Interruption of RNA processing machinery by a small compound, 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1).
Interruption of RNA processing machinery by a small compound, 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1).
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DOI：
10.1158/1535-7163.mct-08-0839
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发表时间：
2009-02
影响因子：
5.7
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Guo W;Wu S;Wang L;Wang RY;Wei X;Liu J;Fang B
蛋白激酶Ciota（PKC 1）被致癌Ras蛋白激活，并且是体内K-Ras诱导的转化和结肠癌发生所需的。然而，PKCι在信号转导和肿瘤发生中的作用尚不清楚。我们最近鉴定了一种称为1-[（4-氯苯基）甲基]-1H-吲哚-3-甲醛（oncrasin-1）的小分子，其可以选择性地杀死K-Ras突变癌细胞并在敏感细胞中诱导PKC 1的异常核聚集，但在抗性细胞中不诱导。为了确定细胞核中PKCι聚集的原因和生物学后果，我们分析了oncrasin-1对参与DNA修复和RNA加工的蛋白质的影响。我们的研究结果表明，oncrasin-1处理导致PKCι和剪接因子共聚集成巨剪接体，但对DNA修复分子Rad 51没有明显影响。此外，oncrasin-1治疗抑制了RNA聚合酶II的最大亚基的磷酸化和无内含子报告基因在敏感细胞中的表达，但在耐药细胞中没有，这表明抑制RNA转录是oncrasin-1治疗的主要作用。用培养的细胞或重组蛋白的研究表明，oncrasin-1可以破坏PKC 1和细胞周期蛋白依赖性蛋白激酶9/细胞周期蛋白T1复合物的相互作用，已知该复合物磷酸化RNA聚合酶II的最大亚基并且是RNA转录所需的。总之，我们的结果表明oncrasin-1抑制RNA加工机制的功能，并且PKCι可能参与RNA加工复合物的生物学功能。
Protein kinase Ciota (PKCι) is activated by oncogenic Ras proteins and is required for K-Ras-induced transformation and colonic carcinogenesis in vivo. However, the role of PKCι in signal transduction and oncogenesis is not clear. We recently identified a small molecule, designated 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1), that can selectively kill K-Ras mutant cancer cells and induce abnormal nuclear aggregation of PKCι in sensitive cells but not resistant cells. To determine the causes and biologic consequences of PKCι aggregates in the nucleus, we analyzed the effect of oncrasin-1 on proteins involved in DNA repair and RNA processing. Our results showed that oncrasin-1 treatment led to co-aggregation of PKCι and splicing factors into megaspliceosomes but had no obvious effects on the DNA repair molecule Rad51. Moreover, oncrasin-1 treatment suppressed the phosphorylation of the largest subunit of RNA polymerase II and the expression of intronless reporter genes in sensitive cells but not in resistant cells, suggesting that suppression of RNA transcription is a major effect of oncrasin-1 treatment. Studies with cultured cells or with recombinant proteins showed that oncrasin-1 can disrupt the interaction of PKCι and cyclin-dependent protein kinase 9/cyclin T1 complex, which is known to phsophorylate the largest subunit of RNA polymerase II and is required for RNA transcription. Together, our results suggest that oncrasin-1 suppresses the function of RNA processing machinery and that PKCι might involve in the biologic function of RNA processing complexes.