Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis
Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis
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DOI：
10.1038/onc.2009.425
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发表时间：
2010-03-04
期刊：
影响因子：
8
通讯作者：
Bykov, V. J. N.
中科院分区：
文献类型：
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作者：
Lambert, J. M. R.;Moshfegh, A.;Bykov, V. J. N.
低分子量化合物PRIMA-1（MET）重新激活突变型p53，并触发人类肿瘤细胞中突变型p53依赖性凋亡。我们研究了PRIMA-1（MET）对整体基因表达的影响，使用微阵列分析表达His 273突变型p53的Saos-2细胞和亲本p53无效Saos-2细胞。PRIMA-1（MET）的影响转录的突变体p53表达细胞中的基因数量显着大于p53空细胞相比。以突变型p53依赖性方式受PRIMA-1（MET）影响的基因包括细胞周期调节因子GADD 45 B和14-3-3 γ以及促凋亡Noxa。一些受影响的基因是已知的p53靶基因和/或含有p53 DNA结合基序。我们还发现了突变型p53依赖性的细胞骨架破坏，以及XBP 1基因的转录激活及其mRNA的切割（内质网应激的标志物）。我们的数据表明，PRIMA-1（MET）通过多种转录依赖性和非依赖性途径诱导细胞凋亡。这种导致细胞凋亡的多个途径的整合参与与突变型p53野生型特性的恢复一致，并且可能降低PRIMA-1（MET）临床应用中耐药性发展的风险。Oncogene（2010）29，1329-1338; doi：10.1038/onc.2009.425; 2009年11月30日在线发表
The low molecular weight compound PRIMA-1(MET) reactivates mutant p53 and triggers mutant p53-dependent apoptosis in human tumor cells. We investigated the effect of PRIMA-1(MET) on global gene expression using microarray analysis of Saos-2 cells expressing His273 mutant p53 and parental p53 null Saos-2 cells. PRIMA-1(MET) affected transcription of a significantly larger number of genes in the mutant p53-expressing cells compared to the p53 null cells. Genes affected by PRIMA-1(MET) in a mutant p53-dependent manner include the cell-cycle regulators GADD45B and 14-3-3 gamma and the pro-apoptotic Noxa. Several of the affected genes are known p53 target genes and/or contain p53 DNA-binding motifs. We also found mutant p53-dependent disruption of the cytoskeleton, as well as transcriptional activation of the XBP1 gene and cleavage of its mRNA, a marker for endoplasmic reticulum stress. Our data show that PRIMA-1(MET) induces apoptosis through multiple transcription-dependent and -independent pathways. Such integral engagement of multiple pathways leading to apoptosis is consistent with restoration of wild-type properties to mutant p53 and is likely to reduce the risk of drug resistance development in clinical applications of PRIMA-1(MET). Oncogene (2010) 29, 1329-1338; doi:10.1038/onc.2009.425; published online 30 November 2009