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MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling

Martins da Costa, P. A. and Salic, K. and Gladka, M.M. and Armand, A.S. and Leptidis, S. and Azzouzi el, H. and Hansen, A. and Roo Coenen-de, C. J. and Bierhuizen, M.F.A. and Nagel van der, R. and Kuik van, J. and Weger de, R. and Bruin de, A. and Condorelli, G. and Arbones, M. L. and Eschenhagen, T. and Windt de, L.J. (2010) MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nature Cell Biology, 12, 1220-7. ISSN 1465-7392.

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Official URL: http://dx.doi.org/10.1038/ncb2126

Abstract

MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length. Increasing evidence implicates miRs in myocardial disease processes. Here we show that miR-199b is a direct calcineurin/NFAT target gene that increases in expression in mouse and human heart failure, and targets the nuclear NFAT kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (Dyrk1a), constituting a pathogenic feed forward mechanism that affects calcineurin-responsive gene expression. Mutant mice overexpressing miR-199b, or haploinsufficient for Dyrk1a, are sensitized to calcineurin/NFAT signalling or pressure overload and show stress-induced cardiomegaly through reduced Dyrk1a expression. In vivo inhibition of miR-199b by a specific antagomir normalized Dyrk1a expression, reduced nuclear NFAT activity and caused marked inhibition and even reversal of hypertrophy and fibrosis in mouse models of heart failure. Our results reveal that microRNAs affect cardiac cellular signalling and gene expression, and implicate miR-199b as a therapeutic target in heart failure.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:9516
Deposited On:07 Feb 2011 01:00
Last Modified:07 Sep 2011 17:01

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