A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis
A novel human tRNA-dihydrouridine synthase involved in pulmonary carcinogenesis
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DOI：
10.1158/0008-5472.can-05-0600
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发表时间：
2005-07-01
期刊：
影响因子：
11.2
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Kato, T;Daigo, Y;Nakamura, Y
近三十年前，人们在人类恶性组织中发现了tRNA（Phe）中二氢尿苷水平升高，但其在致癌过程中的生物学意义仍不清楚。通过分析非小细胞肺癌 (NSCLC) 的全基因组基因表达谱，我们发现了一种新的人类基因（称为 hDUS2）的过度表达，该基因编码一种与 tRNA-二氢尿苷合酶 (DUS) 具有相同结构特征的蛋白质。推导的 493 个氨基酸序列与酿酒酵母的二氢尿苷合酶 2 (Dus2) 有 39% 的同源性，并包含保守的双链 RNA 结合基序 (DSRM)。我们发现 hDUS2 蛋白具有 tRNA-DUS 活性，并且它与 EPRS（一种谷氨酰脯氨酰 tRNA 合成酶）发生物理相互作用，并且可能提高翻译效率。转染到 NSCLC 细胞中的针对 hDUS2 的小干扰 RNA 抑制了该基因的表达，减少了 tRNA 分子中二氢尿苷的含量，并抑制了生长。免疫组织化学分析显示肿瘤中较高水平的 hDUS2 与肺癌患者较差的预后之间存在显着相关性。我们的数据表明，hDUS2 的上调是肺癌发生的一个相对常见的特征，并且选择性抑制 hDUS2 酶活性和/或抑制 hDUS2-tRNA 合成酶复合物的形成可能是治疗许多肺癌的有前途的治疗策略。
An increased level of dihydrouridine in tRNA(Phe) was found in human malignant tissues nearly three decades ago, but its biological significance in carcinogenesis has remained unclear. Through analysis of genome-wide gene-expression profiles among non-small cell lung carcinomas (NSCLC), we identified overexpression of a novel human gene, termed hDUS2, encoding a protein that shared structural features with tRNA-dihydrouridine synthases (DUS). The deduced 493-amino-acid sequence showed 39% homology to the dihydrouridine synthase 2 enzyme (Dus2) of Saccharomycescerevisiae and contained a conserved double-strand RNA-binding motif (DSRM). We found that hDUS2 protein had tRNA-DUS activity and that it physically interacted with EPRS, a glutamyl-prolyl tRNA synthetase, and was likely to enhance translational efficiencies. A small interfering RNA against hDUS2 transfected into NSCLC cells suppressed expression of the gene, reduced the amount of dihydrouridine in tRNA molecules, and suppressed growth. Immunohistochemical analysis showed significant association between higher levels of hDUS2 in tumors and poorer prognosis of lung cancer patients. Our data imply that upregulation of hDUS2 is a relatively common feature of pulmonary carcinogenesis and that selective suppression of hDUS2 enzyme activity and/or inhibition of formation of the hDUS2-tRNA synthetase complex could be a promising therapeutic strategy for treatment of many lung cancers.