An apoptotic pathway of 3'-Ethynylcytidine(ECyd) involving the inhibition of RNA synthesis mediated by RNase L.
An apoptotic pathway of 3'-Ethynylcytidine(ECyd) involving the inhibition of RNA synthesis mediated by RNase L.
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DOI：
10.1093/nass/nrl051
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发表时间：
2006-11
期刊：
影响因子：
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通讯作者：
T. Naito;T. Yokogawa;Hye-Sook Kim;A. Matsuda;Takuma Sasaki;M. Fukushima;Y. Kitade;Y. Wataya
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文献类型：
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作者：
T. Naito;T. Yokogawa;Hye-Sook Kim;A. Matsuda;Takuma Sasaki;M. Fukushima;Y. Kitade;Y. Wataya
RNase L是一种核糖核酸内切酶，需要2‘-5’低聚腺苷酸来切割单链RNA。尽管近年来RNase L的抗病毒作用因其对病毒RNA的降解活性而为人所熟知，但已有研究表明，RNase L与多种抗癌药物诱导的线粒体-caspase依赖性凋亡信号通路有关。此外，它还具有多种功能，包括蛋白质的翻译和转录。在本报告中，我们发现通过竞争性抑制RNA聚合酶I抑制RNA合成的1-（3- c -乙基- β - d -核糖-戊呋喃基）胞嘧啶（ECyd）诱导28S rRNA断裂。ECyd诱导的rRNA的切割模式与RNase L切割的位点相似，且与RNase L切割的位点相同。此外，当已知可诱导RNase L表达的IFN-alpha2a处理肿瘤细胞时，ECyd诱导的细胞凋亡随着RNase L蛋白的表达而升高。为了确定RNase L在ECyd诱导的细胞凋亡中的作用，我们通过小干扰RNA （siRNA）检测到肿瘤细胞系中RNase L水平降低了数倍。这些结果表明，RNase L可能整合ECyd诱导的凋亡信号，为肿瘤化疗提供了新的临床靶点。
RNase L is an endoribonuclease that requires 2'-5' oligoadenylate to cleave single-stranded RNA. Although the antiviral effects of RNase L are well known because of its viral RNA degradation activity recently but it has been suggested that RNase L is concerned in mitochondrial-caspase dependent apoptotic signaling pathway induced by a number of anticancer agents. Moreover, it has variety of functions including translation and transcription of proteins. In this report, we found that 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (ECyd), which inhibits RNA synthesis through competitive inhibition of RNA polymerase I induced 28S rRNA fragmentation. The cleavage pattern of rRNA induced by ECyd was similar and the cleavage sites were identical to those cleaved by RNase L. Additionaly, apoptosis induced by ECyd was elevated following the protein expression of RNase L in the tumor cells when treated with IFN-alpha2a which was known to induce RNase L expression. To identify the role of RNase L in apoptosis induced by ECyd, we detected the decreased level of RNase L by several folds in the tumor cell lines through a small interfering RNA (siRNA). These results indicated that RNase L might integrate apoptotic signals induced by ECyd and provide the possibility to be a novel clinical target for cancer chemotherapy.