Nature Cell Biology
1, 20 - 26 (1999)
doi:10.1038/8991
Nucleolar Arf sequesters Mdm2 and activates p53Jason D. Weber1, 2, 4, Laura J. Taylor4, 3, Martine F. Roussel2, Charles J. Sherr1, 2
& Dafna Bar-Sagi31
Howard Hughes Medical Institute, St Jude's Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee
38105, USA
2
Department of Tumor Cell Biology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee
38105, USA
Department of Molecular Genetics and Microbiology, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794, USA 4
These authors contributed equally to this work
Correspondence should be addressed to Charles J. Sherr sherr@stjude.orgThe 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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