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

Takeshi Yoshikawa1, Jianfeng Wu2, Motoyuki Otsuka3

  • 1Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Nucleic Acids Research
|July 19, 2015
PubMed

Insights

Global microRNA (miRNA) function, often impaired in diseases, can be enhanced by Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors. This enhancement involves PAIP2 and transcription factor HNF4A, revealing a new therapeutic avenue.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Reduced microRNA (miRNA) expression and function are linked to human diseases, including cancers.
  • Mechanisms for upregulating global miRNA function remain largely unexplored.

Purpose of the Study:

  • To investigate the potential of Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors to enhance global miRNA function.
  • To elucidate the molecular pathways involved in ROCK inhibitor-mediated miRNA function upregulation.

Main Methods:

  • Investigated the effect of ROCK inhibitors on miRNA function.
  • Analyzed the role of poly(A)-binding protein-interacting protein 2 (PAIP2) in miRNA regulation.
  • Examined the interaction between ROCK1 and hepatocyte nuclear factor 4 alpha (HNF4A) in regulating PAIP2 transcription.

Main Results:

  • ROCK inhibitors were found to enhance global miRNA function.
  • PAIP2 mediates the upregulation of miRNA function by enhancing poly(A)-shortening of miRNA-targeted mRNAs.
  • ROCK1 acts as a cofactor for HNF4A to enhance PAIP2 transcription in the presence of ROCK inhibitors.

Conclusions:

  • ROCK inhibitors offer a novel strategy to enhance global miRNA function.
  • The ROCK1-HNF4A-PAIP2 axis represents a key pathway for modulating miRNA activity.
  • ROCK inhibitors hold potential therapeutic value for diseases characterized by impaired miRNA function.

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