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Molecular mechanisms of tributyltin-induced cellular damage : possible involvement of the immediate early genes

三丁基锡诱导细胞损伤的分子机制：可能涉及早期基因

基本信息

批准号：
10670331
负责人：
MATSUOKA Masato
金额：
$ 1.54万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670331/
关键词：
tributyltin organotin compounds immediate early genes c-Fos mitogen-activated protein kinase signal transduction cadmium mercury JNK SAPK

项目摘要

Effects of tributyltin chloride (TBT) and other organotin compounds on mitogen-activated protein kinases (MAPKs) were examined in CCRF-CEM human T cell line. The levels of phosphorylated form of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK increased in a dose-dependent manner. The phosphorylation was observed after 15 min and lasted for 4 h following TBT exposure. On the other hand, no clear changes were found in the total protein levels of ERK, JNK and p38 MAPK.The potential of MAPKs phosphorylation was TBT > dibutyltin dichloride > monobutyltin trichloride. When compared to other triorganotin compounds such as trimethyltin chloride, triphenyltin chloride and triethyltin bromide, TBT exposure induced the most marked phosphorylation of MAPKs. Chelation of intracellular Ca^<2+> with BAPTA/AM suppressed TBT-induced MAPKs phosphorylation and subsequent apoptosis. These results showed that tributyltin is a potent activator of ERK, JNK and p38 MAPK pathways, and intracellular Ca^<2+> plays an important role for MAPKs phosphorylation. Phosphorylation of MAPKs and subsequent expression of the immediate early genes may be responsible for TBT-induced cellular damage. The exposure to cadmium or inorganic mercury also induced the phosphorylation of MAPKs in CCRF-CEM cells. ERK was found to be involved in cadmium-induced apoptotic cell death in this T cell line. LL-Z1640-2, a macrocyclic nonaketide, was a potent inhibitor of metals-induced MAPKs activation in CCRF-CEM cells.TBT and other metals have been known to induce the expression of c-fos gene in the various cell types. The c-Fos-deficient fibroblasts were more severely affected than wild-type cells following the exposure to TBT and other metals, suggesting that c-fos may play a protective role against the cytotoxic effects of metals at least in fibroblasts.

本文研究了氯化三丁基锡（TBT）等有机锡化合物对CCRF-CEM人T细胞系丝裂原活化蛋白激酶（MAPK）的影响。磷酸化的细胞外信号调节蛋白激酶（ERK）、c-Jun N-末端激酶（JNK）和p38 MAPK的水平呈剂量依赖性增加。TBT暴露后15 min观察到磷酸化，并持续4 h。ERK、JNK和p38 MAPK的总蛋白水平无明显变化，MAPK磷酸化的潜力为TBT >二丁基二氯化锡>单丁基二氯化锡。与其他三有机锡化合物如氯化三甲基锡、氯化三苯基锡和溴化三乙基锡相比，三丁基锡化合物暴露诱导的MAPK磷酸化最为显著。用BAPTA/AM螯合细胞内Ca^<2+>抑制TBT诱导的MAPK磷酸化和随后的凋亡。这些结果表明，三丁基锡是ERK、JNK和p38 MAPK通路的有效激活剂，细胞内Ca^<2+>在MAPK磷酸化中起重要作用。磷酸化的MAPK和随后的立即早期基因的表达可能是负责TBT诱导的细胞损伤。镉或无机汞暴露也诱导CCRF-CEM细胞中MAPK的磷酸化。ERK被发现参与镉诱导的细胞凋亡的T细胞系。LL-Z1640-2是一种大环九酮类化合物，能有效抑制金属离子诱导的CCRF-CEM细胞MAPK的活化，TBT等金属离子可诱导多种细胞c-fos基因的表达。c-Fos缺陷的成纤维细胞受到更严重的影响比野生型细胞后，暴露于TBT和其他金属，这表明c-Fos可能发挥保护作用，至少在成纤维细胞对金属的细胞毒性作用。