Among translational effecters, p70(S6k) is uniquely sensitive to inhibition by glucocorticoids

Fundamental cellular processes such as cell differentiation and growth, apo ptosis and cellular metabolism are regulated differentially by glucocortico id hormones in a cell-context-related fashion. However, these basic process es are not governed by isolated signals but are influenced by the integrati on of both synergistic and antagonistic extracellular and intracellular sti muli. Because glucocorticoids and insulin-like growth factor I (IGF-I) reci procally modulate growth-regulated processes such as translation initiation , especially in skeletal muscle, a study was undertaken to address the natu re of this counter-regulation. Quiescent L6 skeletal myoblasts pretreated f or 4 h with the synthetic glucocorticoid dexamethasone exhibited a marked a ttenuation of IGF-I-induced activation of the ribosomal protein S6 kinase ( p70(S6k)). The adverse effects of glucocorticoids on the activity of the en dogenous enzyme were due to differential dephosphorylation at discrete resi dues, suggesting that, physiologically, some but not all phosphorylation si tes are subject to mitogenic regulation. Furthermore, the translational rep ressor eIF4E-binding protein 1 (4E-BP1), which in many circumstances is co- ordinately regulated with p70(S6k), was dephosphorylated in response to glu cocorticoids; however, hyperphosphorylation of the protein after stimulatio n with IGF-I was refractory to inhibition by glucocorticoids, as was its di ssociation from its binding partner, eIF4E. Although both basal and IGF-I-s timulated rates of protein synthesis were modestly affected by glucocortico ids, the synthesis of EF1A, whose mRNA precursor is a prototype for the ter minal oligopyrimidine ('TOP') transcript family and whose expression is con trolled by the activity of p70(S6k), was markedly affected. Therefore in th is 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.