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首页> 外文期刊>Nucleic Acids Research >Cancer-derived p53 mutants suppress p53-target gene expression - potential mechanism for gain of function of mutant p53
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Cancer-derived p53 mutants suppress p53-target gene expression - potential mechanism for gain of function of mutant p53

机译：癌症衍生的p53突变体抑制p53-靶基因表达-突变体p53功能获得的潜在机制

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摘要

Tumour-derived p53 mutants are thought to have acquired 'gain-of-function' properties that contribute to oncogenicity. We have tested the hypothesis that p53 mutants suppress p53-target gene expression, leading to enhanced cellular growth. Silencing of mutant p53 expression in several human cell lines was found to lead to the upregulation of wild-type p53-target genes such as p21, gadd45, PERP and PTEN. The expression of these genes was also suppressed in H1299-based isogenic cell lines expressing various hot-spot p53 mutants, and silencing of mutant p53, but not TAp73, abrogated the suppression. Consistently, these hot-spot p53 mutants were able to suppress a variety of p53-target gene promoters. Analysis using the proto-type p21 promoter construct indicated that the p53-binding sites are dispensable for mutant p53-mediated suppression. However, treatment with the histone deacetylase inhibitor trichostatin-A resulted in relief of mutant p53-mediated suppression, suggesting that mutant p53 may induce hypo-acetylation of target gene promoters leading to the suppressive effects. Finally, we show that stable down-regulation of mutant p53 expression resulted in reduced cellular colony growth in human cancer cells, which was found to be due to the induction of apoptosis. Together, the results demonstrate another mechanism through which p53 mutants could promote cellular growth.
机译：肿瘤来源的p53突变体被认为具有“致癌性”的“功能获得”特性。我们已经测试了p53突变体抑制p53靶基因表达，从而导致细胞生长增强的假说。发现在几种人类细胞系中突变p53表达的沉默导致野生型p53靶基因（如p21，gadd45，PERP和PTEN）的上调。这些基因的表达在表达各种热点p53突变体的基于H1299的等基因细胞系中也受到抑制，并且突变体p53（而不是TAp73）的沉默消除了这种抑制作用。一致地，这些热点p53突变体能够抑制多种p53靶基因启动子。使用原型p21启动子构建体的分析表明，p53结合位点对于突变体p53介导的抑制是必不可少的。但是，用组蛋白脱乙酰基酶抑制剂曲古抑菌素-A处理可减轻突变体p53介导的抑制作用，这表明突变体p53可能诱导靶基因启动子的低乙酰化，从而产生抑制作用。最后，我们表明稳定的下调突变体p53表达导致人类癌细胞中细胞集落的减少，这是由于凋亡的诱导。在一起，结果表明p53突变体可以促进细胞生长的另一种机制。

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