151. ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
- Author
-
Jiahuai Han, Young Jun Kang, Chikako Shibata, Felicia Han, Takeshi Yoshikawa, Takahiro Kishikawa, Motoyuki Otsuka, Kazuhiko Koike, Motoko Ohno, Ann-Bin Shyu, Jianfeng Wu, Akemi Takata, and Chyi-Ying A. Chen
- Subjects
Pyridines ,RNA-binding protein ,Biology ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,microRNA ,Genetics ,Animals ,Humans ,ROCK1 ,RNA, Messenger ,Enzyme Inhibitors ,Protein kinase A ,Transcription factor ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,rho-Associated Kinases ,RNA-Binding Proteins ,Molecular biology ,Amides ,Cell biology ,Repressor Proteins ,MicroRNAs ,HEK293 Cells ,Hepatocyte nuclear factor 4 ,Gene Expression Regulation ,Hepatocyte Nuclear Factor 4 ,Hepatocyte nuclear factor 4 alpha ,030220 oncology & carcinogenesis ,RNA ,Caco-2 Cells - 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.
- Published
- 2015