Interferons α and γ induce p53-dependent and p53-independent apoptosis, respectively
Interferons α and γ induce p53-dependent and p53-independent apoptosis, respectively
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DOI：
10.1038/sj.onc.1208204
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发表时间：
2005-01-20
期刊：
影响因子：
8
通讯作者：
Chelbi-Alix, MK
中科院分区：
文献类型：
--
作者：
Porta, C;Hadj-Slimane, R;Chelbi-Alix, MK
I 型干扰素 (IFN) 增强肿瘤抑制基因 p53 的转录。为了阐明介导 IFN 诱导细胞凋亡的分子机制，我们分析了 I 型 (IFNα) 或 II 型 (IFNgamma) 治疗与 p53 状态相关的程序性细胞死亡。在两种细胞系（MCF-7、SKNSH）中，IFNα（而非 IFNγ）以 p53 依赖性方式增强细胞凋亡。此外，只有 IFNα 上调 p53 以及 p53 靶基因（Noxa、Mdm2 和 CD95）。 ZB4（一种抗 CD95 抗体）存在时，细胞凋亡对 IFNα 的反应减弱，表明 CD95 参与了这一过程。当p53被E6病毒蛋白或p53突变体的表达失活时，IFNα诱导的细胞凋亡和p53靶基因的上调被消除。总而言之，这些结果表明 p53 在 IFNα 诱导的细胞凋亡反应中发挥着关键作用。 IFNα诱导的PML无法将p53募集到核体中，并且siRNA对其的下调不会改变CD95的表达。相反，IFNγ诱导的细胞凋亡不依赖于p53。 CD95 和 IFN 调节因子 1 (IRF1) 直接被该细胞因子上调。 ZB4 存在时，对 IFNgamma 的细胞凋亡反应会降低，IRF1 siRNA 会显着减弱，这表明 CD95 和 IRF1 均参与 IFNgamma 诱导的细胞凋亡反应。综上所述，这些结果表明，在两种不同的细胞系中，IFNα和IFNγ分别诱导p53依赖性-非依赖性细胞凋亡。
Type I interferon (IFN) enhances the transcription of the tumor suppressor gene p53. To elucidate the molecular mechanism mediating IFN-induced apoptosis, we analysed programmed cell death in response to type I (IFNalpha) or type II (IFNgamma) treatment in relation to p53 status. In two cell lines (MCF-7, SKNSH), IFNalpha, but not IFNgamma, enhanced apoptosis in a p53-dependent manner. Furthermore, only IFNalpha upregulated p53 as well as p53 target genes (Noxa, Mdm2 and CD95). The apoptotic response to IFNalpha decreased in the presence of ZB4, an anti-CD95 antibody, suggesting that CD95 is involved in this process. When p53 was inactivated by the E6 viral protein or the expression of a p53 mutant, IFNalpha-induced apoptosis and p53 target genes upregulation were abrogated. Altogether these results demonstrate that p53 plays a pivotal role in the IFNalpha-induced apoptotic response. IFNalpha-induced PML was unable to recruit p53 into nuclear bodies and its downregulation by siRNA did not alter CD95 expression. In contrast, IFNgamma-induced apoptosis is p53-independent. CD95 and IFN-regulatory factor 1 (IRF1) are directly upregulated by this cytokine. Apoptotic response to IFNgamma is decreased in the presence of ZB4 and strongly diminished by IRF1 siRNA, implicating both CD95 and IRF1 in IFNgamma-induced apoptotic response. Taken together, these results show that in two different cell lines, IFNalpha and IFNgamma, induce p53-dependent - independent apoptosis, respectively.