Monoubiquitylation promotes mitochondrial p53 translocation
Open accessAbstract
A major function of the p53 tumor suppressor is the induction of a pleiotropic apoptotic program in response to stress through transcription-dependent and -independent mechanisms. In particular, this includes a direct apoptotic role of p53 at the mitochondria. Stress-induced p53 translocation to the mitochondria with subsequent outer membrane permeabilization is a common early component in p53-mediated apoptosis in normal and transformed cells. However, the mechanism of p53 delivery to the mitochondria remains unknown. Here, we show that the cytoplasm contains a separate and distinct p53 pool that is the major source for p53 translocation to the mitochondria upon its stress-induced stabilization. Using various manipulations that enhance or diminish p53 ubiquitylation, our data provide evidence that Mdm2-mediated monoubiquitylation of p53 greatly promotes its mitochondrial translocation and thus its direct mitochondrial apoptosis. On the other hand, p53 does not require Mdm2 as a shuttler. Upon arrival at the mitochondria, our data suggest that p53 undergoes rapid deubiquitylation by mitochondrial HAUSP via a stress-induced mitochondrial p53-HAUSP complex. This generates the apoptotically active non-ubiquitylated p53. Taken together, we propose a novel model for mitochondrial p53 targeting, whereby a distinct cytoplasmic pool of stabilized monoubiquitylated p53, generated in resting cells by basal levels of Mdm2-type ligases, is subject to a binary switch from a fate of inactivation via subsequent polyubiquitylation and degradation in unstressed cells, to a fate of activation via mitochondrial trafficking.
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Mdm2-dependent mono-ubiquitination induces translocation of p53 to the mitochondria, where it can activate transcription-independent apoptosis.
“Consistent with this, recent data suggest that Mdm2-dependent mono-ubiquitination induces translocation of p53 to the mitochondria [113], where it can activate transcription-independent apoptosis.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [113]
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Self-citation
- Authors
- Marchenko, N. D., Wolff, S., Erster, S., Becker, K., & Moll, U. M.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Moll, Ute M
- Venue
- The EMBO Journal
- Published
- 2007-02-01
- Volume
- 26
- Issue
- 4
- Pages
- 923-934
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1852828
- OpenAlex
- W2126390187
- Cited by
- 286
- References
- 48
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 10 · 2019: 2 · 2018: 8 · 2017: 7 · 2016: 16 · 2015: 13 · 2014: 21 · 2013: 19 · 2012: 21
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- New York State Department of Health
- Health Research Board
- National Cancer Institute (R01CA093853, CA93853)
- 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 › Cell death mechanisms and regulation
- Keywords
- p53, monoubiquitylation, mitochondrial translocation, MDM2, USP7, deubiquitination, p53-dependent apoptosis, outer membrane permeabilization, polyubiquitination, mitochondrial targeting
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Camptothecin, Cytoplasm, Humans, Mitochondria, Models, Biological, Endopeptidases, Immunoblotting, Tumor Suppressor Protein p53, Apoptosis, Protein Transport, Ubiquitin, Ubiquitin Thiolesterase, Cell Line, Tumor, Immunoprecipitation, Proto-Oncogene Proteins c-mdm2
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