An intronic microRNA links Rb/E2F and EGFR signaling

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• dc.contributor.author Truscott, Maryca
• dc.contributor.author Islam, Abul, 1978-ca
• dc.contributor.author Lightfoot, Jamesca
• dc.contributor.author López Bigas, Núriaca
• dc.contributor.author Frolov, Maxim V.ca
• dc.date.accessioned 2015-04-29T07:24:04Z
• dc.date.available 2015-04-29T07:24:04Z
• dc.date.issued 2014ca
• dc.description.abstract The importance of microRNAs in the regulation of various aspects of biology and disease is well recognized. However, what remains largely unappreciated is that a significant number of miRNAs are embedded within and are often co-expressed with protein-coding host genes. Such a configuration raises the possibility of a functional interaction between a miRNA and the gene it resides in. This is exemplified by the Drosophila melanogaster dE2f1 gene that harbors two miRNAs, mir-11 and mir-998, within its last intron. miR-11 was demonstrated to limit the proapoptotic function of dE2F1 by repressing cell death genes that are directly regulated by dE2F1, however the biological role of miR-998 was unknown. Here we show that one of the functions of miR-998 is to suppress dE2F1-dependent cell death specifically in rbf mutants by elevating EGFR signaling. Mechanistically, miR-998 operates by repressing dCbl, a negative regulator of EGFR signaling. Significantly, dCbl is a critical target of miR-998 since dCbl phenocopies the effects of miR-998 on dE2f1-dependent apoptosis in rbf mutants. Importantly, this regulation is conserved, as the miR-998 seed family member miR-29 repressed c-Cbl, and enhanced MAPK activity and wound healing in mammalian cells. Therefore, the two intronic miRNAs embedded in the dE2f1 gene limit the apoptotic function of dE2f1, but operate in different contexts and act through distinct mechanisms. These results also illustrate that examining an intronic miRNA in the context of its host's function can be valuable in elucidating the biological function of the miRNA, and provide new information about the regulation of the host gene itself.en
• dc.description.sponsorship This research was supported by grant GM093827 from the National Institutes of Health to MVF, by a Scholar Award from Leukemia & Lymphoma Society to MVF, and by a Postdoctoral Fellowship to MT from the Fonds de Recherches en Santé Québec. NLB acknowledges funding from the Spanish Ministerio de Educación y Ciencia grant number SAF2009-06954. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscripten
• dc.format.mimetype application/pdfca
• dc.identifier.citation Truscott M, Islam A, Lightfoot J, Lopez-Bigas N, Frolov MV. An intronic microRNA links Rb/E2F and EGFR signaling. PLoS Genetics. 2014;10(7):e1004493. DOI: 10.1371/journal.pgen.1004493ca
• dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1004493
• dc.identifier.issn 1553-7390ca
• dc.identifier.uri http://hdl.handle.net/10230/23485
• dc.language.iso engca
• dc.publisher Public Library of Science (PLoS)ca
• dc.relation.ispartof PLoS Genetics. 2014;10(7):e1004493
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-06954
• dc.rights © 2014 Truscott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits/nunrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Drosòfila -- Genèticaca
• dc.subject.other RNA no missatgersca
• dc.subject.other Genètica -- Regulacióca
• dc.title An intronic microRNA links Rb/E2F and EGFR signalingen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca