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Updated: Sep 29, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Elevated susceptibility of the p53 knockout mouse esophagus to methyl-N-amylnitrosamine carcinogenesis
Norimitsu Shirai1, Tetsuya Tsukamoto, Masami Yamamoto
1Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa, Nagoya 464-8681, Japan.
Abstract:
Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers, including those in the esophagus. Mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this study we investigated the susceptibility of p53 nullizygous (-/-), heterozygous (+/-) and wild-type (+/+) mice to methyl-N-amylnitrosamine (MNAN), which specifically induces esophageal tumors in mice and rats. The p53 (+/-) and (+/+) mice were treated with 5 or 15 p.p.m. MNAN in their drinking water for 8 weeks then maintained without further treatment for an additional 7 or 17 weeks, being killed at experimental weeks 15 or 25. An additional group of p53 (-/-) mice were given 5 p.p.m. MNAN for 8 weeks and killed at week 15. At 15 weeks in the 5 p.p.m. groups, squamous cell carcinomas (SCCs) were observed in 10/12 (83.3%) p53 (-/-) and 1/15 (6.7%) p53 (+/-) mice, but in none of the p53 (+/+) mice. In the animals receiving 15 p.p.m., 2/14 (14.3%) p53 (+/-) and 1/11 (9.1%) p53 (+/+) mice developed SCCs. At 25 weeks, the incidence of SCCs was 7/16 (43.8%) and 8/14 (57.1%) in p53 (+/-) mice and 1/13 (7.7%) and 2/10 (20.0%) in p53 (+/+) mice at 5 and 15 p.p.m., respectively. Of the SCCs examined by PCR-single strand conformation polymorphism analysis, 61% (14/23) from p53 (+/-) and 50% (6/12) from p53 (+/+) mice demonstrated mutations in the p53 gene (exons 5-8). These results indicate the order of susceptibility to MNAN-induced esophageal tumorigenesis to be as follows: nullizygotes (-/-) > heterozygotes (+/-) > wild-type (+/+), and provide strong evidence of involvement of p53 mutations in the development of esophageal SCCs.
Insights
Mice lacking the p53 gene are more susceptible to esophageal tumors induced by MNAN. p53 mutations are strongly implicated in the development of these esophageal squamous cell carcinomas.
Area of Science:
- Oncology
- Genetics
- Toxicology
Background:
- p53 tumor suppressor gene mutations are common in human cancers, including esophageal cancer.
- Mice lacking p53 function are utilized to study chemical genotoxicity.
- Methyl-N-amylnitrosamine (MNAN) is a known inducer of esophageal tumors in rodents.
Purpose of the Study:
- To investigate the susceptibility of p53-deficient mice (nullizygous and heterozygous) and wild-type mice to MNAN-induced esophageal tumorigenesis.
- To determine the role of p53 mutations in the development of esophageal squamous cell carcinomas (SCCs) following MNAN exposure.
Main Methods:
- p53 nullizygous (-/-), heterozygous (+/-), and wild-type (+/+) mice were exposed to MNAN in drinking water for 8 weeks.
- Mice were analyzed at 15 and 25 weeks post-exposure for the incidence of esophageal SCCs.
- Tumor samples were analyzed for p53 gene mutations using PCR-single strand conformation polymorphism (PCR-SSCP).
Main Results:
- p53 nullizygous mice showed the highest incidence of SCCs (83.3%) at 15 weeks with 5 p.p.m. MNAN.
- Esophageal SCC incidence increased with MNAN dose and duration of observation in p53 heterozygous and wild-type mice.
- p53 gene mutations were detected in 61% of SCCs from p53 heterozygous and 50% from wild-type mice.
Conclusions:
- Susceptibility to MNAN-induced esophageal tumorigenesis follows the order: p53 nullizygotes > heterozygotes > wild-type.
- These findings provide strong evidence for the involvement of p53 mutations in the pathogenesis of MNAN-induced esophageal SCCs.
