Manganese Superoxide Dismutase Is a p53 -Regulated Gene That Switches Cancers between Early and Advanced Stages
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Abstract
Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life, and its aberrant expression has been implicated in carcinogenesis and tumor resistance to therapy. However, despite extensive studies in MnSOD regulation and its role in cancer, when and how the alteration of MnSOD expression occurs during the process of tumor development in vivo are unknown. Here, we generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter-enhancer elements and investigated the changes of MnSOD transcription using the 7,12-dimethylbenz(α)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model. The results show that MnSOD expression was suppressed at a very early stage but increased at late stages of skin carcinogenesis. The suppression and subsequent restoration of MnSOD expression were mediated by two transcription-factors, Sp1 and p53. Exposure to DMBA and TPA activated p53 and decreased MnSOD expression via p53-mediated suppression of Sp1 binding to the MnSOD promoter in normal-appearing skin and benign papillomas. In squamous cell carcinomas, Sp1 binding increased because of the loss of functional p53. We used chromatin immunoprecipitation, electrophoretic mobility shift assay, and both knockdown and overexpression of Sp1 and p53 to verify their roles in the expression of MnSOD at each stage of cancer development. The results identify MnSOD as a p53-regulated gene that switches between early and advanced stages of cancer. These findings also provide strong support for the development of means to reactivate p53 for the prevention of tumor progression.
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The increase in MnSOD in p53 knockout mice is consistent with p53 transcriptional repression of MnSOD.
“which is consistent with the p53 transcriptional repression of MnSOD [90,91]”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [91]
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- Authors
- Dhar, S. K., Tangpong, J., Chaiswing, L., Oberley, T. D., & St. Clair, D. K.
- Affiliations
- University of Wisconsin–Madison (US)
- Authors' Affiliations: 1Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky; and 2Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Venue
- Cancer Research
- Published
- 2011-10-30
- Volume
- 71
- Issue
- 21
- Pages
- 6684-6695
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3206134
- OpenAlex
- W2161465168
- Cited by
- 106
- References
- 45
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 6 · 2017: 10 · 2016: 6 · 2015: 10 · 2014: 8 · 2013: 15 · 2012: 8
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA 73599, R01CA073599, CA49797, R01CA049797)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- manganese superoxide dismutase, p53, Sp1, transcriptional regulation, skin carcinogenesis, squamous cell carcinoma, tumor progression, p53 reactivation, transcription factor binding
- MeSH terms
- Animals, Carcinogens, Carcinoma, Squamous Cell, Cocarcinogenesis, Enhancer Elements, Genetic, Female, Genes, Synthetic, Humans, Mice, Transgenic, Neoplasm Proteins, Papilloma, Promoter Regions, Genetic, Recombinant Fusion Proteins, Skin Neoplasms, Superoxide Dismutase, Tetradecanoylphorbol Acetate, Transcription, Genetic, 9,10-Dimethyl-1,2-benzanthracene, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Sp1 Transcription Factor, Genes, Reporter, Disease Progression, Mice, Gene Knockdown Techniques
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