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Mex-3B induces apoptosis by inhibiting miR-92a access to the Bim-3′UTR

Oncogenevolume 37pages52335247 (2018) | Download Citation

Abstract

Cells respond to a variety of cellular stresses, including DNA damage, by regulating genes whose expression modulates cell cycle arrest, DNA repair, senescence, and/or apoptosis. MicroRNAs (miRNAs) play essential roles in both normal development and disease pathogenesis by destabilizing mRNAs and inhibiting translation. In turn, miRNA biogenesis, turnover, and activity can be regulated by specific RNA-binding proteins. Here we show that Mex-3B, an hnRNP K homology (KH) domain-containing RNA-binding protein, critically modulates DNA stress-induced apoptosis by posttranscriptionally upregulating the pro-apoptotic BH3 (Bcl-2 homology region 3)-only family member Bim. Furthermore, our data indicate that binding of Mex-3B to the 3′-untranslated region (3′UTR) of Bim interferes with the interaction of an Argonaute (Ago)–miR-92a complex with a miR-92a target site present in the Bim RNA. Our results provide novel insights into the posttranscriptional mechanisms that are critical for cellular stress responses.

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Acknowledgements

We are grateful to Y Nakamura for adenovirus expressing p53. This work was supported by P-CREATE (Project for Cancer Research and Therapeutic Evolution: Grant No. 17cm0106103h0002) and P-DIRECT (Project for Development of Innovative Research on Cancer Therapeutics: Grant No. 15cm0106016h0005) grants from the Japan Agency for Medical Research and Development, and Grants-in-Aid for Scientific Research on Innovative Areas (Integrative Analysis and Regulation of Cellular Diversity: Grant No. 17H06325) from MEXT, Japan.

Author contributions:

TO performed most of the experiments. TH worked on the role of Mex-3B in DNA damage-induced apoptosis. YY, AK, and SK generated constructs and performed luciferase assays. YY and YS-S performed cross-link bridge RT-qPCR analysis. SK and SS performed immunoblotting analysis. TO, YY, and TA analyzed the data. TO and TA wrote the paper.

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  1. Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan

    • Takeaki Oda
    • , Yusuke Yamazumi
    • , Takatoshi Hiroko
    • , Atsushi Kamiya
    • , Saori Kiriya
    • , Saki Suyama
    • , Yumi Shiozaki-Sato
    •  & Tetsu Akiyama

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Tetsu Akiyama.

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DOI

https://doi.org/10.1038/s41388-018-0336-7