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Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program

Oncogene volume 33, pages 474–483 (2014)Cite this article

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Abstract

S6 kinases (S6Ks) are mechanistic target of rapamycin substrates that participate in cell growth control. S6Ks phosphorylate ribosomal protein S6 (rpS6) and additional proteins involved in the translational machinery, although the functional roles of these modifications remain elusive. Here we analyze the S6K-dependent transcriptional and translational regulation of gene expression by comparing whole-genome microarray of total and polysomal mouse liver RNA after feeding. We show that tissue lacking S6Ks 1 and 2 (S6K1 and S6K2), displays a defect in the ribosome biogenesis (RiBi) transcriptional program after feeding. Over 75% of RiBi factors are controlled by S6K, including Nop56, Nop14, Gar1, Rrp9, Rrp15, Rrp12 and Pwp2 nucleolar proteins. Importantly, the reduced activity of RiBi transcriptional promoters in S6K1;S6K2−/− cells is also observed in rpS6 knock-in mutants that cannot be phosphorylated. As ribosomal protein synthesis is not affected by these mutations, our data reveal a distinct and specific aspect of RiBi under the control of rpS6 kinase activity, that is, the RiBi transcriptional program.

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Acknowledgements

We thank the Novartis Foundation and George Thomas laboratory for the use of S6K mutant mice. We are grateful to the members of INSERM-U845 for support, and to Stefano Fumagalli and Olivier Jean-Jean for helpful discussions and sharing reagents. We thank Sophie Berissi, Ana Diaz and Sylvie Fabrega for excellent technical support. We thank Pfizer for the generous gift of Temsirolimus. This work was supported by grants to MP from the European Research Council, from Fondation de la Recherche Medicale, from Fondation Schlumberger pour l’Education et la Recherche and from ANR and by grants to OM from the US-Israel Binational Science Foundation (2009054), Israel Cancer Research Fund and Ministry of Health. CC received a fellowship from the Coddim Ile de France.

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Authors and Affiliations

  1. INSERM, U845, Paris, France

    C Chauvin, V Koka, A Nouschi, V Mieulet & M Pende

  2. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, UMRS-845, Paris, France

    C Chauvin, V Koka, A Nouschi, V Mieulet, N Cagnard & M Pende

  3. Laboratoire de Biologie Moléculaire Eucaryote, Université de Toulouse-UPS and Centre National de La Recherche Scientifique, Toulouse, France

    C Hoareau-Aveilla & T Kiss

  4. Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    A Dreazen & O Meyuhas

  5. Plateforme Post-Génomique Pitié-Salpétrière, Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France

    W Carpentier

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  1. C Chauvin
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Chauvin, C., Koka, V., Nouschi, A. et al. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 33, 474–483 (2014). https://doi.org/10.1038/onc.2012.606

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