Glucocorticoids abate p70(S6k) and eIF4E function in L6 skeletal myoblasts

The catabolic properties of glucocorticoid hormones are largely attributabl e to dual regulation of protein degradation and synthesis. With regard to t he latter, glucocorticoids modulate the translational machinery, namely tha t component functional in translation initiation. This investigation reveal ed that in L6 myoblasts, dexamethasone, a synthetic glucocorticoid, deactiv ated the ribosomal protein S6 kinase (p70(S6k)) within 4 h, as evidenced by diminished phosphorylation of its physiological substrate, the 40S ribosom al protein S6. This deactivation correlated with dephosphorylation of p70(S 6k) at Thr(389), whereas phosphorylation of Ser(411) was unaffected. Furthe rmore, glucocorticoid administration induced dephosphorylation of the cap-d ependent translational repressor, eukaryotic initiation factor 4E (eIF4E) b inding protein 1 (4E-BP1), thereby facilitating conjunction of the inhibito r and eIF4E. The mechanism of action is reminiscent of classical transcript ional regulation by steroid hormone receptors in that these effects were pr eceded 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 dephospho rylation of p70(S6k) and 4E-BP1, implicating a PP1- and/or PP2A-like protei n phosphatase( s) in the observed phenomena. Hence, glucocorticoids attenua te distal constituents of the phosphatidylinositol-3 kinase signaling pathw ay and thereby encumber the protein synthetic apparatus.