Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells <i>in vivo</i>
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- Sarah Francoz
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Pascal Froment
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Sven Bogaerts
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Sarah De Clercq
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Marion Maetens
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Gilles Doumont
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Eric Bellefroid
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
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- Jean-Christophe Marine
- Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9052 Ghent, Belgium; and
書誌事項
- 公開日
- 2006-02-21
- DOI
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- 10.1073/pnas.0508476103
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p> The Mdm2 and Mdm4 oncoproteins are key negative regulators of the p53 tumor suppressor. However, their physiological contributions to the regulation of p53 stability and activity remain highly controversial. Here, we combined a <jats:italic>p53</jats:italic> knock-in allele, in which <jats:italic>p53</jats:italic> is silenced by a transcriptional stop element flanked by loxP sites, with the <jats:italic>mdm2</jats:italic> - and <jats:italic>mdm4</jats:italic> -null alleles. This approach allows Cre-mediated conditional p53 expression in tissues <jats:italic>in vivo</jats:italic> and cells <jats:italic>in vitro</jats:italic> lacking Mdm2, Mdm4, or both. Using this strategy, we show that Mdm2 and Mdm4 are essential in a nonredundant manner for preventing p53 activity in the same cell type, irrespective of the proliferation/differentiation status of the cells. Although Mdm2 prevents accumulation of the p53 protein, Mdm4 contributes to the overall inhibition of p53 activity independent of Mdm2. We propose a model in which Mdm2 is critical for the regulation of p53 levels and Mdm4 is critical for the fine-tuning of p53 transcriptional activity, both proteins acting synergistically to keep p53 in check. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 103 (9), 3232-3237, 2006-02-21
Proceedings of the National Academy of Sciences