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Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Oncogene volume 31, pages 4536–4549 (2012)Cite this article

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Abstract

Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsense-mediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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Acknowledgements

We thank S Kato and J Marie for providing wild-type and mutant ddx5 and ddx17 expression vectors. We thank Emanuele Buratti for providing pTB minigene construct. We thank Coralie Poulard and Muriel Le Romancer-Cherifi for their help with PLA. This work was supported by EC (NoE EURASNET), Institut National du Cancer, Association pour la Recherche sur le Cancer, Ligue Nationale Contre le Cancer and Agence Nationale de la Recherche. S Germann, B Gaudineau and M Fougère were supported by Association pour la Recherche sur le Cancer; L Gratadou by Agence Nationale de la Recherche; E Zonta by the French Ministry of Education; E Dardenne by Ligue Nationale Contre le Cancer.

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Authors and Affiliations

  1. Université de Lyon, Lyon, France

    S Germann, L Gratadou, E Zonta, E Dardenne, S Samaan, M Dutertre & D Auboeuf

  2. Inserm U1052, Lyon, France

    S Germann, L Gratadou, E Zonta, E Dardenne, S Samaan, M Dutertre & D Auboeuf

  3. CNRS UMR5286, Lyon, France

    S Germann, L Gratadou, E Zonta, E Dardenne, S Samaan, M Dutertre & D Auboeuf

  4. Centre de Recherche en Cancérologie de Lyon, Lyon, France

    S Germann, L Gratadou, E Zonta, E Dardenne, S Samaan, M Dutertre & D Auboeuf

  5. Université Lyon 1, Lyon, France

    S Germann, L Gratadou, E Zonta, E Dardenne, S Samaan, M Dutertre & D Auboeuf

  6. CNRS UMR7212, INSERM U944, Université Paris Diderot, Institut d’Hématologie, Hôpital Saint-Louis, Paris, France

    B Gaudineau, M Fougère & S Jauliac

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  1. S Germann
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Germann, S., Gratadou, L., Zonta, E. et al. Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor. Oncogene 31, 4536–4549 (2012). https://doi.org/10.1038/onc.2011.618

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