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 14-3-3gamma 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).

中文翻译：

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PRIMA-1MET对p53的重新激活可诱导多种信号通路收敛于细胞凋亡。

低分子量化合物PRIMA-1（MET）在人类肿瘤细胞中重新激活突变型p53，并触发突变型p53依赖性细胞凋亡。我们使用表达His273突变p53和亲本p53空Saos-2细胞的Saos-2细胞进行微阵列分析，调查了PRIMA-1（MET）对全局基因表达的影响。与p53无效细胞相比，PRIMA-1（MET）影响了突变p53表达细胞中大量基因的转录。受PRIMA-1（MET）突变的p53依赖的基因包括细胞周期调节因子GADD45B和14-3-3γ和促凋亡的Noxa。一些受影响的基因是已知的p53靶基因和/或包含p53 DNA结合基序。我们还发现了突变的p53依赖的细胞骨架破坏，以及XBP1基因的转录激活和其mRNA的切割，内质网应激的标记。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。导致细胞凋亡的多种途径的这种整体参与与突变体p53的野​​生型特性的恢复一致，并有可能降低PRIMA-1（MET）临床应用中耐药性发展的风险。