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首页> 外文期刊>Apoptosis >Transcriptional modulation of apoptosis regulators by roscovitine and related compounds
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Transcriptional modulation of apoptosis regulators by roscovitine and related compounds

机译：罗斯科啡及其相关化合物对凋亡调节子的转录调控。

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Chemical inhibitors of cyclin-dependent kinase (CDK), like roscovitine, are promising drugs in the context of new cancer therapies. Roscovitine and related compounds, like seliciclib and olomoucine, are effective inducers of apoptosis in many proliferating cells in culture. These compounds are known to activate the intrinsic or mitochondrial pathway of apoptosis. In order to better characterize this intrinsic pathway, a transcriptional analysis was performed using the reverse transcriptase-multiplex ligation-dependent probe amplification procedure (RT-MLPA). In five cell lines, we detected an early and marked reduction of most transcripts, which is consistent with the disruption of transcription that results from the inhibition of CDK7 and CDK9. However, the mRNA of p53-upregulated modulator of apoptosis (PUMA) gene escaped from this transcription inhibition in neuroblastoma cells with a functional p53 protein. The increase of PUMA mRNA was not found in roscovitine-treated cell lines defective in p53, which underwent apoptosis like their p53 proficient counterparts. In addition, in SH-SY5Y cells, sublethal and lethal concentrations of roscovitine produced equivalent increases of PUMA mRNA and protein. In conclusion, the increased expression of PUMA was not associated with apoptosis induction. On the contrary, mRNA and protein depletion of MCL-1 gene correlated the best with cell demise. Moreover, NOXA protein suffered a far minor decrease than MCL-1. Because of the selective neutralization of NOXA by MCL-1, we hypothesize that the disruption of this balance is a critical event in apoptosis induction by roscovitine and related compounds.
机译：细胞周期蛋白依赖性激酶（CDK）的化学抑制剂，如roscovitine，在新的癌症治疗方法中是很有前途的药物。 Roscovitine和相关化合物，如seliciclib和olomoucine，是培养物中许多增殖细胞中凋亡的有效诱导剂。已知这些化合物可激活细胞凋亡的内在或线粒体途径。为了更好地表征此内在途径，使用逆转录酶多重连接依赖性探针扩增程序（RT-MLPA）进行了转录分析。在五个细胞系中，我们检测到大多数转录物的早期显着减少，这与抑制CDK7和CDK9导致的转录破坏一致。但是，在具有功能性p53蛋白的成神经细胞瘤细胞中，p53上调的凋亡调节因子（PUMA）基因的mRNA逃避了这种转录抑制作用。在经roscovitine处理的p53缺陷细胞系中未发现PUMA mRNA的增加，该细胞系像p53熟练的对应细胞一样经历了凋亡。此外，在SH-SY5Y细胞中，roscovitine的亚致死浓度和致死浓度会产生PUMA mRNA和蛋白质的同等增加。总之，PUMA表达的增加与细胞凋亡的诱导无关。相反，MCL-1基因的mRNA和蛋白质耗竭与细胞死亡相关性最好。此外，NOXA蛋白的下降幅度远小于MCL-1。由于MCL-1对NOXA的选择性中和，我们假设这种平衡的破坏是罗斯科维汀和相关化合物诱导细胞凋亡的关键事件。

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