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首页> 外文期刊>Molecular and Cellular Biology >Inhibition of DNA topoisomerase II alpha gene expression by the p53 tumor suppressor.
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Inhibition of DNA topoisomerase II alpha gene expression by the p53 tumor suppressor.

机译：p53肿瘤抑制因子抑制DNA拓扑异构酶IIα基因表达。

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DNA topoisomerase II (topo II) is an essential nuclear enzyme involved in major cellular functions such as DNA replication, transcription, recombination, and mitosis. While an elevated level of topo II alpha is associated with cell proliferation, wild-type (wt) p53 inhibits the expression of various growth-stimulatory genes. To determine if p53 downregulates topo II alpha gene expression, a murine cell line, (10)1val, that expresses a temperature-sensitive p53 was utilized. The (10)1val cells had significantly lower levels of topo II alpha mRNA and protein following incubation for 24 h at 32 degrees C (p53 with wt conformation) than at 39 degrees C (p53 with mutant conformation). The effect of p53 on the human topo II alpha gene promoter was determined by using luciferase reporter plasmids containing varying lengths of the topo II alpha promoter transiently cotransfected into p53-deficient (10)1 cells together with wt or mutant p53 expression plasmids. Transcription from the full-length (bp -557 to +90) topo II alpha promoter was decreased 15-fold by wt p53 in a concentration-dependent manner, whereas mutant p53 exerted much weaker inhibition. Consecutive deletion of the five inverted CCAAT elements (ICEs) from the topo II alpha promoter reduced both the basal promoter activity and wt p53-induced suppression. Transcription of the minimal promoter (-32 to +90), which contains no ICE, was slightly stimulated by wt or mutant p53 expression. When point mutations were introduced into the most proximal ICE (-68), the inhibitory effect of wt p53 was alleviated and stimulation of topo II alpha expression resulted. Our study suggests that wt p53 functions as a transcriptional repressor of topo II alpha gene expression, possibly through a functional interaction with specific ICEs. Inactivation of wt p53 may reduce normal regulatory suppression of topo II alpha and contribute to abortive cell cycle checkpoints, accelerated cell proliferation, and alterations in genomic stability associated with neoplasia.
机译：DNA拓扑异构酶II（拓扑II）是参与主要细胞功能（如DNA复制，转录，重组和有丝分裂）的必不可少的核酶。尽管升高的topo IIα水平与细胞增殖有关，但野生型（wt）p53抑制了各种生长刺激基因的表达。为了确定p53是否下调topo II alpha基因表达，使用了表达温度敏感p53的鼠细胞系（10）1val。 （10）1val细胞在32°C（具有wt构象的p53）孵育24小时后，与39°C（具有突变构象的p53）相比，其topo IIαmRNA和蛋白质的水平明显降低。通过使用萤光素酶报道质粒来确定p53对人topo IIα基因启动子的作用，该质粒含有不同长度的瞬时被共转染到p53缺陷型（10）1细胞中的topo IIα启动子，以及wt或突变的p53表达质粒。 wt p53从全长（bp -557至+90 bp）topo II alpha启动子的转录以浓度依赖性方式降低15倍，而突变体p53的抑制作用弱得多。从topo II alpha启动子中连续删除五个反向CCAAT元件（ICEs）减少了基础启动子活性和wt p53诱导的抑制。 wt或突变体p53表达略微刺激了不含ICE的最小启动子（-32至+90）的转录。当将点突变引入最接近的ICE（-68）时，wt p53的抑制作用得到缓解，并刺激了topo IIα表达。我们的研究表明，wt p53可能通过与特定ICE的功能相互作用而充当topo II alpha基因表达的转录阻遏物。 wt p53的失活可能会降低对topo IIα的正常调节抑制作用，并有助于流产细胞周期检查点，加速细胞增殖以及与瘤形成相关的基因组稳定性改变。

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