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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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We thank A. J. Levine and Y. Xiong for communicating unpublished results; G. Lozano for MEFs lacking both Mdm2 and p53; F. Zindy for MEFs of different genotypes and passage levels; G. Zambetti and P. Tegtmeyer for HDM2 and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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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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DOI: https://doi.org/10.1038/8991
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