Among translational effectors, p70S6k is uniquely sensitive to inhibition by glucocorticoids.
Fundamental cellular processes such as cell differentiation and growth, apoptosis and cellular metabolism are regulated differentially by glucocorticoid hormones in a cell-context-related fashion. However, these basic processes are not governed by isolated signals but are influenced by the integration of both synergistic and antagonistic extracellular and intracellular stimuli. Because glucocorticoids and insulin-like growth factor I (IGF-I) reciprocally modulate growth-regulated processes such as translation initiation, especially in skeletal muscle, a study was undertaken to address the nature of this counter-regulation. Quiescent L6 skeletal myoblasts pretreated for 4 h with the synthetic glucocorticoid dexamethasone exhibited a marked attenuation of IGF-I-induced activation of the ribosomal protein S6 kinase (p70(S6k)). The adverse effects of glucocorticoids on the activity of the endogenous enzyme were due to differential dephosphorylation at discrete residues, suggesting that, physiologically, some but not all phosphorylation sites are subject to mitogenic regulation. Furthermore, the translational repressor eIF4E-binding protein 1 (4E-BP1), which in many circumstances is co-ordinately regulated with p70(S6k), was dephosphorylated in response to glucocorticoids; however, hyperphosphorylation of the protein after stimulation with IGF-I was refractory to inhibition by glucocorticoids, as was its dissociation from its binding partner, eIF4E. Although both basal and IGF-I-stimulated rates of protein synthesis were modestly affected by glucocorticoids, the synthesis of EF1A, whose mRNA precursor is a prototype for the terminal oligopyrimidine ('TOP') transcript family and whose expression is controlled by the activity of p70(S6k), was markedly affected. Therefore in this cell system it seems that, despite the mutual control of p70(S6k) and 4E-BP1 that is often observed, p70(S6k) is more sensitive to down-regulation by glucocorticoids under growth-promoting conditions than is 4E-BP1.
Shah
O J
OJ
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033, USA.
Kimball
S R
SR
Jefferson
L S
LS
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000595:Amino Acid Sequence; D002352:Carrier Proteins; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E; D005938:Glucocorticoids / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis; D010448:Peptide Initiation Factors / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D002352:Carrier Proteins; D039561:Eukaryotic Initiation Factor-4E; D005938:Glucocorticoids; D020648:Peptide Elongation Factor 1; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases