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Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses

Rubbi, C.P. and Milner, J. (2003) Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO Journal, 22. pp. 6068-6077. ISSN 0261-4189

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p53 protects against cancer through its capacity to induce cell cycle arrest or apoptosis under a large variety of cellular stresses. It is not known how such diversity of signals can be integrated by a single molecule. However, the literature reveals that a common denominator in all p53-inducing stresses is nucleolar disruption. We thus postulated that the impairment of nucleolar function might stabilize p53 by preventing its degradation. Using micropore irradiation, we demonstrate that large amounts of nuclear DNA damage fail to stabilize p53 unless the nucleolus is also disrupted. Forcing nucleolar disruption by anti-upstream binding factor (UBF) microinjection (in the absence of DNA damage) also causes p53 stabilization. We propose that the nucleolus is a stress sensor responsible for maintenance of low levels of p53, which are automatically elevated as soon as nucleolar function is impaired in response to stress. Our model integrates all known p53-inducing agents and also explains cell cycle-related variations in p53 levels which correlate with established phases of nucleolar assembly/disassembly through the cell cycle.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Biology (York)
Depositing User: York RAE Import
Date Deposited: 11 Jun 2009 14:01
Last Modified: 11 Jun 2009 14:01
Published Version: http://dx.doi.org/10.1093/emboj/cdg579
Status: Published
Publisher: Nature Publishing Group
Identification Number: 10.1093/emboj/cdg579
URI: http://eprints.whiterose.ac.uk/id/eprint/6042

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