Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation.
J Cell Biol, 2012/10/01;199(1):77-95.
Marzi MJ[1], Puggioni EM, Dall'Olio V, Bucci G, Bernard L, Bianchi F, Crescenzi M, Di Fiore PP, Nicassio F
Affiliations
PMID: 23027903DOI: 10.1083/jcb.201206033
Impact factor: 8.077
Abstract
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.
MeSH terms
Adenovirus E1A Proteins; Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; E2F Transcription Factors; HEK293 Cells; Humans; Mice; MicroRNAs; Myoblasts; RNA, Messenger; Retinoblastoma Protein
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