Microarray analysis of p53-dependent gene expression in response to hypoxia and DNA damage
Microarray analysis of p53-dependent gene expression in response to hypoxia and DNA damage
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DOI：
10.4161/cbt.6.12.5330
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发表时间：
2007-12-01
影响因子：
3.6
通讯作者：
El-Deiry, Wafik S.
中科院分区：
文献类型：
--
作者：
Corn, Paul G.;El-Deiry, Wafik S.
缺氧是实体瘤的常见特征，并促进对诱导DNA损伤的癌症疗法的细胞凋亡的抗性。然而，这种耐药性的机制仍不清楚。由于p53通路的激活在确定细胞是否响应DNA损伤而发生凋亡中起着重要作用，因此我们对DNA损伤与缺氧相结合引起的p53依赖性基因表达变化进行了微阵列分析。当H460人肺癌细胞系用缺氧和依托泊苷（一种诱导双链DNA断裂的化疗剂）处理时，显性转录反应以p53依赖的方式受DNA损伤的调节。然而，有趣的是，DNA损伤结合缺氧调节p53反应的强度和下游靶基因的组成。例如，存在已知的p53靶基因如p21和gadd 45的协同激活，以及其他潜在的新p53靶基因包括Rad和I-Rel的独特诱导。此外，抑制基因的分析支持缺氧中c-Myc信号传导拮抗作用的模型，该模型基于几个已知c-Myc靶基因的下调和c-Myc拮抗剂Mxi 1的诱导。这些数据表明，缺氧和DNA损伤的组合通过引发有利于细胞周期停滞而不是细胞凋亡的转录应答来促进对治疗的抗性。
Hypoxia is a common feature of solid tumors and promotes resistance to apoptosis from cancer therapies that induce DNA damage. The mechanism for this resistance, however, remains unclear. Since activation of the p53 pathway plays a major role in determining whether cells undergo apoptosis in response to DNA damage, we performed a microarray analysis of p53-dependent gene expression changes in response to DNA damage combined with hypoxia. When the H460 human lung cancer cell line was treated with hypoxia and etoposide, a chemotherapy agent that induces double-stranded DNA breaks, the dominant transcriptional response was regulated by DNA damage in a p53-dependent manner. Interestingly, however, DNA damage combined with hypoxia modulated both the intensity of the p53 response and the composition of downstream target genes. For example, there was synergistic activation of known p53 target genes such as p21 and gadd45, and the unique induction of other potentially novel p53 target genes including Rad and I-Rel. In addition, analysis of repressed genes supported a model for antagonism of c-Myc signaling in hypoxia, based on the downregulation of several known c-Myc target genes and the induction of Mxi1, a c-Myc antagonist. These data suggest a hypothesis that the combination of hypoxia and DNA damage promotes resistance to therapy by eliciting a transcriptional response that favors cell cycle arrest over apoptosis.