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The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

Oncogene volume 30, pages 3274–3288 (2011)Cite this article

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Abstract

Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up- and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.

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Acknowledgements

This work was supported by the Roberto and Cornelia Pallotti's Legacy for Cancer Research, the Vanini–Cavagnino Grant and the Italian Ministry of Education, University and Research (MIUR: grants for orientated fundamental research). We thank Professor U Scheer for the generous gift of the anti-ribosomal protein S14 antibody. We are indebted with Dr Maurizio Brigotti for performing polysomal fraction analysis.

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  1. G Donati and S Bertoni: These authors contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy

    G Donati, S Bertoni, E Brighenti, M Vici, D Treré & L Montanaro

  2. Centro Interdipartimentale per le Ricerche sul Cancro ‘G. Prodi’, Università di Bologna, Bologna, Italy

    E Brighenti

  3. Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka, Croatia

    S Volarevic

  4. Dipartimento Clinico di Scienze Radiologiche e Istocitopatologiche, Università di Bologna, Bologna, Italy

    M Derenzini

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  1. G Donati
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Donati, G., Bertoni, S., Brighenti, E. et al. The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells. Oncogene 30, 3274–3288 (2011). https://doi.org/10.1038/onc.2011.48

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