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Department of Anatomy and Physiology, Medical Sciences Institute, University of Dundee, Dundee DD1 5EH, United Kingdom
Insulin acutely activates protein
synthesis in ventricular cardiomyocytes from adult rats. In this study,
we have established the methodology for studying the regulation of the
signaling pathways and translation factors that may be involved in this
response and have examined the effects of acute insulin treatment on
them. Insulin rapidly activated the 70-kDa ribosomal S6 kinase (p70 S6k), and this effect was inhibited both by rapamycin and by inhibitors of phosphatidylinositol 3-kinase. The activation of p70 S6k is mediated
by a signaling pathway involving the mammalian target of rapamycin
(mTOR), which also modulates other translation factors. These include
the eukaryotic initiation factor (eIF) 4E binding proteins (4E-BPs) and
eukaryotic elongation factor 2 (eEF2). Insulin caused phosphorylation
of 4E-BP1 and induced its dissociation from eIF4E, and these effects
were also blocked by rapamycin. Concomitant with this, insulin
increased the binding of eIF4E to eIF4G. Insulin also activated protein
kinase B (PKB), which may lie upstream of p70 S6k and 4E-BP1, with the
activation of the different isoforms being in the order
>
>
. Insulin also caused inhibition of glycogen synthase
kinase 3, which lies downstream of PKB, and of eEF2 kinase. The
phosphorylation of eEF2 itself was also decreased by insulin, and this
effect and the inactivation of eEF2 kinase were attenuated by
rapamycin. The activation of overall protein synthesis by insulin in
cardiomyocytes was substantially inhibited by rapamycin (but not by
inhibitors of other specific signaling pathways, e.g.,
mitogen-activated protein kinase), showing that signaling events linked
to mTOR play a major role in the control of translation by insulin in
this cell type.
heart; initiation factor; protein kinase, protein synthesis
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