c-Myc-regulated microRNAs modulate E2F1 expression
c-Myc-regulated microRNAs modulate E2F1 expression
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DOI：
10.1038/nature03677
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发表时间：
2005-06-09
期刊：
影响因子：
64.8
通讯作者：
Mendell, JT
中科院分区：
文献类型：
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作者：
O'Donnell, KA;Wentzel, EA;Mendell, JT
microRNA（miRNA）是21-23个核苷酸RNA分子，可调节目标信使RNAS1的稳定性或翻译效率。 miRNA具有多种功能，包括调节细胞分化，增殖和凋亡（2）。尽管严格的组织和发育阶段特异性表达对于适当的miRNA功能至关重要，但尚未鉴定出调节miRNA的哺乳动物转录因子。原始癌基因C-MYC编码调节细胞增殖，生长和凋亡的转录因子（3）。 C-MYC的表达或功能失调是人类恶性肿瘤中最常见的异常之一（4）。在这里，我们表明C-MYC激活了13人类染色体上六个miRNA的簇的表达。染色质免疫沉淀实验表明，C-MYC直接与该基因座结合。转录因子E2F1是促进细胞周期进程的C-MYC的附加靶标（5-7）。我们发现，在miR-17-5p和miR-20a的集群中，E2F1的表达受到两个miRNA的负调节。这些发现扩大了C-MYC目标基因网络中已知的转录本类别，并揭示了一种机制，C-MYC同时激活E2F1转录并限制其翻译，从而允许紧密控制的增殖信号。
MicroRNAs ( miRNAs) are 21 - 23 nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs1. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis(2). Although strict tissue- and developmental-stage-specific expression is critical for appropriate miRNA function, mammalian transcription factors that regulate miRNAs have not yet been identified. The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth and apoptosis(3). Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy(4). Here we show that c-Myc activates expression of a cluster of six miRNAs on human chromosome 13. Chromatin immunoprecipation experiments show that c-Myc binds directly to this locus. The transcription factor E2F1 is an additional target of c-Myc that promotes cell cycle progression(5-7). We find that expression of E2F1 is negatively regulated by two miRNAs in this cluster, miR-17-5p and miR-20a. These findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.