title: Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation.
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.
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.
authors.forename: Matteo J
authors.initials: MJ
authors.lastname: Marzi
authors.forename: Eleonora M R
authors.initials: EM
authors.lastname: Puggioni
authors.forename: Valentina
authors.initials: V
authors.lastname: Dall'Olio
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bucci
authors.forename: Loris
authors.initials: L
authors.lastname: Bernard
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bianchi
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicassio
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017500:Adenovirus E1A Proteins; D050684:E2F Transcription Factors; D035683:MicroRNAs; D012333:RNA, Messenger; D016160:Retinoblastoma Protein