TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death
TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death
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DOI：
10.4161/cbt.7.12.7460
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发表时间：
2008-12-01
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：
Kuribayashi, Kageaki;Krigsfeld, Gabriel;El-Deiry, Wafik S.
我们已经确定TNFSF10(TRAIL)是P53转录的靶基因。人TNFSF10启动子区域有两个p53 DNA结合位点，分别位于转录起始点上游346和625个碱基。表达人P53基因的腺病毒(Ad-P53)诱导HCT116人结肠癌细胞TRAIL基因和蛋白表达。人TRAIL启动子报告分析显示，与对照组相比，携带两个P53 DNA结合基序的启动子载体在Ad-P53感染后荧光素酶活性增加。在HCT116细胞中，通过siRNA抑制TNFSF10的基因沉默抑制了caspase3和7的活性，即使在用DNA破坏的化疗药物阿霉素治疗后也是如此。阿霉素处理的乳腺癌细胞TRAIL蛋白表达增加。在体内，5-氟尿嘧啶诱导小鼠自然杀伤细胞在24小时内表达TRAIL。化疗后自然杀伤细胞中依赖于P53的TRAIL诱导提供了肿瘤抑制因子P53与癌症治疗期间宿主免疫反应以及旁分泌介导的细胞-外源性死亡反应之间的联系。我们的发现为p53依赖的细胞死亡和肿瘤抑制的信号转导提供了新的机制见解，包括体内宿主免疫系统和自然杀伤细胞参与化疗的抗肿瘤效果。
We have identified TNFSF10 (TRAIL) as a p53-transcriptional target gene. There are two p53 DNA-binding sites in the human TNFSF10 promoter region, at 346 and 625 bp upstream of the transcription start site. A human p53-expressing adenovirus (Ad-p53) induced TRAIL mRNA and protein expression in HCT116 p53(-/-) human colon cancer cells. A human TRAIL-promoter reporter assay showed increased luciferase activity with the promoter vector that contains two p53 DNA-binding motifs, following Ad-p53 infection, compared to the control adenovirus infection. Using HCT116 cells, gene silencing of TNFSF10 by siRNA suppressed caspase 3 and 7 activity, even after treatment with the DNA-damaging chemotherapeutic agent adriamycin. TRAIL protein expression was elevated in adriamycin-treated breast cancer cells. In vivo, TRAIL expression was induced in mouse natural killer cells at 24 hours after systemic treatment with 5-Fluorouracil. p53-dependent TRAIL induction in natural killer cells after chemotherapy exposure provides a link between the tumor suppressor p53 and the host immune response during cancer therapy as well as a paracrine-mediated cell-extrinsic death response. Our findings provide new mechanistic insights into the signaling of p53-dependent cell death and tumor suppression, including the involvement of the host immune system and natural killer cells in vivo in the anti-tumor efficacy of chemotherapy.