Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage.
Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage.
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DOI：
10.1093/nar/gkn910
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发表时间：
2009-01
影响因子：
14.9
通讯作者：
Ladner RD
中科院分区：
文献类型：
--
作者：
Wilson PM;Fazzone W;LaBonte MJ;Lenz HJ;Ladner RD
脱氧尿苷三磷酸核苷酸水解酶（dUTH）催化dUTP水解为dUMP和PPi。虽然dUTP是DNA合成中的正常中间体，但它的积累和错误掺入DNA是致命的。重要的是，尿嘧啶错误掺入是由氟尿嘧啶化疗剂（包括5-氟尿嘧啶（5-FU））诱导的细胞毒性的机制，并且dUTR的表达升高与对5-FU治疗的临床应答负相关。在这项研究中，我们进行了第一个功能特性的dUTR启动子，并证明了E2 F-1和Sp1在驱动dUTR表达的作用。我们建立了突变型和野生型p53在调节dUTR启动子活性中的直接作用。用DNA损伤剂奥沙利铂处理HCT 116 p53+/+细胞诱导了dUTR的p53依赖性转录下调，而在同基因无效细胞系中未观察到。奥沙利铂处理诱导p53在dUTR启动子处富集，同时Sp1减少。奥沙利铂对dUTP的抑制促进了dUTP水平的升高，随后加入氟嘧啶可增强dUTP水平。奥沙利铂下调dUTR表达的新观察结果可能为临床上观察到的5-FU和奥沙利铂之间的协同作用提供了机制基础。此外，这些研究提供了第一个证据的直接转录之间的联系的必要酶dUTR和肿瘤抑制基因p53。
Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) catalyzes the hydrolysis of dUTP to dUMP and PPi. Although dUTP is a normal intermediate in DNA synthesis, its accumulation and misincorporation into DNA is lethal. Importantly, uracil misincorporation is a mechanism of cytotoxicity induced by fluoropyrimidine chemotherapeutic agents including 5-fluorouracil (5-FU) and elevated expression of dUTPase is negatively correlated with clinical response to 5-FU-therapy. In this study we performed the first functional characterization of the dUTPase promoter and demonstrate a role for E2F-1 and Sp1 in driving dUTPase expression. We establish a direct role for both mutant and wild-type forms of p53 in modulating dUTPase promoter activity. Treatment of HCT116 p53+/+ cells with the DNA-damaging agent oxaliplatin induced a p53-dependent transcriptional downregulation of dUTPase not observed in the isogenic null cell line. Oxaliplatin treatment induced enrichment of p53 at the dUTPase promoter with a concomitant reduction in Sp1. The suppression of dUTPase by oxaliplatin promoted increased levels of dUTP that was enhanced by subsequent addition of fluoropyrimidines. The novel observation that oxaliplatin downregulates dUTPase expression may provide a mechanistic basis contributing to the synergy observed between 5-FU and oxaliplatin in the clinic. Furthermore, these studies provide the first evidence of a direct transcriptional link between the essential enzyme dUTPase and the tumor suppressor p53.
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影响因子：
11.4
作者：
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