FK506 requires stimulation of the extracellular signal-regulated kinase 1/2 and the steroid receptor chaperone protein p23 for neurite elongation
FK506 requires stimulation of the extracellular signal-regulated kinase 1/2 and the steroid receptor chaperone protein p23 for neurite elongation
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DOI：
10.1159/000076565
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Zhong, YP
中科院分区：
文献类型：
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作者：
Gold, BG;Zhong, YP
免疫抑制药物FK 506（他克莫司）在体内加速神经再生，并在体外增加神经突伸长。我们已经提出，该机制涉及结合FK 506结合蛋白52，成熟类固醇受体复合物的伴侣蛋白成分，以及随后的“功能获得”，涉及p23从复合物中的Hsp-90解离和细胞外信号调节激酶（ERK）激活。在这里，我们测试了ERK和p23在FK 506诱导的人SH-SY 5 Y细胞神经突延长中的作用。FK 506（10 nM）在12和24 h增加ERK 12磷酸化，在24 h引起3.5倍增加，重组人p23抗体（JJ 3）以浓度依赖性方式抑制。FK 506（10 nM）的神经突伸长，通过测量96和168小时的神经突长度来确定，被有丝分裂原活化蛋白激酶抑制剂PD 098059（10 μ M）完全阻断，并以浓度依赖性方式被p23抗体阻止。综上所述，结果表明ERK和p23在FK 506的神经突延伸活性中的功能作用，并揭示了一种涉及p23激活ERK的新信号转导途径。我们认为刺激或模拟p23的化合物可能有助于加速神经再生。版权所有（C）2004 S. Karger AG，巴塞尔。
The immunosuppressant drug FK506 (tacrolimus) accelerates nerve regeneration in vivo and increases neurite elongation in vitro. We have proposed that the mechanism involves binding to the FK506-binding protein 52, a chaperone component of mature steroid receptor complexes, and a subsequent 'gain-of-function' involving p23 dissociation from Hsp-90 in the complex and extracellular signal-regulated kinase (ERK) activation. Here, we tested the involvement of the ERK and p23 in neurite elongation by FK506 in human SH-SY5Y cells. FK506 (10 nM) increased ERK1/2 phosphorylation at 12 and 24 h, eliciting a 3.5-fold increase at 24 h, which was inhibited in a concentration-dependent manner by an antibody (JJ3) to recombinant human p23. Neurite elongation by FK506 ( 10 nM), determined by measuring neurite lengths at 96 and 168 h, was completely blocked by the mitogen-activated protein kinase inhibitor PD 098059 (10 muM) and prevented, in a concentration-dependent fashion, by the p23 antibody. Taken together, the results demonstrate the functional role for ERK and p23 in the neurite elongation activity of FK506 and reveal a novel signal transduction pathway involving p23 activation of ERK. We suggest that compounds that stimulate or mimic p23 may be useful for accelerating nerve regeneration. Copyright (C) 2004 S. Karger AG, Basel.