Cytotoxic Ribonucleases and RNA Interference (RNAi)
Cytotoxic Ribonucleases and RNA Interference (RNAi)
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DOI：
10.4161/cc.2.1.232
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发表时间：
2003-01-01
期刊：
影响因子：
4.3
通讯作者：
Darzynkiewicz, Zbigniew
中科院分区：
文献类型：
--
作者：
Ardelt, Barbara;Ardelt, Wojciech;Darzynkiewicz, Zbigniew
从两栖动物卵母细胞或胚胎中分离出了几种与胰腺rna酶A同源的细胞毒性核糖核酸酶（CRs）。其中，onconase (Onc)，一种显示出抗肿瘤特性并处于III期临床试验的CR，是研究最广泛的。tRNA被Onc内化到细胞中降解，从而抑制蛋白质合成被认为是其细胞毒性的机制。然而，一些发现不能仅用蛋白质合成的非特异性下降来解释，并提出了其他或替代机制。因此，我们假设mirna和/或RNA干扰（RNAi）也可能是CRs的靶标。以下论点支持这一假设：(A) mirna和sirna似乎不受蛋白质保护，因此，作为tRNA，可被cr获取和降解；(B) Onc在trna上有优先的切割位点：它们的切割可能产生干扰翻译的dsRNA片段。因此，与Dicer类似，细胞内的CRs可以产生具有干扰特性的小rna；(C) CRs在卵母细胞和胚胎发育过程中丰富；他们在那里的作用是未知的。由于细胞在胚胎发生过程中经历了永久的分化，因此CRs的功能很可能是通过(A)和(B)中列出的机制提供额外水平的基因表达调节。
Several cytotoxic ribonucleases (CRs), homologs of the pancreatic RNase A, have been isolated from amphibian oocytes or embryos. Of them, onconase (Onc), the CR that shows antitumor properties and is in phase III clinical trials, was the most extensively researched. Degradation of tRNA by Onc internalized into cells that leads to inhibition of protein synthesis is considered the mechanism of its cytotoxicity. Several findings, however, cannot be explained by nonspecific decline in protein synthesis alone and suggest additional or alternative mechanism(s). We postulate therefore that miRNAs and/or RNA interference (RNAi) may also be targets of CRs. The following arguments support this postulate: (A) miRNAs and siRNAs appear to be unprotected by proteins and therefore, as tRNA, accessible and degradable by CRs; (B) Onc has preferred cleavage sites on tRNAs: their cleavage may generate segments of dsRNA that interfere with translation. Analogous to Dicer, thus, small RNAs with interfering properties may be generated by CRs within the cell; (C) CRs are abundant in oocytes and during embryonic development; their role there is unknown. Since cells undergo perpetual differentiation during embryogenesis it is likely that the function of CRs is to provide additional level of regulation of gene expression via the mechanisms listed in (A) and/or (B).