Mutant p53R175H upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells
Mutant p53R175H upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells
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DOI：
10.1038/cdd.2010.94
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发表时间：
2011-02-01
影响因子：
12.4
通讯作者：
Rotter, V.
中科院分区：
文献类型：
--
作者：
Kogan-Sakin, I.;Tabach, Y.;Rotter, V.
p53肿瘤抑制基因的一个等位基因内的突变可以显性失活的方式使剩余的野生型等位基因失活，并且在某些情况下可以发挥额外的致癌活性，称为突变型p53“功能获得”（GOF）。为了研究 p53 突变在前列腺癌中的作用并区分突变 p53 的显性失活效应和 GOF 活性，我们使用微阵列测量了表达野生型、失活 p53 或突变 p53 的三种永生化前列腺上皮培养物的表达谱。对这些基因表达谱的分析表明，失活的 p53 和 p53(R175H) 突变体表达均导致细胞周期进展基因的上调。第二组仅由突变体 p53(R175H) 上调，主要富集发育基因。这组基因包括 Twist1，它是转移和上皮间质转化 (EMT) 的调节因子。 Twist1 水平在转移性前列腺癌衍生细胞系 DU145、永生化肺成纤维细胞和肺癌样本子集中也有所升高，所有这些均以突变 p53 依赖性方式升高。携带永生化上皮细胞的p53（R175H）突变体表现出EMT的典型特征，例如间充质标记物的高表达、上皮标记物的低表达以及体外侵袭特性增强。 p53(R175H) 突变体诱导 Twist1 表达的机制涉及减轻表观遗传抑制。我们的数据表明，癌细胞中 p53 突变后 Twist1 表达可能上调。细胞死亡与分化 (2011) 18, 271-281; doi：10.1038/cdd.2010.94； 2010 年 8 月 6 日在线发布
A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53(R175H) mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53(R175H), was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53(R175H) mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53(R175H) mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells. Cell Death and Differentiation (2011) 18, 271-281; doi: 10.1038/cdd.2010.94; published online 6 August 2010