Glucocorticoids abate p70(S6k) and eIF4E function in L6 skeletal myoblasts.
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 (p70(S6k)) within 4 h, as evidenced by diminished phosphorylation of its physiological substrate, the 40S ribosomal protein S6. This deactivation correlated with dephosphorylation of p70(S6k) at Thr(389), whereas phosphorylation of Ser(411) 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 p70(S6k) 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.
Shah
O J
OJ
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Kimball
S R
SR
Jefferson
L S
LS
D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E; D005938:Glucocorticoids / Q000494:pharmacology*; D008387:Marine Toxins; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D010766:Phosphorylation; D038601:Ribosomal Protein S6; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D005938:Glucocorticoids; D008387:Marine Toxins; D010080:Oxazoles; D010448:Peptide Initiation Factors; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D019319:Okadaic Acid; C059041:calyculin A; D003907:Dexamethasone; D019893:Ribosomal Protein S6 Kinases