A novel cyathane diterpene, cyrneine A, induces neurite outgrowth in a Rac1-dependent mechanism in PC12 cells
A novel cyathane diterpene, cyrneine A, induces neurite outgrowth in a Rac1-dependent mechanism in PC12 cells
复制标题
DOI：
10.1016/j.lfs.2007.01.057
复制
发表时间：
2007-04-10
期刊：
影响因子：
6.1
通讯作者：
Nakahata, Norimichi
中科院分区：
文献类型：
--
作者：
Obara, Yutaro;Hoshino, Tomohiro;Nakahata, Norimichi
我们研究了从蘑菇Sarcodon cycloneus中分离的一种新的二萜类化合物-响应于马槟榔碱A，PC 12细胞延长了它们的神经突，这种作用部分地被细胞外信号调节激酶（ERK）激酶抑制剂PD 98059阻断，但不被蛋白激酶C抑制剂GF 109203 X阻断，也不被磷脂酰肌醇-3-激酶抑制剂渥曼青霉素阻断。Cyrneine A在测试的任何时间点（5-120分钟）都不激活ERK，表明对于Cyrneine A诱导的神经突生长仅需要ERK的基础活性。由于轴突延伸需要转录调控，因此确定了三种主要转录因子的活性。Cyrneine A增强了转录因子激活蛋白-1（AP-1）和核因子-κ B的激活，但不增强CREB的激活，并且这伴随着c-fos表达的增强。此外，我们确定了Rac 1，一个小的GTdR蛋白的Rho家族，调节肌动蛋白的动力学，在神经氨酸A诱导的神经突生长的作用。用甜菜碱A处理导致肌动蛋白易位，随后，在神经突尖端积累F-肌动蛋白。Rac 1的活性增加，显着抑制的显性负Rac 1突变体的表达，显着抑制了显着的神经突起的延伸，马槟榔碱A。这些结果表明，马槟榔碱A诱导的Rac 1依赖性机制的神经突起生长。(c)2007爱思唯尔公司All rights reserved.
We examined the effects of cyrneine A, a novel diterpene isolated from the mushroom Sarcodon cyrneus, on morphology of rat pheochromocytoma cells (PC 12). In response to cyrneine A, PC 12 cells extended their neurites, an effect partially blocked by the extracellular signal-regulated kinase (ERK) kinase inhibitor PD98059, but not by the protein kinase C inhibitor GF109203X, nor the phosphatidylinositol-3-kinase inhibitor wortmannin. Cyrneine A did not activate ERK at any of the time points tested (5-120 min), indicating that only the basal activity of ERK is required for cyrneine A-induced neurite outgrowth. As transcriptional regulation is required for neurite extension, the activity of three major transcription factors was determined. Cyrneine A enhanced activation of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa B, but not CREB, and this was accompanied by enhanced c-fos expression. Moreover, we determined the role of Rac1, a small GTPase protein of the Rho family that regulates actin dynamics, in cyrneine A-induced neurite outgrowth. Treatment with cyrneine A led to actin translocation and subsequently, to accumulation of F-actin at the tip of neurites. Rac1 activity was increased by cyrneine A and expression of a dominant-negative Rac1 mutant significantly inhibited the cyrneine A-induced extension of neurites. These results suggest that cyrneine A induces neurite outgrowth in a Rac1-dependent mechanism. (c) 2007 Elsevier Inc. All rights reserved.