title: ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression.
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.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Motoyuki
authors.identifier: http://orcid.org/0000-0003-2869-2881
authors.initials: M
authors.lastname: Otsuka
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kishikawa
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Shibata
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Takata
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Felicia
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, TX, USA.
authors.forename: Chyi-Ying A
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical School, Houston, TX, USA.
authors.forename: Ann-Bin
authors.initials: AB
authors.lastname: Shyu
authors.affiliation: State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China otsukamo-tky@umin.ac.jp.
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D051557:Hepatocyte Nuclear Factor 4; D035683:MicroRNAs; C488448:PAIP2 protein, human; D011725:Pyridines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C108830:Y 27632; D054460:rho-Associated Kinases