TY - JOUR
T1 - Age-related mutation accumulation at a lacZ reporter locus in normal and tumor tissues of Trp53-deficient mice
AU - Giese, Heidi
AU - Snyder, Wendy K.
AU - Van Oostrom, Conny
AU - Van Steeg, Harry
AU - Dollé, Martijn E.T.
AU - Vijg, Jan
N1 - Funding Information:
We thank Drs. Ruth Lipman and Roderick Bronson for assistance with macroscopical analysis of tissues and histopathological analysis. This research was supported by NIH grants CA 75653, AG 17242, AG13319 and ES11044.
PY - 2002/2/15
Y1 - 2002/2/15
N2 - 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.
AB - 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.
KW - Aging
KW - LacZ transgenic reporter mice
KW - Mutation accumulation
KW - Trp53-knockout mice
KW - Tumors
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U2 - 10.1016/S1383-5718(01)00329-1
DO - 10.1016/S1383-5718(01)00329-1
M3 - Article
C2 - 11815254
AN - SCOPUS:0037082948
SN - 1383-5718
VL - 514
SP - 153
EP - 163
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
IS - 1-2
ER -