Among translational effectors, p70S6k is uniquely sensitive to inhibition by glucocorticoids.
Among translational effectors, p70S6k is uniquely sensitive to inhibition by glucocorticoids.
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DOI：
10.1042/0264-6021:3470389
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发表时间：
2000-04
期刊：
影响因子：
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通讯作者：
O. Shah;S. Kimball;L. Jefferson
中科院分区：
文献类型：
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作者：
O. Shah;S. Kimball;L. Jefferson
糖皮质激素以与细胞环境相关的方式对细胞分化和生长、细胞凋亡和细胞代谢等基本细胞过程进行差异调节。然而，这些基本过程并不受孤立信号的支配，而是受到协同和拮抗细胞外和细胞内刺激的整合的影响。由于糖皮质激素和胰岛素样生长因子I（IGF-I）可调节生长调节过程，如翻译起始，特别是在骨骼肌中，因此进行了一项研究，以解决这种反调节的性质。静止的L 6骨骼肌成肌细胞预处理4小时的合成糖皮质激素地塞米松表现出显着衰减IGF-I诱导的核糖体蛋白S6激酶（p70（S6 k））的激活。糖皮质激素对内源性酶活性的不利影响是由于在离散残基的差异去磷酸化，这表明，生理上，一些但不是所有的磷酸化位点受到促有丝分裂调节。此外，翻译抑制因子eIF 4 E结合蛋白1（4 E-BP 1），在许多情况下与p70（S6 k）协同调节，在糖皮质激素的反应中去磷酸化;然而，在用IGF-I刺激后，蛋白质的过度磷酸化难以被糖皮质激素抑制，因为它与其结合伴侣eIF 4 E解离。尽管糖皮质激素对蛋白质合成的基础速率和IGF-I刺激速率都有适度影响，但EF 1A的合成受到显著影响，EF 1A的mRNA前体是末端寡嘧啶（“TOP”）转录物家族的原型，其表达受p70（S6 k）活性控制。因此，在该细胞系统中，似乎尽管经常观察到p70（S6 k）和4 E-BP 1的相互控制，但在生长促进条件下，p70（S6 k）对糖皮质激素的下调比4 E-BP 1更敏感。
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.