Mutant p53 cooperates with ETS2 to promote etoposide resistance
Mutant p53 cooperates with ETS2 to promote etoposide resistance
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DOI：
10.1101/gad.181685.111
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发表时间：
2012-04-15
影响因子：
10.5
通讯作者：
Martinez, Luis A.
中科院分区：
文献类型：
--
作者：
Do, Phi M.;Varanasi, Lakshman;Martinez, Luis A.
突变体 p53 (mtp53) 通过多种机制促进化疗耐药，包括禁用促凋亡蛋白和调节基因表达。 mtp53 结合的全基因组分析比较表明，ETS 结合位点基序 (EBS) 在预测的 mtp53 结合位点中普遍存在。我们证明 mtp53 通过启动子中的 EBS 调节基因表达，而 ETS2 介导与该基序的相互作用。重要的是，我们确定了 TDP2（一种参与修复依托泊苷引起的 DNA 损伤的 5'-酪氨酰 DNA 磷酸二酯酶）作为 mtp53 的转录靶标。我们证明，抑制 TDP2 可使表达 mtp53 的细胞对依托泊苷敏感，并且 mtp53 和 TDP2 在人类肺癌中经常过度表达；因此，我们的分析确定了 mtp53 功能获得活性的潜在“可药物”成分。
Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable'' component of mtp53's gain-of-function activity.