p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase
Open accessAbstract
The tumor suppressor gene p53 is activated by reactive oxygen species-generating agents. After activation, p53 migrates to mitochondria and nucleus, a response that eventually leads to apoptosis, but how the two events are related is unknown. Herein, we show that p53 translocation to mitochondria precedes its translocation to nucleus in JB6 skin epidermal cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Translocation of p53 to mitochondria occurs within 10 minutes after TPA application. In the mitochondria, p53 interacts with the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), consistent with the reduction of its superoxide scavenging activity, and a subsequent decrease of mitochondrial membrane potential. In contrast to the immediate action on mitochondria, p53 transcriptional activity in the nucleus increases at 1 hour following TPA application, accompanied by an increase in the levels of its target gene bax at 15 hours following TPA treatment. Activation of p53 transcriptional activity is preventable by application of a SOD mimetic (MnTE-2-PyP5+). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explains the observed mitochondrial dysfunction, which leads to transcription-dependent mechanisms of p53-induced apoptosis.
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MnSOD activity is suppressed by the binding of p53.
“MnSOD activity is suppressed by the binding of p53 [85].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [85]
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- Authors
- Zhao, Y., Chaiswing, L., Velez, J. M., Batinic-Haberle, I., Colburn, N. H., Oberley, T. D., & St. Clair, D. K.
- Affiliations
- University of Kentucky (US)
- University of Wisconsin–Madison (US)
- 4Department of Radiation Oncology, Duke University, Durham, North Carolina; and
- National Cancer Institute (US)
- 1Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky;
- Venue
- Cancer Research
- Published
- 2005-05-01
- Volume
- 65
- Issue
- 9
- Pages
- 3745-3750
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2049637750
- Cited by
- 245
- References
- 27
- Citations by year
- 2026: 6 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 12 · 2020: 13 · 2019: 8 · 2018: 8 · 2017: 14 · 2016: 18 · 2015: 11 · 2014: 18 · 2013: 15 · 2012: 16
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- University of Kentucky
- Thailand Research Fund
- National Institutes of Health (CA49797)
- National Cancer Institute (CA 73599, R01CA073599, CA49797)
- Congressionally Directed Medical Research Programs
- 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 › Mitochondrial Function and Pathology
- Keywords
- p53, mitochondrial translocation, nuclear translocation, manganese superoxide dismutase, oxidative stress, phorbol myristate acetate, Bax, mitochondrial membrane potential, superoxide dismutase mimetic, transcriptional activation, apoptosis, tumor suppressor, reactive oxygen species, JB6 epidermal cells
- MeSH terms
- Animals, Cell Line, Cell Nucleus, DNA, Immunohistochemistry, Metalloporphyrins, Mitochondria, Skin, Skin Neoplasms, Superoxide Dismutase, Tetradecanoylphorbol Acetate, Transcriptional Activation, Tumor Suppressor Protein p53, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Biomimetic Materials, bcl-2-Associated X Protein, Mice
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