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首页> 外文期刊>Cell cycle >Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation.
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Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation.

机译:多种独立于p53的基因沉默机制定义了细胞对p53激活的反应。

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摘要

The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 repressor MDM2, varies widely among human cancer-derived cell types. Whereas HCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 leukemia cells undergo rapid apoptosis and other cell lines show an intermediate response. We found that the expression of the p53 target genes p21, 14-3-3sigma and the microRNA miR-34a correlates tightly with the cell fate choice adopted. All three genes were strongly induced in arresting cells, but silenced in cells undergoing Nutlin-3-induced apoptosis. In contrast, key apoptotic p53 target genes were equally expressed in arresting and apoptotic cells. Interestingly, we establish that miR-34a cooperates with p21 and 14-3-3sigma to override the apoptotic signals generated by p53 activation. Strikingly, p53 binding to chromatin and p53-mediated recruitment of certain coactivators to all three target loci does not vary among cell types. Instead, the cell type-specific silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma promoter DNA methylation and reduced processing of the miR-34a primary transcript. Thus, p53-independent events regulating expression of protein-coding genes and microRNAs within the network can define the cellular outcome of p53 activation.
机译:对Nutlin-3(p53阻遏物MDM2的小分子抑制剂)的细胞反应在人类癌症衍生的细胞类型中差异很大。 HCT116大肠癌细胞表现出持续的细胞周期停滞,而BV173白血病细胞则经历快速凋亡,而其他细胞系则表现出中等反应。我们发现,p53靶基因p21、14-3-3sigma和microRNA miR-34a的表达与所采用的细胞命运选择紧密相关。所有这三个基因在阻滞细胞中被强烈诱导,但是在经历Nutlin-3诱导的细胞凋亡的细胞中却沉默了。相反,关键的凋亡p53靶基因在阻滞细胞和凋亡细胞中均表达。有趣的是,我们建立了miR-34a与p21和14-3-3sigma协同作用,以覆盖由p53激活产生的凋亡信号。令人惊讶的是,p53与染色质的结合以及某些共激活因子的p53介导募集到所有三个靶基因座在不同细胞类型之间没有差异。相反,这些基因的细胞类型特异性沉默是由于增强的p21 mRNA降解,14-3-3sigma启动子DNA甲基化和miR-34a初级转录物的加工减少。因此,调节网络中蛋白质编码基因和microRNA表达的p53独立事件可以定义p53激活的细胞结果。

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