An E2F/miR-20a autoregulatory feedback loop
An E2F/miR-20a autoregulatory feedback loop
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DOI：
10.1074/jbc.m608939200
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发表时间：
2007-01-26
影响因子：
4.8
通讯作者：
Chartrand, Pascal
中科院分区：
文献类型：
--
作者：
Sylvestre, Yannick;De Guire, Vincent;Chartrand, Pascal
E2F转录因子家族在细胞周期和细胞凋亡的调控中起着至关重要的作用。虽然E2F1-3的活性受到视网膜母细胞瘤蛋白家族的严格控制，但这些因子的表达也在转录水平、翻译后修饰和蛋白质稳定性方面受到调节。最近，人们发现了一种新的E2FS调控水平，其中来自mir-17-92簇的microRNAs(MiRNAs)影响E2F1 mRNA的翻译。我们现在报道，mir-17-92簇的成员miR-20a通过3‘-非翻译区的结合位点调控E2F2和E2F3 mRNAs的翻译。我们还发现，内源E2F1、E2F2和E2F3直接与mir-17-92簇的启动子结合激活其转录，表明E2F因子与mir-17-92簇的miRNAs之间存在自我调节反馈环。我们的数据还表明miR-20a具有抗凋亡作用，因为过表达miR-20a减少了前列腺癌细胞系的凋亡，而反义寡核苷酸抑制miR-20a会导致阿霉素治疗后细胞死亡增加。MiR-20a的这种抗凋亡作用可能解释了mir-17-92簇的一些致癌能力。这些结果表明，E2F1-3和miR-20a之间的自身调节对于防止E2F1-3的异常积聚具有重要意义，并可能在细胞增殖和凋亡的调节中发挥作用。
The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1-3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17 - 92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17 - 92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3'-untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17 - 92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17 - 92 cluster. Our data also point toward an antiapoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17 - 92 cluster. Altogether, these results suggest that the autoregulation between E2F1-3 and miR-20a is important for preventing an abnormal accumulation of E2F1-3 and may play a role in the regulation of cellular proliferation and apoptosis.