PD0325901 Inhibition of the Erk Pathway and Effects on Pancreatic Growth
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Authors
Lodewyk, Kevin B.
Issue Date
2012
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
The pancreas secretes a range of enzymes that together have the capacity to digest
virtually all ingested macromolecules into forms that are capable of being absorbed.
Regulated by the composition of food in the stomach, the secretion of digestive enzymes
from the exocrine pancreas can be increased simultaneously at the transcriptional and
translational level. However, once this finite capacity is exceeded, the pancreas must
grow or regenerate in order to compensate. The extracellular signal-regulated kinase
(Erk) regulates the expression of several early response genes encoding factors that
regulate proliferation in many cell types. The aim of this study was to elucidate whether
Erk pathway activation is necessary for pancreatic growth in a mouse model of
upregulated endogenous cholecystokinin (CCK) release, a model known to stimulate
pancreatic growth. In mice fed chow containing the synthetic trypsin inhibitor camostat,
phosphorylation levels of Erk increased significantly in comparison to controls. The
camostat-induced increase in phosphorylated Erk was blocked to levels below that of the
control upon administration of the Erk inhibitor PD0325901 2 h prior to camostat
feeding. In contrast, increased phosphorylation of c-Jun and S6, biomarkers of pathways
believed to be required for growth, were unaffected by PD0325901. At the mRNA level,
a camostat-induced increase in expression of Erk-mediated early response genes Egr-1, c-
Fos, and RCAN1 were significantly blocked upon administration of PD0325901, while
the upregulation of c-Jun was not affected. Chronic growth studies monitoring changes in
pancreatic mass were employed; however, administration of PD0325901 resulted in the
unexplained death of 3 out of 12 test subjects. Those mice which did survive illustrated
varying decreases in pancreatic growth. We conclude that PD0325901 showed successful
inhibition of the Erk pathway, however the necessity of the Erk pathway in pancreatic
growth remains inconclusive.
Description
v, 40 p.
Citation
Publisher
Kalamazoo College
License
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