DOI: 10.1073/pnas.0508476103. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells <i>in vivo</i>

Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo

10.1073/pnas.0508476103

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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 p53 knock-in allele, in which p53 is silenced by a transcriptional stop element flanked by loxP sites, with the mdm2 - and mdm4 -null alleles. This approach allows Cre-mediated conditional p53 expression in tissues in vivo and cells in vitro 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.

Bibliography

Francoz, S., Froment, P., Bogaerts, S., De Clercq, S., Maetens, M., Doumont, G., Bellefroid, E., & Marine, J.-C. (2006). Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proceedings of the National Academy of Sciences, 103(9), 3232â3237.

Authors 8

Sarah Francoz (first)
Pascal Froment (additional)
Sven Bogaerts (additional)
Sarah De Clercq (additional)
Marion Maetens (additional)
Gilles Doumont (additional)
Eric Bellefroid (additional)
Jean-Christophe Marine (additional)

References 33 Referenced 206

Dates

Type	When
Created	19 years, 6 months ago (Feb. 21, 2006, 11:03 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 2:10 p.m.)
Indexed	4 days, 16 hours ago (Aug. 31, 2025, 6:32 a.m.)
Issued	19 years, 6 months ago (Feb. 21, 2006)
Published	19 years, 6 months ago (Feb. 21, 2006)
Published Online	19 years, 6 months ago (Feb. 21, 2006)
Published Print	19 years, 6 months ago (Feb. 28, 2006)

Funders 0

None

BibTeX

@article{Francoz_2006, title={Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo}, volume={103}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0508476103}, DOI={10.1073/pnas.0508476103}, number={9}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Francoz, Sarah and Froment, Pascal and Bogaerts, Sven and De Clercq, Sarah and Maetens, Marion and Doumont, Gilles and Bellefroid, Eric and Marine, Jean-Christophe}, year={2006}, month=feb, pages={3232–3237} }

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