Cisplatin inhibits protein synthesis in rabbit reticulocyte lysate by causing an arrest in elongation
Cisplatin inhibits protein synthesis in rabbit reticulocyte lysate by causing an arrest in elongation
复制标题
DOI：
10.1006/abbi.1997.0198
复制
发表时间：
1997-08-01
影响因子：
3.9
通讯作者：
Matts, RL
中科院分区：
文献类型：
--
作者：
Heminger, KA;Hartson, SD;Matts, RL
顺铂抑制兔网织红细胞蛋白质合成的机制。顺铂和反铂引起蛋白质合成速率的逐渐减慢，最终导致翻译的完全停滞。抑制作用依赖于化合物的水合作用。加入真核起始因子eIF-2、eIF-2B、cAMP、MgGTP或二硫苏糖醇既不能阻止也不能逆转顺铂诱导的抑制，表明顺铂诱导的翻译抑制机制不同于其他有毒重金属离子诱导的抑制（Hurst，R.，Schatz，J.R.，和Matts，R. L.（1987）J. Biol. Chem，262，15939-15945; Matts，R. L.，Schatz，J.R.，赫斯特河，和Kagen，R.（1991）J.Biol.Chem.266，12695-12702）。对顺铂抑制的网织红细胞裂解物的多核糖体谱的分析表明，顺铂阻止了蛋白质合成的延伸阶段，琼脂糖凝胶电泳和北方印迹分析表明，在从顺铂处理的裂解物的多核糖体提取RNA时，mRNA和rRNA交联形成非常高分子量的加合物，二乙基二硫代氨基甲酸酯，这降低了顺铂在体内的细胞毒性，保护网织红细胞裂解物中的蛋白质合成免受顺铂的抑制。这些数据表明，广泛的衍生化网织红细胞裂解物RNA的顺式和反式的结果疾病的翻译核糖体的逮捕。由于翻译延伸的逮捕是一个明确定义的几个家庭的毒素的作用机制，我们认为，它可能有助于顺铂的细胞毒性作用在某些细胞群体中观察到。(C)北京：科学出版社.
The mechanism through which cisplatin (cis-diamminedichloroplatinum) inhibits protein synthesis in rabbit reticulocyte. lysate was characterized, Cisplatin and transplatin caused a progressive slowing in the rate of protein synthesis culminating in the complete arrest of translation, Inhibition was dependent upon the aquation of the compounds. Addition of eukaryotic initiation factor eIF-2, eIF-2B, cAMP, MgGTP, or dithiothreitol neither prevented nor reversed the inhibition induced by cisplatin, indicating that the mechanism of cisplatin-induced translational inhibition is distinct from the inhibition induced by other toxic heavy metal ions (Hurst, R., Schatz, J. R., and Matts, R. L. (1987) J. Biol. Chem, 262, 15939-15945; Matts, R. L., Schatz, J. R., Hurst, R., and Kagen, R. (1991) J. Biol. Chem. 266, 12695-12702). Analysis of the polyribosome profile of cisplatin-inhibited reticulocyte lysate indicated that cisplatin arrests the elongation stage of protein synthesis, Agarose gel electrophoresis and Northern blot analysis indicated that mRNA and rRNA become crosslinked to form very high-molecular-weight adducts upon extraction of the RNA from polyribosomes of cisplatin-treated lysates, Diethyldithiocarbamate, which reduces the cytotoxicity of cisplatin in vivo, protects protein synthesis in reticulocyte lysate from inhibition by cisplatin. The data suggest that extensive derivatization of reticulocyte lysate RNA by cis- and transplatin results ill the arrest of translating ribosomes. Since arrest of translational elongation is a well-defined mechanism of action of several families of toxins, we suggest that it may contribute to the cytotoxic action of cisplatin observed in certain populations of cells. (C) 1997 Academic Press.