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Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction

Nature Cell Biology volume 11, pages 501–508 (2009)Cite this article

Abstract

Impaired ribosome biogenesis is attributed to nucleolar disruption and diffusion of a subset of 60S ribosomal proteins, particularly ribosomal protein (rp)L11, into the nucleoplasm, where they inhibit MDM2, leading to p53 induction and cell-cycle arrest1,2,3,4. Previously, we demonstrated that deletion of the 40S rpS6 gene in mouse liver prevents hepatocytes from re-entering the cell cycle after partial hepatectomy5. Here, we show that this response leads to an increase in p53, which is recapitulated in culture by rpS6-siRNA treatment and rescued by the simultaneous depletion of p53. However, disruption of biogenesis of 40S ribosomes had no effect on nucleolar integrity, although p53 induction was mediated by rpL11, leading to the finding that the cell selectively upregulates the translation of mRNAs with a polypyrimidine tract at their 5′-transcriptional start site (5′-TOP mRNAs), including that encoding rpL11, on impairment of 40S ribosome biogenesis. Increased 5′-TOP mRNA translation takes place despite continued 60S ribosome biogenesis and a decrease in global translation. Thus, in proliferative human disorders involving hypomorphic mutations in 40S ribosomal proteins6,7, specific targeting of rpL11 upregulation would spare other stress pathways that mediate the potential benefits of p53 induction8.

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Figure 1: Depletion of rpS6 leads to p53-dependent cell-cycle arrest.
Figure 2: Depletion of rpS6 does not result in nucleolar disruption.
Figure 3: Upregulation of p53 by depletion of ribosomal proteins is mediated by rpL11.
Figure 4: Depletion of 40S ribosomal proteins results in translational upregulation of the rpL11 mRNA.
Figure 5: Depletion of rpS6 upregulates 5′-TOP mediated translation.

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Acknowledgements

We are indebted to P. D. Plas, A. Selvaraj and P. B. Dennis for their critical reading of the manuscript, as well as members of the laboratory for numerous discussions. We are also thankful to K. Vousden for the L11 polyclonal antibody. Finally we thank G. Doerman and M. Daston for computer graphics and the editing of the manuscript, respectively. A.D.C. was supported by fellowship from the Boehringer Ingelheim Fund. These studies were supported by the Mouse Models in Human Cancer Consortium grant U01 CA-84292 to P.P.P. and G.T., and G.T. is also supported by the Gladys and John Strauss Chair in Cancer Research and start-up funds from the University of Cincinnati.

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Authors and Affiliations

  1. Department of Cancer and Cell Biology, Genome Research Institute, University of Cincinnati, 2180 East Galbraith Road, Cincinnati, 45237, Ohio, USA

    Stefano Fumagalli, Arti Neb-Gulati & George Thomas

  2. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, PO Box 2543, CH-4058, Basel, Switzerland

    Alessandro Di Cara

  3. Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Lichtstrasse 35, CH-4002, Basel, Switzerland

    Francois Natt & Jonathan Hall

  4. Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670558, Cincinnati, 45267-0558, Ohio, USA

    Sandy Schwemberger & George F. Babcock

  5. Cincinnati Shriner's Hospital for Children, 3229 Burnet Avenue, Cincinnati, 45229-3095, Ohio, USA

    George F. Babcock

  6. San Raffaele, Institute Via Olgettina, Milano, 5820132, Italy

    Rosa Bernardi

  7. Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Pier Paolo Pandolfi

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Fumagalli, S., Di Cara, A., Neb-Gulati, A. et al. Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction. Nat Cell Biol 11, 501–508 (2009). https://doi.org/10.1038/ncb1858

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