TY - JOUR
T1 - Among translational effecters, p70(S6k) is uniquely sensitive to inhibition by glucocorticoids
AU - Shah, O. Jameel
AU - Kimball, Scot R.
AU - Jefferson, Leonard S.
N1 - Copyright:
Copyright 2004 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 2000/4/15
Y1 - 2000/4/15
N2 - 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 I (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.
AB - 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 I (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.
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U2 - 10.1042/0264-6021:3470389
DO - 10.1042/0264-6021:3470389
M3 - Article
C2 - 10749668
AN - SCOPUS:0034654659
VL - 347
SP - 389
EP - 397
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 2
ER -