Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation.
Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation.
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DOI：
10.1083/jcb.201206033
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Nicassio F
中科院分区：
文献类型：
--
作者：
Marzi MJ;Puggioni EM;Dall'Olio V;Bucci G;Bernard L;Bianchi F;Crescenzi M;Di Fiore PP;Nicassio F
Rb-E2 F的转录调节和microRNA的转录后调节控制细胞周期和DNA复制基因的表达并限制细胞增殖。与癌症相关的microRNA（miRNA）表达缺失通过很大程度上未知的机制导致增殖优势和侵袭行为。在这里，我们利用一个模型系统，重演生理终末分化及其逆转癌基因表达分析协调mRNA/miRNA的反应。E1 A癌基因迫使肌管重新进入细胞周期，这与mRNA/miRNA调节模式相关，该模式与成肌细胞分化成肌管期间诱导的模式基本上是相互的。E1 A诱导的mRNA反应主要依赖于视网膜母细胞瘤蛋白（Rb）。相反，miRNA反应主要是Rb独立的，并通过组织特异性因子和Myc发挥作用。这些miRNAs的一个子集（miR-1、miR-34、miR-22、miR-365、miR-29、miR-145和Let-7）显示协同靶向Rb依赖性细胞周期和DNA复制mRNA。因此，通过Rb-E2 F的转录调控和通过miRNA的转录后调控的双重水平的调节赋予细胞周期控制的鲁棒性，并提供了分子基础，以了解癌症中的miRNA颠覆的作用。
Transcriptional regulation by Rb–E2F and posttranscriptional regulation by microRNAs control the expression of cell cycle and DNA replication genes and restrict cellular proliferation. The cancer-associated loss of microRNA (miRNA) expression leads to a proliferative advantage and aggressive behavior through largely unknown mechanisms. Here, we exploit a model system that recapitulates physiological terminal differentiation and its reversal upon oncogene expression to analyze coordinated mRNA/miRNA responses. The cell cycle reentry of myotubes, forced by the E1A oncogene, was associated with a pattern of mRNA/miRNA modulation that was largely reciprocal to that induced during the differentiation of myoblasts into myotubes. The E1A-induced mRNA response was preponderantly Retinoblastoma protein (Rb)-dependent. Conversely, the miRNA response was mostly Rb-independent and exerted through tissue-specific factors and Myc. A subset of these miRNAs (miR-1, miR-34, miR-22, miR-365, miR-29, miR-145, and Let-7) was shown to coordinately target Rb-dependent cell cycle and DNA replication mRNAs. Thus, a dual level of regulation—transcriptional regulation via Rb–E2F and posttranscriptional regulation via miRNAs—confers robustness to cell cycle control and provides a molecular basis to understand the role of miRNA subversion in cancer.
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影响因子：
64.8
作者：
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通讯作者：
Bartel, David P.
影响因子：
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影响因子：
30.8
作者：
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通讯作者：
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