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Nucleolar Arf sequesters Mdm2 and activates p53

Nature Cell Biology volume 1, pages 20–26 (1999)Cite this article

Abstract

The Ink4/Arf locus encodes two tumour-suppressor proteins, p16Ink4a and p19Arf, that govern the antiproliferative functions of the retinoblastoma and p53 proteins, respectively. Here we show that Arf binds to the product of the Mdm2 gene and sequesters it into the nucleolus, thereby preventing negative-feedback regulation of p53 by Mdm2 and leading to the activation of p53 in the nucleoplasm. Arf and Mdm2 co-localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence. These topological interactions of Arf and Mdm2 point towards a new mechanism for p53 activation.

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Figure 1: Subcellular localization of p19Arf and relocalization of HDM2 in cells expressing exogenous Arf proteins.
Figure 2: Nucleolar accumulation of Arf and Mdm2 as MEFs approach replicative senescence.
Figure 3: Myc induces nucleolar accumulation of Mdm2 in an Arf-dependent manner.
Figure 4: Induction of p53 by Arf requires nucleolar recruitment of Mdm2.
Figure 5: Ectopically overexpressed p53 and Mdm2 prevent the nucleolar localization of Arf.

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Acknowledgements

We thank A. J. Levine and Y. Xiong for communicating unpublished results; G. Lozano for MEFs lacking both Mdm2 and p53; F. Zindy for MEFs of different genotypes and passage levels; G. Zambetti and P. Tegtmeyer for HDM2 and p53 expression plasmids, and for the 2A10 monoclonal antibody to Mdm2; and R. Matthew and E. Van de Kamp for technical assistance. C.J.S is an Investigator of the Howard Hughes Medical Institute. D.B.-S and M.F.R acknowledge grant support from the NIH.

Correspondence and requests for materials should be addressed to C.J.S.

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Author notes

  1. Jason D. Weber, Laura J. Taylor and Dafna Bar-Sagi: These authors contributed equally to this work

Authors and Affiliations

  1. Howard Hughes Medical Institute, St Jude’s Children’s Research Hospital, 332 N. Lauderdale, Memphis, 38105, Tennessee, USA

    Jason D. Weber & Charles J. Sherr

  2. Department of Tumor Cell Biology, St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, 38105, Tennessee, USA

    Laura J. Taylor & Dafna Bar-Sagi

  3. Department of Molecular Genetics and Microbiology, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York, 11794, USA

    Jason D. Weber & Dafna Bar-Sagi

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Correspondence to Charles J. Sherr.

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Weber, J., Taylor, L., Roussel, M. et al. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1, 20–26 (1999). https://doi.org/10.1038/8991

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