Department of Biochemistry, University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Genes Dev. 2012 Apr 15;26(8):830-45. doi: 10.1101/gad.181685.111.
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.
突变型 p53（mtp53）通过多种机制促进化疗耐药性，包括失活促凋亡蛋白和调节基因表达。对 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 结合位点内普遍存在。我们证明 mtp53 通过启动子中的 EBS 调节基因表达，并且 ETS2 介导与该基序的相互作用。重要的是，我们鉴定了 TDP2，一种参与修复依托泊苷引起的 DNA 损伤的 5'-酪氨酸 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表达；因此，我们的分析确定了 mtp53 获得性功能的潜在“可药物化”成分。
