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Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression
S Ambs1, S P Hussain, C C Harris
1Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
Abstract:
The tumor suppressor gene product p53 plays an important role in the cellular response to DNA damage. DNA damage can lead to p53-mediated growth arrest and apoptosis. High concentrations of nitric oxide (NO) and NO metabolites such as peroxynitrite and NO2 cause DNA damage and have been shown to be mutagenic. Furthermore, NO induces p53 accumulation and, as part of a feedback loop, p53 mediates transcriptional transrepression of inducible nitric oxide synthase. Recent studies have shown increased expression and activity of nitric oxide synthase isoforms in human cancer. NO has both genotoxic and angiogenic properties, so that increased NO production may select mutant p53 cells and contribute to human carcinogenesis and tumor progression.
Insights
Nitric oxide (NO) causes DNA damage and mutagenicity, leading to p53 accumulation. This interaction may promote cancer development and progression by selecting for mutant p53 cells.
Area of Science:
- Molecular biology
- Cancer research
- Cellular signaling
Background:
- The tumor suppressor protein p53 is crucial for cellular responses to DNA damage, mediating growth arrest and apoptosis.
- High levels of nitric oxide (NO) and its metabolites (peroxynitrite, NO2) induce DNA damage and are mutagenic.
- Increased nitric oxide synthase (NOS) expression and activity are observed in human cancers.
Purpose of the Study:
- To investigate the role of nitric oxide (NO) in DNA damage response and its interplay with the p53 pathway in cancer.
- To elucidate the mechanisms by which NO contributes to mutagenesis and tumor progression.
Main Methods:
- Review of recent studies on NO, DNA damage, and p53 interactions.
- Analysis of the feedback loop between NO and p53 transcriptional activity.
- Examination of the genotoxic and angiogenic properties of NO in the context of cancer.
Main Results:
- NO and its metabolites directly damage DNA, exhibiting mutagenic properties.
- NO induces the accumulation of p53 protein.
- p53 regulates inducible nitric oxide synthase (iNOS) expression via transcriptional transrepression, forming a feedback loop.
- NO possesses both genotoxic and angiogenic effects.
Conclusions:
- Increased NO production in cancer may facilitate the selection of cells with mutant p53.
- NO-mediated genotoxicity and angiogenesis contribute to human carcinogenesis and tumor progression.
- The interplay between NO and p53 is a significant factor in cancer development.