Cisplatin inhibits synthesis of ribosomal RNA in vivo
Cisplatin inhibits synthesis of ribosomal RNA in vivo
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DOI：
10.1093/nar/26.12.2831
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发表时间：
1998-06-15
影响因子：
14.9
通讯作者：
Carmo-Fonseca, M
中科院分区：
文献类型：
--
作者：
Jordan, P;Carmo-Fonseca, M
顺二氨二氯铂（cis-diamminine dichloroplatinum，II）（cisplatin或cis-DDP）是一种DNA损伤剂，广泛用于癌症化疗。顺铂交联DNA，所得加合物与含有高迁移率基团（HMG）结构域的蛋白质相互作用，如UBF（上游结合因子）。UBF是一种转录因子，可与核糖体RNA（rRNA）基因的启动子结合，从而支持RNA聚合酶I启动转录。我们在此报道顺铂引起人细胞核仁中UBF的重新分布，类似于抑制rRNA合成后观察到的结果。观察到rRNA转录机制的主要成分TBP、TAF（I）s和RNA聚合酶I也发生了类似的重新分布。此外，我们提供了第一次直接在体内的证据表明，顺铂块合成的rRNA。而RNA聚合酶II的活性继续在整个细胞核中被检测到。临床无效的反式异构体（trans-DDP）不会改变UBF或RNA聚合酶I转录机制的其他组分的定位。这些结果表明，在增殖细胞中刺激的rRNA合成的破坏在顺铂的临床成功中起着重要作用。
Cis-diammininedichloroplatinum(II) (cisplatin or cis-DDP) is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin crosslinks DNA and the resulting adducts interact with proteins that contain high-mobility-group (HMG) domains, such as UBF (upstream binding factor), UBF is a transcription factor that binds to the promoter of ribosomal RNA (rRNA) genes thereby supporting initiation of transcription by RNA polymerase I. Here we report that cisplatin causes a redistribution of UBF in the nucleolus of human cells, similar to that observed after inhibition of rRNA synthesis, A similar redistribution was observed for the major components of the rRNA transcription machinery, namely TBP, TAF(I)s and RNA polymerase I. Furthermore, we provide for the first time direct in vivo evidence that cisplatin blocks synthesis of rRNA. while activity of RNA polymerase II continues to be detected throughout the nucleus. The clinically ineffective trans isomer (trans-DDP) does not alter the localization of either UBF or other components of the RNA polymerase I transcription machinery, These results suggest that disruption of rRNA synthesis, which is stimulated in proliferating cells, plays an important role in the clinical success of cisplatin.