Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1.
Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1.
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E2F1 和 Smac/DIABLO 之间的新联系：促凋亡 Smac/DIABLO 被 E2F1 转录上调
DOI：
10.1093/nar/gkl150
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发表时间：
2006
影响因子：
14.9
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Xie W;Jiang P;Miao L;Zhao Y;Zhimin Z;Qing L;Zhu WG;Wu M
E2F1的表达失调不仅促进S期进入，而且诱导细胞凋亡。虽然已有大量文献证明E2F1能够通过提高ARF活性诱导p53依赖性凋亡，但E2F诱导p53非依赖性凋亡的机制尚不清楚。在这里，我们报告了E2F1可以通过E2F1结合位点BS2（− 542 bp − 535 bp）和BS3（− 200 bp − 193 bp）直接结合并激活线粒体促凋亡基因Smac/DIABLO的启动子。在Smac/DIABLO的激活中，BS2和BS3似乎被E2F1组合使用而不是单独使用。BS2和BS3的激活是E2F1特异性的，因为E2F2和E2F3都不能激活BS2或BS3。使用H1299 ER-E2F1细胞系，其中E2F1活性可以被条件性诱导，E2F1已经显示在4-羟基他莫昔芬处理后在mRNA和蛋白质水平上上调Smac/DIABLO表达，导致增强的E2F1介导的细胞凋亡。然而，通过RNA干扰减少Smac/DIABLO表达显著减少了E2F1诱导的细胞凋亡。这些结果可能提示E2F1通过直接调节其下游线粒体凋亡诱导因子如Smac/DIABLO促进p53非依赖性凋亡的新机制。
Deregulated expression of E2F1 not only promotes S-phase entry but also induces apoptosis. Although it has been well documented that E2F1 is able to induce p53-dependent apoptosis via raising ARF activity, the mechanism by which E2F induces p53-independent apoptosis remains unclear. Here we report that E2F1 can directly bind to and activate the promoter of Smac/DIABLO, a mitochondrial proapoptotic gene, through the E2F1-binding sites BS2 (−542 ∼ −535 bp) and BS3 (−200 ∼ −193 bp). BS2 and BS3 appear to be utilized in combination rather than singly by E2F1 in activation of Smac/DIABLO. Activation of BS2 and BS3 are E2F1-specific, since neither E2F2 nor E2F3 is able to activate BS2 or BS3. Using the H1299 ER-E2F1 cell line where E2F1 activity can be conditionally induced, E2F1 has been shown to upregulate the Smac/DIABLO expression at both mRNA and protein levels upon 4-hydroxytamoxifen treatment, resulting in an enhanced mitochondria-mediated apoptosis. Reversely, reducing the Smac/DIABLO expression by RNA interference significantly diminishes apoptosis induced by E2F1. These results may suggest a novel mechanism by which E2F1 promotes p53-independent apoptosis through directly regulating its downstream mitochondrial apoptosis-inducing factors, such as Smac/DIABLO.
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影响因子：
64.5
作者：
Du, CY;Fang, M;Wang, XD
通讯作者：
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