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Am J Physiol Endocrinol Metab 279: E74-E82, 2000;
0193-1849/00 $5.00
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Vol. 279, Issue 1, E74-E82, July 2000

Glucocorticoids abate p70S6k and eIF4E function in L6 skeletal myoblasts

O. Jameel Shah, Scot R. Kimball, and Leonard S. Jefferson

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

The catabolic properties of glucocorticoid hormones are largely attributable to dual regulation of protein degradation and synthesis. With regard to the latter, glucocorticoids modulate the translational machinery, namely that component functional in translation initiation. This investigation revealed that in L6 myoblasts, dexamethasone, a synthetic glucocorticoid, deactivated the ribosomal protein S6 kinase (p70S6k) within 4 h, as evidenced by diminished phosphorylation of its physiological substrate, the 40S ribosomal protein S6. This deactivation correlated with dephosphorylation of p70S6k at Thr389, whereas phosphorylation of Ser411 was unaffected. Furthermore, glucocorticoid administration induced dephosphorylation of the cap-dependent translational repressor, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), thereby facilitating conjunction of the inhibitor and eIF4E. The mechanism of action is reminiscent of classical transcriptional regulation by steroid hormone receptors in that these effects were preceded by a temporal lag and were sensitive to inhibitors of glucocorticoid receptor function as well as transcriptional and translational inhibition. Okadaic acid and calyculin A corrected the dexamethasone-induced dephosphorylation of p70S6k and 4E-BP1, implicating a PP1- and/or PP2A-like protein phosphatase(s) in the observed phenomena. Hence, glucocorticoids attenuate distal constituents of the phosphatidylinositol-3 kinase signaling pathway and thereby encumber the protein synthetic apparatus.

eIF4E binding protein; eIF4G; dexamethasone; translation initiation


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