Tryprostatin A, a specific and novel inhibitor of microtubule assembly
Tryprostatin A, a specific and novel inhibitor of microtubule assembly
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DOI：
10.1042/bj3330543
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发表时间：
1998-08-01
影响因子：
4.1
通讯作者：
Osada, H
中科院分区：
文献类型：
--
作者：
Usui, T;Kondoh, M;Osada, H
本论文研究了烟曲霉Tryprostatin A（TPS-A）的细胞周期抑制机制及其主要作用靶点。TPS-A以剂量和时间依赖性方式抑制异步培养的M期3 Y1细胞的细胞周期进展。相反，TPS-B（TPS-A的去甲氧基类似物）显示对细胞生长的细胞周期非特异性抑制，即使它在比TPS-A更低的浓度下抑制细胞生长。在特异性抑制M期进展的浓度范围内，通过间接免疫荧光显微镜观察到，TPS-A处理诱导3 Y1细胞的胞质微管可逆破坏。TPS-A抑制从牛脑纯化的微管的体外组装（在250 μ M时抑制40%）;然而，当谷氨酸诱导聚合时，即使在250 μ M TPS-A下，对纯化的微管蛋白的自组装也几乎没有影响。TPS-A不抑制紫杉醇或微管蛋白C-末端结构域消化促进的组装。然而，TPS-A阻断了诱导剂与C-末端结构域、微管相关蛋白2（MAP 2）、tau蛋白和聚-（L-赖氨酸）相互作用诱导的微管蛋白组装。这些结果表明，TPS-A是一种新型的MAP依赖性微管组装的抑制剂，通过破坏微管纺锤体，特异性地抑制细胞周期在M期的进展。
We have investigated the cell cycle inhibition mechanism and primary target of tryprostatin A (TPS-A) purified from Aspergillus fumigatus. TPS-A inhibited cell cycle progression of asynchronously cultured 3Y1 cells in the M phase in a dose- and time-dependent manner. In contrast, TPS-B (the demethoxy analogue of TPS-A) showed cell-cycle non-specific inhibition on cell growth even though it inhibited cell growth at lower concentrations than TPS-A. TPS-A treatment induced the reversible disruption of the cytoplasmic microtubules of 3Y1 cells as observed by indirect immunofluorescence microscopy in the range of concentrations that specifically inhibited M-phase progression. TPS-A inhibited the assembly in vitro of microtubules purified from bovine brains (40 % inhibition at 250 mu M); however, there was little or no effect on the self-assembly of purified tubulin when polymerization was induced by glutamate even at 250 mu M TPS-A. TPS-A did not inhibit assembly promoted by taxol or by digestion of the C-terminal domain of tubulin. However, TPS-A blocked the tubulin assembly induced by inducers interacting with the C-terminal domain, microtubule-associated protein 2 (MAP2), tau and poly-(L-lysine). These results indicate that TPS-A is a novel inhibitor of MAP-dependent microtubule assembly and, through the disruption of the microtubule spindle, specifically inhibits cell cycle progression at the M phase.