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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53 knockout mice (-/-) are more susceptible than (+/-) or (+/+) mice to N-methyl-N-nitrosourea stomach
M Yamamoto1, T Tsukamoto, H Sakai
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. Mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this study we have investigated the susceptibility of p53 nullizygote (-/-), heterozygote (+/-) and wild-type (+/+) mice to N:-methyl-N:-nitrosourea (MNU) gastric carcinogenesis. p53 knockout mice were treated with 30 p.p.m. MNU in the drinking water 1 week on and 1 week off and killed after 5 weeks. The numbers of pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were 1.8, 1.7 and 22.6 in p53 (+/+), (+/-) and (-/-) mice, respectively. In a 15 week experiment, adenomas were found in 0 of 19 (+/+) (0%), 2 of 21 (+/-) (9.5%) and 6 of 10 (-/-) (60.0%) animals. Also, one well-differentiated adenocarcinoma was observed in a p53 (-/-) mouse. After 40 weeks treatment with 120 or 30 p.p.m. MNU there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice. However, mortality from carcinogen-induced lymphomas, leukemias and sarcomas was very much greater in the latter group. Homozygous knockout animals could not be maintained long term. PCR-single strand conformation polymorphism analysis of exons 5-8 of the p53 gene of DNA extracts from 68 gastric tumors consisting of 16 and 20 30 p.p.m. MNU-treated p53 (+/+) and (+/-) mice and 14 and 18 120 p.p.m. MNU-treated p53 (+/+) and (+/-) mice demonstrated no mutations. These results suggest that p53 may not be a direct target of MNU but rather play an important role as a gatekeeper in mouse stomach carcinogenesis induced by this direct acting agent.
Insights
Mice lacking the p53 tumor suppressor gene showed increased susceptibility to N-methyl-N-nitrosourea (MNU) induced gastric preneoplastic lesions and tumors. This suggests p53 acts as a gatekeeper in MNU-induced stomach carcinogenesis.
Area of Science:
- Oncology
- Genetics
- Toxicology
Background:
- Mutations in the p53 tumor suppressor gene are common in human cancers.
- p53-deficient mice are utilized to identify chemical genotoxins.
- Gastric carcinogenesis is a significant area of cancer research.
Purpose of the Study:
- To investigate the role of p53 in N-methyl-N-nitrosourea (MNU) induced gastric carcinogenesis.
- To assess the susceptibility of p53 knockout mice to MNU.
- To determine if p53 is a direct target of MNU.
Main Methods:
- p53 nullizygote, heterozygote, and wild-type mice were treated with MNU.
- Gastric lesions and tumors were quantified after 5 and 15 weeks.
- PCR-single strand conformation polymorphism analysis was used to detect p53 mutations.
Main Results:
- p53 nullizygote mice exhibited significantly higher numbers of pepsinogen-altered pyloric glands (PAPG) and gastric adenomas.
- Adenocarcinomas and other tumors (lymphomas, leukemias, sarcomas) were observed in p53-deficient mice.
- No p53 mutations were detected in gastric tumors from MNU-treated mice.
Conclusions:
- p53 plays a crucial gatekeeper role in MNU-induced mouse stomach carcinogenesis.
- MNU does not appear to directly target the p53 gene.
- p53 deficiency enhances susceptibility to MNU-induced gastric lesions and tumors.
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