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.

Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation / M.J. Marzi, E.M.R. Puggioni, V. Dall'olio, G. Bucci, L. Bernard, F. Bianchi, M. Crescenzi, P.P. Di Fiore, F. Nicassio. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 199:1(2012 Oct 01), pp. 77-95. [10.1083/jcb.201206033]

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

P.P. Di Fiore
Penultimo
;
2012

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.
Settore MED/04 - Patologia Generale
1-ott-2012
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/210194
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