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J Biol Chem, Vol. 273, Issue 8, 4485-4491, February 20, 1998
From the Although glucose regulates the biosynthesis of a
variety of beta cell proteins at the level of translation, the
mechanism responsible for this effect is unknown. We demonstrate that
incubation of pancreatic islets with elevated glucose levels results in
rapid and concentration-dependent phosphorylation of
PHAS-I, an inhibitor of mRNA cap-binding protein, eukaryotic
initiation factor (eIF)-4E. Our initial approach was to determine if
this effect is mediated by the metabolism of glucose and activation of
islet cell protein kinases, or whether insulin secreted from the beta
cell stimulates phosphorylation of PHAS-I via an insulin-receptor
mechanism as described for insulin-sensitive cells. In support of the
latter mechanism, inhibitors of islet cell protein kinases A and C
exert no effect on glucose-stimulated phosphorylation of PHAS-I,
whereas the phosphatidylinositol 3-kinase inhibitor, wortmannin, the
immunosuppressant, rapamycin, and theophylline, a phosphodiesterase
inhibitor, promote marked dephosphorylation of PHAS-I. In addition,
exogenous insulin and endogenous insulin secreted by the beta cell
line,
Insulin Mediates Glucose-stimulated Phosphorylation of PHAS-I by
Pancreatic Beta Cells
AN INSULIN-RECEPTOR MECHANISM FOR AUTOREGULATION OF PROTEIN
SYNTHESIS BY TRANSLATION
,
,
,
,
,
,
Department of Pathology, Washington
University School of Medicine, St. Louis Missouri 63110 and
§ Department of Pharmacology, University of Virginia School
of Medicine, Charlottesville, Virginia 22908
TC6-F7, increase phosphorylation of PHAS-I, suggesting that
beta cells of the islet, in part, mediate this effect. Studies with
beta cell lines and islets indicate that amino acids are required for glucose or exogenous insulin to stimulate the phosphorylation of
PHAS-I, and amino acids alone dose-dependently stimulate
the phosphorylation of PHAS-I, which is further enhanced by insulin. Furthermore, rapamycin inhibits by ~62% the increase in total protein synthesis stimulated by high glucose concentrations. These results indicate that glucose stimulates PHAS-I phosphorylation via
insulin interacting with its own receptor on the beta cell which may
serve as an important mechanism for autoregulation of protein synthesis
by translation.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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