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TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

Oncogene volume 32, pages 4646–4655 (2013)Cite this article

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Abstract

TAF15 (formerly TAFII68) is a member of the FET (FUS, EWS, TAF15) family of RNA- and DNA-binding proteins whose genes are frequently translocated in sarcomas. By performing global gene expression profiling, we found that TAF15 knockdown affects the expression of a large subset of genes, of which a significant percentage is involved in cell cycle and cell death. In agreement, TAF15 depletion had a growth-inhibitory effect and resulted in increased apoptosis. Among the TAF15-regulated genes, targets of microRNAs (miRNAs) generated from the onco-miR-17 locus were overrepresented, with CDKN1A/p21 being the top miRNAs-targeted gene. Interestingly, the levels of onco-miR-17 locus coded miRNAs (miR-17-5p and miR-20a) were decreased upon TAF15 depletion and shown to affect the post-transcriptional regulation of TAF15-dependent genes, such as CDKN1A/p21. Thus, our results demonstrate that TAF15 is required to regulate gene expression of cell cycle regulatory genes post-transcriptionally through a pathway involving miRNAs. The findings that high TAF15 levels are needed for rapid cellular proliferation and that endogenous TAF15 levels decrease during differentiation strongly suggest that TAF15 is a key regulator of maintaining a highly proliferative rate of cellular homeostasis.

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Acknowledgements

We are very grateful to JF Caceres, VN Kim and ME Fiori for providing the Pri-17–92, Flag-DGCR8 and pGL3-p21-3′UTR plasmids, respectively. We also thank N Charlet Berguerand and M Morlando for the advice in miRNA processing assay, D Devys, M Fournier, A Helmrich, P Bheda and P Laneve for critically reading the manuscript, R Contzler for the XCELLigence analysis and the IGBMC cell culture facility. This work was supported by funds from CNRS, INSERM and AICR (09–0258) grants. MB was supported by the Fondation Recherche Medicale and LJ by MRET and Association pour la Recherche sur le Cancer.

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Author notes

  1. L Jobert

    Present address: 4Current address: Biotechnology Center of Oslo, Gaustadallen 21, 0349 Oslo, Norway.,

Authors and Affiliations

  1. Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U964, Université de Strasbourg, Illkirch Cedex, France

    M Ballarino, L Jobert, D Dembélé & L Tora

  2. GenoSplice technology, Hôpital Saint-Louis, Paris, France

    P de la Grange

  3. INSERM U1052, Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France

    D Auboeuf

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  1. M Ballarino
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Correspondence to L Tora.

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Ballarino, M., Jobert, L., Dembélé, D. et al. TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs. Oncogene 32, 4646–4655 (2013). https://doi.org/10.1038/onc.2012.490

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