Early stimulation and late inhibition of extracellular signal-regulated kinase 1/2 phosphorylation by IGF-I: A potential mechanism mediating the switch in IGF-I action on skeletal muscle cell differentiation
Early stimulation and late inhibition of extracellular signal-regulated kinase 1/2 phosphorylation by IGF-I: A potential mechanism mediating the switch in IGF-I action on skeletal muscle cell differentiation
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DOI：
10.1210/en.143.2.511
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发表时间：
2002-02-01
期刊：
影响因子：
4.8
通讯作者：
Rosenthal, SM
中科院分区：
文献类型：
--
作者：
Adi, S;Bin-Abbas, B;Rosenthal, SM
IGF-I 对骨骼肌细胞分化具有独特的双相作用。最初，IGF-I抑制骨骼成肌细胞的分化并促进其增殖。随后，IGF-I 转而刺激这些细胞的分化。导致 IGF 作用转变的机制仍不清楚。我们研究了细胞外信号调节激酶 (Erk)1/2 信号传导在介导 IGF-I 对肌生成素基因表达的早期抑制和晚期刺激作用中的作用，肌生成素是一种对于肌原性分化至关重要的骨骼肌特异性转录因子。我们发现，IGF-I 对肌细胞生成素 mRNA 的早期抑制和晚期刺激作用同时存在，对 Erk1/2 的磷酸化具有双相但相反的作用：与未处理的细胞相比，IGF-I 最初增加 Erk1/2 的磷酸化，随后减少。与 Erk1/2 激活抑制剂共同治疗可防止 Erk1/2 磷酸化的早期 IGF-I 刺激，并部分逆转 IGF-I 对肌生成素 mRNA 的抑制。相反，防止晚期 IGF-I 诱导的 Erk1/2 磷酸化减少会阻断 IGF-I 对肌细胞生成素 mRNA 的刺激。我们的数据表明，IGF-I 对骨骼肌细胞分化的时间依赖性、相反作用至少部分是由对 Erk1/2 MAPK 信号通路激活的双相但相反的作用介导的。
IGF-I has a unique biphasic effect on skeletal muscle cell differentiation. Initially, IGF-I inhibits differentiation and promotes proliferation of skeletal myoblasts. Subsequently, IGF-I switches to stimulating differentiation of these cells. The mechanisms responsible for this switch in IGF action remain unknown. We have examined the role of extracellular signal-regulated kinase (Erk)1/2 signaling in mediating the early inhibitory and late stimulatory effects of IGF-I on the gene expression of myogenin, a skeletal muscle-specific transcription factor essential for myogenic differentiation. We find that, concurrent with its early inhibitory and late stimulatory effects on myogenin mRNA, IGF-I has a biphasic but opposite effect on phosphorylation of Erk1/2: initially, IGF-I increases and subsequently decreases the phosphorylation of Erk1/2 in comparison to untreated cells. Cotreatment with an inhibitor of Erk1/2 activation prevents the early IGF-I-stimulation of Erk1/2 phosphorylation and partially reverses IGF-I-inhibition of myogenin mRNA. Conversely, preventing the late IGF-I-induced decrease in Erk1/2 phosphorylation blocks IGF-I-stimulation of myogenin mRNA. Our data indicate that the time-dependent, opposing effects of IGF-I on skeletal muscle cell differentiation are mediated, at least in part, by biphasic but opposite effects on activation of the Erk1/2 MAPK signaling pathway.