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.

Carcinogenesis
|October 7, 2000
PubMed

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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