Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death
Open accessAbstract
p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death.
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In some tissues and cell types, such as the central nervous system and proliferative intestinal cells, there is a requirement for both Mdm2 and Mdmx.
“Clearly in some tissues and cell types [such as the central nervous system (CNS) and proliferative intestinal cells], there is a requirement for both Mdm2 and Mdmx.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [32]
Mdm2 and Mdmx contribute to p53 regulation to different extents in different tissues in vivo.
“Mdm2 and Mdmx seem to contribute to p53 regulation to different extents in different tissues in vivo (Table 1; [32–40]).”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [32]
In smooth muscle cells, loss of Mdmx has no phenotype.
“However, in other cases, such as smooth muscle cells, loss of Mdmx has no phenotype.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [32]
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References 40 · Cited by 70
- Authors
- Boesten, L. S. M., Zadelaar, S. M., De Clercq, S., Francoz, S., van Nieuwkoop, A., Biessen, E. A. L., Hofmann, F., Feil, S., Feil, R., Jochemsen, A. G., Zurcher, C., Havekes, L. M., van Vlijmen, B. J. M., & Marine, J.-C.
- Affiliations
- Leiden University Medical Center (NL)
- Netherlands Organisation for Applied Scientific Research (NL)
- Vlaams Instituut voor Biotechnologie (BE)
- Leiden University (NL)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Utrecht University (NL)
- Corresponding author
- Marine, J-C
- Venue
- Cell Death & Differentiation
- Published
- 2006-05-26
- Volume
- 13
- Issue
- 12
- Pages
- 2089-2098
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W2054749109
- Cited by
- 70
- References
- 40
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 7 · 2016: 4 · 2015: 3 · 2014: 6 · 2013: 3 · 2012: 3
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- green
- resolver.tno.nl
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- TNO Repository (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Koninklijke Nederlandse Akademie van Wetenschappen
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, MDM4, p53, smooth muscle cells, apoptosis, intestinal smooth muscle, quiescent cells, conditional gene inactivation, p53 regulation
- MeSH terms
- Animals, Cell Differentiation, Gene Expression Regulation, Intestine, Small, Mice, Transgenic, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Apoptosis, Myocytes, Smooth Muscle, Ubiquitin-Protein Ligases, Mice, Proto-Oncogene Proteins c-mdm2, Caspase 3
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