Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis
Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis
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DOI：
10.1038/sj.cdd.4402022
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Wiman, K. G.
中科院分区：
文献类型：
--
作者：
Liu, T.;Laurell, C.;Wiman, K. G.
p53触发细胞凋亡以响应细胞应激。我们分析了p53依赖的基因和蛋白表达在缺氧使用野生型p53携带或p53无效HCT 116结肠癌细胞。缺氧诱导p53蛋白水平和p53依赖的细胞凋亡。cDNA微阵列分析表明，只有有限数量的基因调节p53在缺氧。大多数经典的p53靶基因没有上调。然而，我们发现Fas/CD95以p53依赖的方式在缺氧反应中被显著诱导，以及几个新的p53靶基因，包括ANXA 1，DDIT 3/GADD 153（CHOP），SEL 1L和SMURF 1。使用抗Fas阻断抗体或半胱天冬酶8抑制剂破坏Fas/CD95信号传导可消除p53诱导的缺氧性细胞凋亡。我们的结论是，缺氧触发p53依赖的基因表达模式不同于其他应激剂诱导的，Fas/CD95是一个关键的调节p53依赖的细胞凋亡缺氧。
p53 triggers apoptosis in response to cellular stress. We analyzed p53-dependent gene and protein expression in response to hypoxia using wild-type p53-carrying or p53 null HCT116 colon carcinoma cells. Hypoxia induced p53 protein levels and p53-dependent apoptosis in these cells. cDNA microarray analysis revealed that only a limited number of genes were regulated by p53 upon hypoxia. Most classical p53 target genes were not upregulated. However, we found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/ GADD153 (CHOP), SEL1L and SMURF1. Disruption of Fas/CD95 signalling using anti-Fas-blocking antibody or a caspase 8 inhibitor abrogated p53-induced apoptosis in response to hypoxia. We conclude that hypoxia triggers a p53-dependent gene expression pattern distinct from that induced by other stress agents and that Fas/CD95 is a critical regulator of p53-dependent apoptosis upon hypoxia.