Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A-dependent MEK-ERK1/2 signaling pathway
Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A-dependent MEK-ERK1/2 signaling pathway
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DOI：
10.1111/j.1365-2443.2011.01556.x
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发表时间：
2011-11-01
期刊：
影响因子：
2.1
通讯作者：
Hayashi, Haruhide
中科院分区：
文献类型：
--
作者：
Kudo, Tada-aki;Kanetaka, Hiroyasu;Hayashi, Haruhide
在这项研究中，我们研究了dorsomorphin，骨形态发生蛋白（BMP）信号的选择性抑制剂，对大鼠PC 12嗜铬细胞瘤细胞分化的影响。PC 12细胞可以通过神经生长因子、BMP 2和其他诱导剂诱导分化为具有细长神经突的神经元样细胞。将细胞与BMP 2和/或dorsomorphin孵育，并评价神经突生长的程度。出乎意料的是，BMP 2介导的轴突发生没有被dorsomorphin的共同治疗抑制。我们还发现，单独用dorsomorphin处理，而不是另一种BMP信号传导抑制剂LDN-193189，诱导PC 12细胞中的神经突生长。为了进一步了解dorsomorphin的作用机制，使用以下信号传导抑制剂研究了该药物对细胞内信号传导的影响：ERK激酶（MEK）抑制剂U 0126;原肌球蛋白相关激酶A抑制剂GW 441756;和蛋白激酶A（PKA）抑制剂H89。Dorsomorphin诱导快速和持续的ERK 1/2激活，然而，dorsomorphin介导的ERK 1/2激活和轴突发生强烈抑制U 0126或H89的存在下，但没有GW 441756。这些发现表明，dorsomorphin有可能诱导PC 1/2细胞中的轴突发生，这一反应需要激活PKA依赖的MEK-ERK 1/2信号。
In this study, we investigated the effect of dorsomorphin, a selective inhibitor of bone morphogenetic protein (BMP) signaling, on rat PC12 pheochromocytoma cell differentiation. PC12 cells can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor, BMP2, and other inducers. Cells were incubated with BMP2 and/or dorsomorphin, and the extent of neurite outgrowth was evaluated. Unexpectedly, BMP2-mediated neuritogenesis was not inhibited by co-treatment with dorsomorphin. We also found that treatment with dorsomorphin alone, but not another BMP signaling inhibitor, LDN-193189, induced neurite outgrowth in PC12 cells. To further understand the mechanism of action of dorsomorphin, the effects of this drug on intracellular signaling were investigated using the following signaling inhibitors: the ERK kinase (MEK) inhibitor U0126; the tropomyosin-related kinase A inhibitor GW441756; and the protein kinase A (PKA) inhibitor H89. Dorsomorphin induced rapid and sustained ERK1/2 activation; however, dorsomorphin-mediated ERK1/2 activation and neuritogenesis were robustly inhibited in the presence of U0126 or H89, but not GW441756. These findings suggest that dorsomorphin has the potential to induce neuritogenesis in PC12 cells, a response that requires the activation of PKA-dependent MEK-ERK1/2 signaling.