disease models. The aim of this study was to evaluate the role of ERK signaling in pancreatic adaptive growth using the MEK inhibitors PD-0325901 and trametinib (GSK-1120212). It was determined that PD-0325901 given two times daily by gavage or mixed into powdered chow was an effective and specific inhibitor of ERK signaling in vivo. TI-containing chow led to a robust increase in pancreatic mass, protein, DNA, and RNA content. This pancreatic adaptive growth was blocked in mice fed chow containing the MEK inhibitors. PD-0325901 blocked TI-induced ERK-regulated early response genes, cell-cycle proteins, and mitogenesis by acinar cells. It was determined that ERK signaling is necessary for the initiation of pancreatic adaptive growth but not necessary to maintain it. PD-0325901 blocked adaptive growth when given before cell-cycle initiation but not after mitogenesis had been established. Furthermore, GSK-1120212, a chemically distinct inhibitor of the ERK pathway that is now approved for clinical use, inhibited growth similar to PD-0325901. These data demonstrate that the ERK pathway is required for CCK-stimulated pancreatic adaptive growth.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Holtz
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Lodewyk
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors.forename: Judith S
authors.initials: JS
authors.lastname: Sebolt-Leopold
authors.affiliation: Department of Cellular and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ernst
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan jawillms@umich.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Williams
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002766:Cholecystokinin / Q000378:metabolism*; D004261:DNA Replication; D051765:Early Growth Response Transcription Factors / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D013997:Time Factors; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D051765:Early Growth Response Transcription Factors; D047428:Protein Kinase Inhibitors; D014361:Trypsin Inhibitors; D012313:RNA; D002766:Cholecystokinin; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: GSK-1120212; PD-0325901; cholecystokinin; extracellular signal-related kinase; mitogen-activated protein kinase; mitogen/extracellular signal-regulated kinase inhibitors; pancreatic growth
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 Jun 15;302(12):G1381-96
references.pmid: 22461029
references.citation: Gastroenterology. 2010 Aug;139(2):609-19, 619.e1-6
references.pmid: 20438729
references.citation: Mol Cell Biol. 1998 Sep;18(9):5609-19
references.pmid: 9710644
references.citation: Am J Physiol. 1986 Jul;251(1 Pt 1):G70-4
references.pmid: 3524262
references.citation: J Biol Chem. 2006 Jun 9;281(23):15645-52
references.pmid: 16595679
references.citation: Life Sci. 1990;46(4):281-6
references.pmid: 2304371
references.citation: Cancer Res. 2005 Nov 1;65(21):9934-42
references.pmid: 16267018
references.citation: Int J Gastrointest Cancer. 2002;31(1-3):107-15
references.pmid: 12622421
references.citation: Genes Dev. 2006 Nov 15;20(22):3161-73
references.pmid: 17114586
references.citation: Am J Physiol Cell Physiol. 2004 Aug;287(2):C281-91
references.pmid: 15028555
references.citation: J Biol Chem. 2008 Sep 26;283(39):26577-90
references.pmid: 18667424
references.citation: Bioorg Med Chem Lett. 1998 Oct 20;8(20):2839-44
references.pmid: 9873633
references.citation: Gastroenterology. 1997 Apr;112(4):1354-61
references.pmid: 9098021
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Feb;292(2):G667-77
references.pmid: 17095753
references.citation: Oncogene. 2007 May 14;26(22):3227-39
references.pmid: 17496918
references.citation: Pancreas. 2006 Apr;32(3):314-20
references.pmid: 16628088
references.citation: Immunity. 1995 May;2(5):461-72
references.pmid: 7749981
references.citation: Gut. 1987;28 Suppl:63-9
references.pmid: 2446964
references.citation: Am J Physiol. 1999 May;276(5):G1302-9
references.pmid: 10330022
references.citation: J Cell Sci. 2008 Dec 1;121(Pt 23):3853-7
references.pmid: 19020303
references.citation: J Biol Chem. 1996 Mar 8;271(10):5686-90
references.pmid: 8621433
references.citation: Mol Immunol. 2013 Nov;56(1-2):48-56
references.pmid: 23665382
references.citation: J Biol Chem. 2010 Jan 29;285(5):3510-23
references.pmid: 19933579
references.citation: J Physiol. 2006 Jun 15;573(Pt 3):775-86
references.pmid: 16613881
references.citation: Mol Biol Cell. 2004 Apr;15(4):1833-42
references.pmid: 14767060
references.citation: Pancreas. 1986;1(5):421-9
references.pmid: 2436216
references.citation: Ann N Y Acad Sci. 2010 Feb;1188:96-102
references.pmid: 20201891
references.citation: Nature. 1993 Sep 23;365(6444):352-5
references.pmid: 8397339
references.citation: Am J Physiol. 1992 Apr;262(4 Pt 1):G740-6
references.pmid: 1373568
references.citation: Mol Biol Cell. 2008 Jan;19(1):198-206
references.pmid: 17978097
references.citation: Am J Physiol. 1994 Sep;267(3 Pt 1):G401-8
references.pmid: 7943237
references.citation: Br J Pharmacol. 1989 Mar;96(3):661-9
references.pmid: 2470456
references.citation: Am J Physiol. 1995 Sep;269(3 Pt 1):G319-27
references.pmid: 7573441
references.citation: Oncogene. 2001 Apr 30;20(19):2390-400
references.pmid: 11402335
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Sep;287(3):G667-75
references.pmid: 15117679
references.citation: Pancreas. 1987;2(2):164-9
references.pmid: 3628222
references.citation: Am J Physiol Gastrointest Liver Physiol. 2010 Nov;299(5):G1154-63
references.pmid: 20798356
references.citation: Pharmacol Toxicol. 2002 Dec;91(6):297-303
references.pmid: 12688372
references.citation: Cell Prolif. 2000 Jun;33(3):167-87
references.pmid: 10959625
references.citation: Am J Physiol. 1999 Nov;277(5):G953-9
references.pmid: 10564100
references.citation: Am J Physiol Lung Cell Mol Physiol. 2002 Jun;282(6):L1296-304
references.pmid: 12003786
references.citation: Jpn J Pharmacol. 2002 Jul;89(3):290-5
references.pmid: 12184735
references.citation: Mol Cancer Ther. 2012 May;11(5):1193-202
references.pmid: 22411900
references.citation: Hepatology. 2003 Apr;37(4):824-32
references.pmid: 12668975
references.citation: J Cell Biol. 1962 Feb;12:297-312
references.pmid: 13906693
references.citation: Clin Cancer Res. 2011 Mar 1;17(5):989-1000
references.pmid: 21245089
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G784-90
references.pmid: 14684381
references.citation: Physiol Genomics. 2012 Jan 18;44(1):14-24
references.pmid: 22010007