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J. Biol. Chem., Vol. 279, Issue 52, 53937-53946, December 24, 2004

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Glucose-stimulated Protein Synthesis in Pancreatic -Cells Parallels an Increase in the Availability of the Translational Ternary Complex (eIF2-GTP·Met-tRNAi) and the Dephosphorylation of eIF2^*

Edith Gomez, Michael L. Powell¶, Isabel C. Greenman||, and Terence P. Herbert**

From the Department of Cell Physiology and Pharmacology, University of Leicester, Maurice Shock Medical Sciences Building, University Road, Leicester LE1 9HN, United Kingdom

In pancreatic -cells, glucose causes a rapid increase in the rate of protein synthesis. However, the mechanism by which this occurs is poorly understood. In this report, we demonstrate, in the pancreatic -cell line MIN6, that glucose stimulates the recruitment of ribosomes onto the mRNA, indicative of an increase in the rate of the initiation step of protein synthesis. This increase in the rate of initiation is not mediated through an increase in the availability of the initiation complex eIF4F, because glucose is unable to stimulate eIF4F assembly or, in the absence of amino acids, modulate the phosphorylation status of 4E-BP1. Moreover, in MIN6 cells and isolated islets of Langerhans, rapamycin, an inhibitor of the mammalian target of rapamycin, only partially inhibited glucose-stimulated protein synthesis. However, we show that glucose stimulates the dephosphorylation of eIF2 in MIN6 cells and the assembly of the translational ternary complex, eIF2-GTP·Met-tRNAi, in both MIN6 cells and islets of Langerhans. The changes in the phosphorylation of eIF2 are not mediated by the PKR-like endoplasmic reticulum eIF2 kinase (PERK), because PERK is not phosphorylated at low glucose concentrations and overexpression of a dominant negative form of PERK has no significant effect on either glucose-stimulated protein synthesis or the phosphorylation of eIF2. Taken together, these results indicate that glucose-stimulated protein synthesis in pancreatic -cells is regulated by a mechanism largely independent of the activity of mammalian target of rapamycin, but which is likely to be dependent on the availability of the translational ternary complex, regulated by the phosphorylation status of eIF2.

Received for publication, July 30, 2004 , and in revised form, September 17, 2004.

^* This work was supported in part by Diabetes UK (Grant BDA; RD01/0002162) and a Wellcome Trust project grant (to T. P. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Supported by Diabetes UK and the Wellcome Trust.

^¶ Supported by a Medical Research Council studentship.

^|| Supported by a Biotechnology and Biological Sciences and Research Council case studentship.

^** To whom correspondence should be addressed. Tel: 0116-252-5532; Fax: 0116-252-5045; E-mail: tph4{at}le.ac.uk.

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