Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase
Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase
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DOI：
10.1046/j.1471-4159.2000.0751870.x
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发表时间：
2000-11-01
影响因子：
4.7
通讯作者：
Nielsen, FC
中科院分区：
文献类型：
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作者：
Hansen, TVO;Rehfeld, JF;Nielsen, FC
P38丝裂原活化蛋白激酶(MAPK)通路介导了细胞对炎性细胞因子和环境应激的反应，但最近的研究表明，p38 MAPK可能参与了更广泛的一系列细胞功能。在这里，我们发现cAMP(CAMP)途径的激活诱导了p38MAPK的快速、剂量依赖性的磷酸化和激活，Forsklin和生长因子的联合刺激导致了p38MAPK的相加刺激。P38 MAPK抑制剂SB203580可抑制Forsklin刺激的大鼠嗜铬细胞瘤PC12细胞突起生长。联合应用Forskolin和神经生长因子后，轴突生长明显增加，SB203580对此作用也有抑制作用。最后，表达突变激活环的p38AGF可抑制cAMP介导的神经元分化。结果表明，p38MAPK是cAMP信号通路的下游靶点，p38MAPK在cAMP和生长因子诱导的神经元分化中起关键作用。
The p38 mitogen-activated protein kinase (MAPK) pathway mediates cellular responses to inflammatory cytokines and environmental stress, but recent studies have indicated that p38 MAPK may be involved in a more widespread set of cellular functions. Here we show that activation of the cyclic AMP (cAMP) pathway induces a rapid, dose-dependent phosphorylation and activation of p38 MAPK and that combined stimulation with forskolin and growth factors results in additive stimulation of p38 MAPK. Forskolin-stimulated neurite outgrowth in rat pheochromocytoma PC12 cells was inhibited by the p38 MAPK inhibitor SB203580. With the combination of forskolin and nerve growth factor, neurite outgrowth was additively increased, and this effect was also inhibited by SB203580. Finally, transfection of p38AGF, which exhibits a mutated activation loop, inhibited cAMP-mediated neuronal differentiation. The results indicate that p38 MAPK is a downstream target of the cAMP signaling pathway and that p38 MAPK plays a key role in neuronal differentiation induced by cAMP and growth factors by integration of signals from both pathways.