Age-related mutation accumulation at a lacZ reporter locus in normal and tumor tissues of Trp53-deficient mice

Heidi Giese, Wendy K. Snyder, Conny Van Oostrom, Harry Van Steeg, Martijn E.T. Dollé, Jan Vijg

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Increased genomic instability has been found associated with cancer and aging. The p53 tumor suppressor protein is a major determinant of genomic instability as a regulator of cell cycle control and apoptosis in response to DNA damage. To investigate the rate of age-related mutation accumulation in the absence of p53, we crossed Trp53 null mice with transgenic mice harboring a lacZ mutational target gene. In the hybrid animals, lacZ mutation frequencies at early age (i.e. at about 2 months) were found to be the same as in the control lacZ animals. However, up until about 6 months, when the Trp53-knockout mice usually die from cancer, mutations were found to accumulate with age in the spleen, and to a lesser extent in the liver, at a more rapid rate than in the control Trp53+/+ or Trp53+/-, lacZ hybrid mice. Treatment of 2-3-month-old Trp53-/-, lacZ hybrid mice with the powerful mutagen ethyl nitrosourea (ENU) resulted in a higher number of mutations induced in the liver but not in the spleen, as compared to the Trp53+/+, lacZ mice. These results suggest that p53 is not an important determinant of gene mutation induction, either spontaneously during development or after treatment with a mutagen. The accelerated age-related accumulation of mutations in normal spleen and liver could be explained by the defect in apoptosis, which would prevent severely damaged cells from being eliminated.

Original languageEnglish (US)
Pages (from-to)153-163
Number of pages11
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume514
Issue number1-2
DOIs
Publication statusPublished - Feb 15 2002
Externally publishedYes

    Fingerprint

Keywords

  • Aging
  • LacZ transgenic reporter mice
  • Mutation accumulation
  • Trp53-knockout mice
  • Tumors

ASJC Scopus subject areas

  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this