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Aberrant splicing of cables gene, a CDK regulator, in human cancers.

机译:CDK调节剂Cables基因在人类癌症中的异常剪接。

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Cables is a novel cell cycle regulatory protein that interacts with cdk2, cdk3, and cdk5. Cables inhibits cdk2 activity by enhancing cdk2 tyrosine 15 phosphorylation by Wee1, which consequently leads to inhibition of cell growth. Loss of Cables expression was found in many human cancers, especially colon and endometrial cancer. However, the role of the Cables gene in cancer development remains unclear. This study was undertaken to analyze transcripts of Cables gene in endometrial and colon cancers. The analysis of RT-PCR products of the Cables gene revealed shortened products in each sample along with the product of the expected size. Sequence analysis indicated that these shortened products represented eight intragenic deletions in Cables mRNA transcripts. Analysis of DNA from the same tumor sample failed to show genomic rearrangements corresponding to the transcripts containing deletions, suggesting that the deletions are the result of RNA splicing. Sequence analysis demonstrated that five of the deletions resulted from alternative splicing (splicing at the exon/intron boundary consensus sites), whereas the remaining three deletions resulted from aberrant splicing (splicing at sites not considered to be exon/intron boundary sites). All three aberrant splicing products were only detected in tumor tissues. Ectopic expression of one of the aberrant splicing products, which was detected in both endometrial and colon carcinomas, resulted in increased cell growth rate in human colon carcinoma HT-29 cells, suggesting a role as a dominant negative mutant.
机译:Cables是一种与cdk2,cdk3和cdk5相互作用的新型细胞周期调节蛋白。电缆通过增强Wee1增强cdk2酪氨酸15磷酸化来抑制cdk2活性,从而导致抑制细胞生长。在许多人类癌症,特别是结肠癌和子宫内膜癌中发现电缆表达的损失。但是,Cables基因在癌症发展中的作用仍不清楚。进行这项研究以分析子宫内膜癌和结肠癌中Cables基因的转录本。对Cables基因的RT-PCR产物的分析表明,每个样品中的产物缩短了,而预期大小的产物也缩短了。序列分析表明,这些缩短的产物代表了Cables mRNA转录本中的八个基因内缺失。对来自同一肿瘤样品的DNA的分析未能显示出与含有缺失的转录本相对应的基因组重排,表明这些缺失是RNA剪接的结果。序列分析表明,其中的五个缺失是由选择性剪接(在外显子/内含子边界共有位点剪接)引起的,而其余三个缺失是由异常剪接(在不被视为外显子/内含子的边界位点剪接)引起的。所有三种异常剪接产物仅在肿瘤组织中检测到。在子宫内膜癌和结肠癌中均检测到异常剪接产物之一的异位表达,导致人结肠癌HT-29细胞的细胞生长速率增加,提示其为显性负突变体。

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