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Wild-type p53 and p73 negatively regulate expression of proliferation related genes

机译：野生型p53和p73负调控增殖相关基因的表达

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When normal cells come under stress, the wild-type (WT) p53 level increases resulting in the regulation of gene expression responsible for growth arrest or apoptosis. Here we show that elevated levels of WT p53 or its homologue, p73, inhibit expression of a number of cell cycle regulatory and growth promoting genes. Our analysis also identified a group of genes whose expression is differentially regulated by WT p53 and p73. We have infected p53-null H1299 human lung carcinoma cells with recombinant adenoviruses expressing WT p53, p73 or β-galactosidase, and have undertaken microarray hybridization analyses to identify genes whose expression profile is altered by p53 or p73. Quantitative real-time PCR verified the repression of E2F-5, centromere protein A and E, minichromosome maintenance proteins (MCM)-2, -3, -5, -6 and -7 and human CDC25B after p53 expression. 5-Fluorouracil treatment of colon carcinoma HCT116 cells expressing WT p53 results in a reduction of the cyclin B2 protein level suggesting that DNA damage may indeed cause repression of these genes. Transient transcriptional assays verified that WT p53 repressed promoters of a number of these genes. Interestingly, a gain-of-function p53 mutant instead upregulated a number of these promoters in transient transfection. Using promoter deletion mutants of MCM-7 we have found that WT p53-mediated repression needs a minimal promoter that contains a single E2F site and surrounding sequences. However, a single E2F site cannot be significantly repressed by WT p53. Many of the genes identified are also repressed by p21. Thus, our work shows that WT p53 and p73 repress a number of growth-related genes and that in many instances this repression may be through the induction of p21.
机译：当正常细胞受到压力时，野生型（WT）p53水平增加，导致负责生长停滞或凋亡的基因表达的调节。在这里我们显示，WT p53或其同系物p73的水平升高，抑制了许多细胞周期调控和生长促进基因的表达。我们的分析还确定了一组基因，其表达受野生型p53和p73差异调节。我们已用表达WT p53，p73或β-半乳糖苷酶的重组腺病毒感染了p53无效的H1299人肺癌细胞，并进行了微阵列杂交分析以鉴定其表达谱被p53或p73改变的基因。实时定量PCR验证了p53表达后E2F-5，着丝粒蛋白A和E，微染色体维持蛋白（MCM）-2，-3，-5，-6和-7和人CDC25B的抑制。 5-氟尿嘧啶处理表达WT p53的结肠癌HCT116细胞导致细胞周期蛋白B2蛋白水平降低，这表明DNA损伤确实可能导致这些基因的阻遏。瞬时转录分析证实了WT p53抑制了许多这些基因的启动子。有趣的是，在瞬时转染中，功能获得性p53突变体上调了许多这些启动子。使用MCM-7的启动子缺失突变体，我们发现WT p53介导的阻遏需要一个包含单个E2F位点和周围序列的最小启动子。但是，WT p53不能显着抑制单个E2F位点。 p21也抑制了许多鉴定出的基因。因此，我们的工作表明，WT p53和p73抑制许多与生长相关的基因，并且在许多情况下，这种抑制可能是通过诱导p21来实现的。

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