@article{bb393314ca544872a68fe8e0ff9ba0f7,
title = "Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation",
abstract = "Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation.",
keywords = "cardiomyocyte, cell cycle, Cofilin2, cytoskeleton, Hippo, microRNA, regeneration, YAP",
author = "Consuelo Torrini and Cubero, {Ryan John} and Ellen Dirkx and Luca Braga and Hashim Ali and Giulia Prosdocimo and Gutierrez, {Maria Ines} and Chiara Collesi and Danilo Licastro and Lorena Zentilin and Miguel Mano and Serena Zacchigna and Michele Vendruscolo and Matteo Marsili and Areejit Samal and Mauro Giacca",
note = "Funding Information: The authors are grateful to Willy De Mattia and Stefano Artico for the efficient assistance for animal experimentation. This work was supported by European Research Council (ERC) ( 250124 to M.G.), Leducq Foundation Transatlantic Network of Excellence ( 14CVD04 to M.G.), the University of Trieste ( FRA2018 to C.C.), and the Fondazione CRTrieste, Trieste, Italy . C.T., L.B., H.A., and G.P. were supported by ICGEB Arturo Falaschi pre- and post-doctoral fellowships. E.D. was supported by an EMBO long-term fellowship ( EMBO ALTF 848-2013 ) and a FP7 Marie Curie Intra-European Fellowship (project number 627539 ). Funding Information: The authors are grateful to Willy De Mattia and Stefano Artico for the efficient assistance for animal experimentation. This work was supported by European Research Council (ERC) (250124 to M.G.), Leducq Foundation Transatlantic Network of Excellence (14CVD04 to M.G.), the University of Trieste (FRA2018 to C.C.), and the Fondazione CRTrieste, Trieste, Italy. C.T. L.B. H.A. and G.P. were supported by ICGEB Arturo Falaschi pre- and post-doctoral fellowships. E.D. was supported by an EMBO long-term fellowship (EMBO ALTF 848-2013) and a FP7 Marie Curie Intra-European Fellowship (project number 627539). C.T. E.D. L.B. H.A. G.P. M.I.G. and C.C. performed molecular and immunofluorescence analysis. R.J.C. D.L. M.V. M. Marsili, and A.S. performed bioinformatics analysis. L.Z. M. Mano, and S.Z. provided essential advice for the experimental design and assisted in writing the manuscript. M.G. supervised the project and wrote the manuscript. The authors declare no competing financial interests. The use of some of the microRNAs described in work for cardiac regeneration is covered by patent ?MicroRNAs for cardiac regeneration through induction of cardiac myocyte proliferation,? grant 2794882. Funding Information: The authors are grateful to Willy De Mattia and Stefano Artico for the efficient assistance for animal experimentation. This work was supported by European Research Council (ERC) (250124 to M.G.), Leducq Foundation Transatlantic Network of Excellence (14CVD04 to M.G.), the University of Trieste (FRA2018 to C.C.), and the Fondazione CRTrieste, Trieste, Italy. C.T. L.B. H.A. and G.P. were supported by ICGEB Arturo Falaschi pre- and post-doctoral fellowships. E.D. was supported by an EMBO long-term fellowship (EMBO ALTF 848-2013) and a FP7 Marie Curie Intra-European Fellowship (project number 627539). C.T. E.D. L.B. H.A. G.P. M.I.G. and C.C. performed molecular and immunofluorescence analysis. R.J.C. D.L. M.V. M. Marsili, and A.S. performed bioinformatics analysis. L.Z. M. Mano, and S.Z. provided essential advice for the experimental design and assisted in writing the manuscript. M.G. supervised the project and wrote the manuscript. The authors declare no competing financial interests. The use of some of the microRNAs described in work for cardiac regeneration is covered by patent “MicroRNAs for cardiac regeneration through induction of cardiac myocyte proliferation,” grant 2794882. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = may,
day = "28",
doi = "10.1016/j.celrep.2019.05.005",
language = "English",
volume = "27",
pages = "2759--2771.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier BV",
number = "9",
}