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Nucleic Acids Res. 2015 Sep 3;43(15):7577-89. doi: 10.1093/nar/gkv728. Epub 2015 Jul 17.

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression.

Author information

1
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
2
State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
3
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama 332-0012, Japan otsukamo-tky@umin.ac.jp.
4
Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
5
Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, TX, USA.
6
State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China otsukamo-tky@umin.ac.jp.

Abstract

The reduced expression levels and functional impairment of global miRNAs are related to various human diseases, including cancers. However, relatively little is known about how global miRNA function may be upregulated. Here, we report that global miRNA function can be enhanced by Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors. The regulation of miRNA function by ROCK inhibitors is mediated, at least in part, by poly(A)-binding protein-interacting protein 2 (PAIP2), which enhances poly(A)-shortening of miRNA-targeted mRNAs and leads to global upregulation of miRNA function. In the presence of a ROCK inhibitor, PAIP2 expression is enhanced by the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) through increased ROCK1 nuclear localization and enhanced ROCK1 association with HNF4A. Our data reveal an unexpected role of ROCK1 as a cofactor of HNF4A in enhancing PAIP2 transcription. ROCK inhibitors may be useful for the various pathologies associated with the impairment of global miRNA function.

PMID:
26187994
PMCID:
PMC4551943
DOI:
10.1093/nar/gkv728
[Indexed for MEDLINE]
Free PMC Article

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