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

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, coi...

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Autores principales: Yoshikawa, Takeshi, Wu, Jianfeng, Otsuka, Motoyuki, Kishikawa, Takahiro, Ohno, Motoko, Shibata, Chikako, Takata, Akemi, Han, Felicia, Kang, Young Jun, Chen, Chyi-Ying A., Shyu, Ann-Bin, Han, Jiahuai, Koike, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
RNA
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551943/
https://www.ncbi.nlm.nih.gov/pubmed/26187994
http://dx.doi.org/10.1093/nar/gkv728
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author Yoshikawa, Takeshi
Wu, Jianfeng
Otsuka, Motoyuki
Kishikawa, Takahiro
Ohno, Motoko
Shibata, Chikako
Takata, Akemi
Han, Felicia
Kang, Young Jun
Chen, Chyi-Ying A.
Shyu, Ann-Bin
Han, Jiahuai
Koike, Kazuhiko
author_facet Yoshikawa, Takeshi
Wu, Jianfeng
Otsuka, Motoyuki
Kishikawa, Takahiro
Ohno, Motoko
Shibata, Chikako
Takata, Akemi
Han, Felicia
Kang, Young Jun
Chen, Chyi-Ying A.
Shyu, Ann-Bin
Han, Jiahuai
Koike, Kazuhiko
author_sort Yoshikawa, Takeshi
collection PubMed
description 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.
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spelling pubmed-45519432015-08-28 ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression Yoshikawa, Takeshi Wu, Jianfeng Otsuka, Motoyuki Kishikawa, Takahiro Ohno, Motoko Shibata, Chikako Takata, Akemi Han, Felicia Kang, Young Jun Chen, Chyi-Ying A. Shyu, Ann-Bin Han, Jiahuai Koike, Kazuhiko Nucleic Acids Res RNA 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. Oxford University Press 2015-09-03 2015-07-17 /pmc/articles/PMC4551943/ /pubmed/26187994 http://dx.doi.org/10.1093/nar/gkv728 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle RNA
Yoshikawa, Takeshi
Wu, Jianfeng
Otsuka, Motoyuki
Kishikawa, Takahiro
Ohno, Motoko
Shibata, Chikako
Takata, Akemi
Han, Felicia
Kang, Young Jun
Chen, Chyi-Ying A.
Shyu, Ann-Bin
Han, Jiahuai
Koike, Kazuhiko
ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
title ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
title_full ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
title_fullStr ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
title_full_unstemmed ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
title_short ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression
title_sort rock inhibition enhances microrna function by promoting deadenylation of targeted mrnas via increasing paip2 expression
topic RNA
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551943/
https://www.ncbi.nlm.nih.gov/pubmed/26187994
http://dx.doi.org/10.1093/nar/gkv728
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