Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes
Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes
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DOI：
10.1038/sj.onc.1207553
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发表时间：
2004-05-27
期刊：
影响因子：
8
通讯作者：
Deb, S
中科院分区：
文献类型：
--
作者：
Scian, MJ;Stagliano, KER;Deb, S
我们使用几种肿瘤衍生突变体研究了突变体 p53 介导的肿瘤发生机制。使用集落形成测定，我们发现与载体相比，大多数突变体增加了形成的集落数量。肿瘤来源的 p53 突变体的表达增加了细胞生长速率，表明 p53 突变体具有“功能获得”特性。我们研究了基因表达亲。表达肿瘤来源的 p53-D281G 的细胞来鉴定被突变体 p53 反式激活的基因。我们报告了天冬酰胺合成酶和人端粒酶逆转录酶这两个基因的反式激活。实时定量 PCR 证实了这种上调。瞬时转染启动子测定证实肿瘤来源的 p53 突变体显着反式激活这些启动子。电泳迁移率变动分析表明，肿瘤来源的 p53 突变体不能与野生型 p53 共有序列结合。这里提出的结果提供了突变 p53 介导的反式激活的可能机制的一些证据。
We have studied the mechanism of mutant p53-mediated oncogenesis using several tumor-derived mutants. Using a colony formation assay, we found that the majority of the mutants increased the number of colonies formed compared to the vector. Expression of tumor-derived p53 mutants increases the rate of cell growth, suggesting that the p53 mutants have 'gain of function' properties. We have studied the gene expression pro. le of cells expressing tumor-derived p53-D281G to identify genes transactivated by mutant p53. We report the transactivation of two genes, asparagine synthetase and human telomerase reverse transcriptase. Quantitative real-time PCR confirms this upregulation. Transient transfection promoter assays verify that tumor-derived p53 mutants trans-activate these promoters significantly. An electrophoretic mobility shift assay shows that tumor-derived p53-mutants cannot bind to the wild-type p53 consensus sequence. The results presented here provide some evidence of a possible mechanism for mutant p53-mediated transactivation.