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Am J Physiol Gastrointest Liver Physiol. 2014 Oct 1;307(7):G700-10. doi: 10.1152/ajpgi.00163.2014. Epub 2014 Aug 7.

ERK activation is required for CCK-mediated pancreatic adaptive growth in mice.

Author information

1
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
2
Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan;
3
Department of Cellular and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan; and.
4
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.

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.

KEYWORDS:

GSK-1120212; PD-0325901; cholecystokinin; extracellular signal-related kinase; mitogen-activated protein kinase; mitogen/extracellular signal-regulated kinase inhibitors; pancreatic growth

PMID:
25104499
PMCID:
PMC4187068
DOI:
10.1152/ajpgi.00163.2014
[Indexed for MEDLINE]
Free PMC Article

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