Letter abstract
Nature Cell Biology 11, 501 - 508 (2009)
Published online: 15 March 2009 | doi:10.1038/ncb1858
Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction
Stefano Fumagalli1, Alessandro Di Cara2, Arti Neb-Gulati1, Francois Natt3, Sandy Schwemberger4, Jonathan Hall3, George F. Babcock4,5, Rosa Bernardi6, Pier Paolo Pandolfi7 & George Thomas1
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.
- Department of Cancer and Cell Biology, Genome Research Institute, University of Cincinnati, 2180 East Galbraith Road, Cincinnati, Ohio 45237, USA.
- Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, PO Box 2543, CH-4058 Basel, Switzerland.
- Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Lichtstrasse 35, CH-4002 Basel, Switzerland.
- Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670558, Cincinnati, Ohio 45267-0558, USA.
- Cincinnati Shriner's Hospital for Children, 3229 Burnet Avenue, Cincinnati, Ohio 45229-3095, USA.
- San Raffaele, Institute Via Olgettina, 5820132 Milano, Italy.
- Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Correspondence to: Stefano Fumagalli1 e-mail: fumagas@uc.edu
Correspondence to: George Thomas1 e-mail: thomasg4@uc.edu
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