Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis
Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis
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DOI：
10.1038/labinvest.3700280
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发表时间：
2005-06-01
影响因子：
5
通讯作者：
Toyokuni, S
中科院分区：
文献类型：
--
作者：
Dutta, KK;Nishinaka, Y;Toyokuni, S
硫氧还蛋白是巯基还原系统的主要组成部分。最近，我们确定硫氧还蛋白结合蛋白-2（TBP-2）作为硫氧还蛋白的负调节因子。在这里，我们报告的作用TBP-2在氧化肾小管损伤和随后的致癌作用，铁氮基三乙酸。TBP-2在大鼠肾组织中表达丰富。免疫组化分析显示，TBP-2与近端肾小管细胞的细胞核和线粒体膜间隙相关，并与细胞色素c共沉淀。急性氧化性肾小管损伤后，TBP-2蛋白，但不是信使RNA，显着减少，表明这种蛋白质的半衰期缩短。大多数诱导性肾癌组织中TBP-2蛋白水平检测不到，这与启动子区CpG岛甲基化有关。基因组序列分析鉴定了3'非翻译区的poly-A道作为这种非选择性环境中的突变热点。总的来说，TBP-2蛋白的量与肾小管细胞的增殖呈负相关，如增殖细胞核抗原所评估的。这些结果表明，TBP-2的损失是必不可少的，不仅肿瘤，而且非肿瘤性肾小管细胞的增殖，TBP-2是氧化应激诱导的肾癌由次氮基三乙酸铁的靶基因。
Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3' untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate.