Sphingosine 1-phosphate regulates myogenic differentiation:: a major role for S1P2 receptor
Sphingosine 1-phosphate regulates myogenic differentiation:: a major role for S1P2 receptor
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DOI：
10.1096/fj.04-1780fje
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发表时间：
2004-12-01
期刊：
影响因子：
4.8
通讯作者：
Bruni, P
中科院分区：
文献类型：
--
作者：
Donati, C;Meacci, E;Bruni, P
在这项研究中，1-磷酸鞘氨醇（S1 P）在C2 C12成肌细胞中的一种新的生物活性被鉴定。在这些细胞中，生物活性脂质通过减少血清诱导的细胞增殖，并通过增强生肌分化标志物（如肌细胞生成素、肌球蛋白重链和小窝蛋白-3）的表达，发挥抗有丝分裂活性，从而深刻地调节肌生成。S1 P（2）的反义寡脱氧核糖核苷酸（ODN）可消除血清诱导的标记胸苷掺入的S1 P依赖性减少，但对同样在C2 C12细胞中表达的S1 P（1）或S1 P（3）受体无效，表明S1 P（2）参与了生物学反应。使用反义ODN和短干扰RNA处理，我们强调了S1 P（2）在S1 P依赖性诱导肌肉特异性基因产物中所起的关键作用。值得注意的是，与对照细胞相比，S1 P（2）过表达增加了肌源性标志物的含量，并加速了分化肌肉表型的发生。用百日咳毒素处理细胞不影响对S1 P的生物学应答，排除了鞘脂促进的信号传导中Gi介导的事件的参与。在S1 P激活的各种信号通路中，ERK 1/ERK 2和p38 MAPK的激活，均被鉴定为S1 P的下游效应物（2），分别是抑制细胞增殖和刺激肌源性分化所必需的。
In this study a novel biological activity of sphingosine 1-phosphate (S1P) in C2C12 myoblasts was identified. In these cells the bioactive lipid profoundly regulated myogenesis exerting an antimitogenic activity, by reducing serum-induced cell proliferation, and acting as powerful prodifferentiating agent by enhancing the expression of myogenic differentiation markers such as myogenin, myosin heavy chain, and caveolin-3. The S1P-dependent diminution of serum-induced labeled thymidine incorporation was abrogated by antisense oligodeoxyribonucleotides (ODN) to S1P(2), but not to S1P(1) or S1P(3) receptor, also expressed in C2C12 cells, implicating S1P(2) in the biological response. Using antisense ODN and short interfering RNA treatment, we highlighted the key role played by S1P(2) in the S1P-dependent induction of muscle-specific gene products. Notably, S1P(2) overexpression increased the content of myogenic markers and hastened the onset of differentiated muscle phenotype in comparison with control cells. Cell treatment with pertussis toxin did not affect the biological responses to S1P, ruling out the involvement of Gi-mediated events in the signaling promoted by the sphingolipid. Among the various signaling pathways activated by S1P, the activation of ERK1/ERK2 and p38 MAPK, both identified as downstream effectors of S1P(2), was required for the inhibition of cell proliferation and the stimulation of myogenic differentiation, respectively.