Apoptosis induction by the satratoxins and other trichothecene mycotoxins: Relationship to ERK, p38 MARK, and SAP/JNK activation
Apoptosis induction by the satratoxins and other trichothecene mycotoxins: Relationship to ERK, p38 MARK, and SAP/JNK activation
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DOI：
10.1006/taap.1999.8888
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发表时间：
2000-04-15
影响因子：
3.8
通讯作者：
Pestka, JJ
中科院分区：
文献类型：
--
作者：
Yang, GH;Jarvis, BB;Pestka, JJ
satratoxins是由Stachybocyanin真菌产生的葡萄球菌毒素家族的成员，并且在病原学上与建筑物相关的健康问题有关。本研究的目的是将satratoxins和其他的喜树碱的细胞毒性和凋亡能力与三组促分裂原活化蛋白激酶（MAPK）（细胞外信号调节蛋白激酶（ERK）、p38 MAPK和应激活化蛋白激酶/c-Jun N-末端激酶（SAPK/JNK））的活化联系起来。在评估3-细胞中代表性的单端孢菌时，使用了两种骨髓模型，即RAW 264.7小鼠巨噬细胞和U937人白血病细胞。（4，5-二甲基噻唑-2-基）2，5-二苯基溴化四唑（MTT）裂解测定，根据以下等级顺序，细胞毒性是明显的：satratoxin G、roridin A和verrucarin A > T-2毒素、satratoxin F、H >雪腐镰刀菌烯醇和呕吐毒素。当使用DNA片段化和荧光显微镜测定来测量双孢菌素介导的细胞凋亡时，发现了可比较的结果，从而表明细胞毒性是通过凋亡过程介导的。用Western blot分析MAPK活化的评估表明，喜树碱不仅激活SAPK/JNK和p38 MAPK，而且还激活ERK。satratoxin G对蛋白质合成的抑制作用与MAPK的激活和细胞凋亡所需的浓度相关，放线菌酮对三种MAPK的激活和细胞凋亡的诱导作用与放线菌酮相似，提示核糖体结合或蛋白质合成的抑制可能在MAPK的激活和细胞凋亡诱导中起作用。当ERK特异性抑制剂PD 98059选择性抑制ERK激活时，Satratoxin G和vomitoxin诱导的细胞凋亡明显增强，表明ERK的负性作用。用p38特异性抑制剂SB 203580抑制p38 MAPK活性对高毒性Satratoxin G诱导的细胞凋亡没有影响。然而，SB 203580适度抑制细胞凋亡诱导的毒性较低的喜树碱呕吐毒素，从而暗示p38 MAPK在喜树碱诱导的细胞凋亡的部分作用，结果表明，satratoxins是最有效的喜树碱和MAPK可能发挥不可或缺的作用，在这些真菌毒素的各种毒性表现。(C)北京大学出版社.
The satratoxins are members of the trichothecene mycotoxin family that are produced by the fungus Stachybotrys and that have been etiologically associated with building-related health problems. The purpose of this study was to relate cytotoxic and apoptotic capacities of satratoxins and other trichothecenes to the activation of three groups of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated protein kinase (ERK), p38 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)). Two myeloid models, RAW 264.7 murine macrophage and U937 human leukemic cells were used, Upon evaluating representative trichothecenes in the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) cleavage assay, cytotoxicity was evident according to the following rank order: satratoxin G, roridin A, and verrucarin A > T-2 toxin, satratoxin F, H > nivalenol, and vomitoxin, Comparable results were found when measuring trichothecene-mediated apoptosis using DNA fragmentation and fluorescence microscopy assays, thus suggesting that cytotoxicity was mediated through an apoptotic process. Assessment of MAPK activation using Western blot analysis revealed that trichothecenes activated not only SAPK/JNK and p38 MAPK but also ERK, Activation of MAPKs by satratoxins and other trichothecenes correlated with and preceded apoptosis. The concentration of satratoxin G sufficient for protein synthesis inhibition correlated with that required for apoptosis and activation of all three MAPKs, Cycloheximide had similar effects to trichothecenes, suggesting that ribosome binding or protein synthesis inhibition may play roles in MAPK activation and apoptosis induction. Apoptosis induction by satratoxin G and vomitoxin was markedly enhanced when ERK activation was selectively inhibited by ERK-specific inhibitor PD98059, thus indicating a negative role for ERK, Inhibition of p38 MAPK activity with the p38-specific inhibitor SB203580 had no effect on apoptosis induction by the highly toxic satratoxin G. However, SB203580 moderately inhibited apoptosis induction by the less toxic trichothecene vomitoxin, thus implying a partial role of p38 MAPK in trichothecene-induced apoptosis, The results suggest that the satratoxins are among the most potent trichothecenes and that MAPKs may play integral roles in the diverse toxic manifestations of these mycotoxins. (C) 2000 Academic Press.