Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium chloride
Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium chloride
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DOI：
10.1074/jbc.m414303200
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发表时间：
2005-07-01
影响因子：
4.8
通讯作者：
Joseph, P
中科院分区：
文献类型：
--
作者：
Othumpangat, S;Kashon, M;Joseph, P
翻译起始因子4 E（eIF 4 E），mRNA帽结合和翻译所需的限速因子，是否是镉，人类致癌物诱导的细胞毒性和细胞死亡的目标，进行了研究。人细胞系HCT 15、PLC/PR/5、HeLa和Chang暴露于氯化镉导致细胞毒性和细胞死亡，这与eIF 4 E蛋白水平的显著降低有关。类似地，由小干扰RNA引起的eIF 4 E基因表达的特异性沉默导致显著的细胞毒性和细胞死亡。另一方面，eIF 4 E基因的过表达对镉诱导的细胞毒性和细胞死亡具有保护作用。进一步的研究显示，镉处理的细胞中eIF 4 E mRNA水平没有改变，尽管它们的eIF 4 E蛋白水平降低。此外，细胞暴露于镉导致eIF 4 E蛋白的泛素化增强，而蛋白酶体活性的抑制剂逆转镉诱导的eIF 4 E蛋白的减少。细胞暴露于镉，以及eIF 4 E基因的特异性沉默，也导致细胞周期蛋白D1，一个关键的细胞周期和生长调节基因的细胞水平降低，这表明在镉处理的细胞中观察到的细胞周期蛋白D1基因表达的抑制很可能是由于细胞水平降低eIF 4 E。两者合计，我们的研究结果表明，细胞暴露于氯化镉导致细胞毒性和细胞死亡，由于增强泛素化和随后的蛋白水解eIF 4 E蛋白，这反过来又减少了细胞水平的关键基因，如细胞周期蛋白D1。
Whether translation initiation factor 4E (eIF4E), the mRNA cap binding and rate-limiting factor required for translation, is a target for cytotoxicity and cell death induced by cadmium, a human carcinogen, was investigated. Exposure of human cell lines, HCT15, PLC/PR/5, HeLa, and Chang, to cadmium chloride resulted in cytotoxicity and cell death, and this was associated with a significant decrease in eIF4E protein levels. Similarly, specific silencing of the expression of the eIF4E gene, caused by a small interfering RNA, resulted in significant cytotoxicity and cell death. On the other hand, overexpression of the eIF4E gene was protective against the cadmium-induced cytotoxicity and cell death. Further studies revealed the absence of alterations in the eIF4E mRNA level in the cadmium-treated cells despite their decreased eIF4E protein level. In addition, exposure of cells to cadmium resulted in enhanced ubiquitination of eIF4E protein while inhibitors of proteasome activity reversed the cadmium-induced decrease of eIF4E protein. Exposure of cells to cadmium, as well as the specific silencing of eIF4E gene, also resulted in decreased cellular levels of cyclin D1, a critical cell cycle and growth regulating gene, suggesting that the observed inhibition of cyclin D1 gene expression in the cadmium-treated cells is most likely due to decreased cellular level of eIF4E. Taken together, our results demonstrate that the exposure of cells to cadmium chloride resulted in cytotoxicity and cell death due to enhanced ubiquitination and consequent proteolysis of eIF4E protein, which in turn diminished cellular levels of critical genes such as cyclin D1.