Reconstitution of Mdm2-dependent post-translational modifications of p53 in yeast
Open accessAbstract
p53 mediates cell cycle arrest or apoptosis in response to DNA damage. Its activity is subject to a tight regulation involving a multitude of post-translational modifications. The plethora of functional protein interactions of p53 at present precludes a clear understanding of regulatory principles in the p53 signaling network. To circumvent this complexity, we studied here the minimal requirements for functionally relevant p53 post-translational modifications by expressing human p53 together with its best characterized modifier Mdm2 in budding yeast. We find that expression of the human p53-Mdm2 module in yeast is sufficient to faithfully recapitulate key aspects of p53 regulation in higher eukaryotes, such as Mdm2-dependent targeting of p53 for degradation, sumoylation at lysine 386 and further regulation of this process by p14(ARF). Interestingly, sumoylation is necessary for the recruitment of p53-Mdm2 complexes to yeast nuclear bodies morphologically akin to human PML bodies. These results suggest a novel role for Mdm2 as well as for p53 sumoylation in the recruitment of p53 to nuclear bodies. The reductionist yeast model that was established and validated in this study will now allow to incrementally study simplified parts of the intricate p53 network, thus helping elucidate the core mechanisms of p53 regulation as well as test novel strategies to counteract p53 malfunctions.
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Arf can stimulate Mdm2-dependent SUMOylation of itself and of p53 at K386, and SUMOylation is associated with relocalization of p53 to subnuclear structures.
“There is some consensus that Arf can stimulate the Mdm2-dependent SUMOylation of both itself and of p53 at K386 [119,120] and that SUMOylation is associated with relocalization of p53 to subnuclear structures [121,122].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [121]
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The p53 orchestra: Mdm2 and Mdmx set the tone
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- Authors
- Di Ventura, B., Funaya, C., Antony, C., Knop, M., & Serrano, L.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-01-30
- Volume
- 3
- Issue
- 1
- Pages
- e1507
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2200829
- OpenAlex
- W1976399704
- Cited by
- 31
- References
- 26
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 3 · 2017: 3 · 2016: 2 · 2014: 1 · 2013: 1 · 2012: 4
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, MDM2, post-translational modification, SUMOylation, p14ARF, protein degradation, PML bodies, nuclear bodies, yeast model, p53 regulation, DNA damage response, apoptosis
- MeSH terms
- Cell Nucleus, Fungal Proteins, Humans, Microscopy, Electron, Protein Processing, Post-Translational, Saccharomyces cerevisiae, Tumor Suppressor Protein p53, Protein Transport, Tumor Suppressor Protein p14ARF, SUMO-1 Protein
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