Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation

作者：Marzi Matteo J; Puggioni Eleonora M R; Dall' Olio Valentina; Bucci Gabriele; Bernard Loris; Bianchi Fabrizio; Crescenzi Marco; Di Fiore Pier Paolo; Nicassio Francesco^*

来源：The Journal of Cell Biology, 2012, 199(1): 77-95.

DOI：10.1083/jcb.201206033

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.

• 出版日期2012-10-1