Age-related mutation accumulation at a lacZ reporter locus in normal and tumor tissues of Trp53-deficient mice.
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.
Giese
Heidi
H
Department of Physiology, Sam and Ann Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, Texas Research Park, 15355 Lambda Drive, Rm. 2.200, San Antonio, TX 78245, USA.
Snyder
Wendy K
WK
van Oostrom
Conny
C
van Steeg
Harry
H
Dollé
Martijn E T
ME
Vijg
Jan
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D005038:Ethylnitrosourea / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D017930:Genes, Reporter; D016158:Genes, p53; D007763:Lac Operon / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D005038:Ethylnitrosourea