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Organ-Specific Increase in Mutation Accumulation and Apoptosis Rate in CuZn-Superoxide Dismutase–Deficient Mice

Cited 59 time in Web of Science Cited 62 time in Scopus
Authors
Busuttil, Rita A; Garcia, Ana Maria; Cabrera, Carlos; Rodriguez, Armando; Suh, Yousin; Kim, Woo Ho; Huang, Ting-Ting; Vijg, Jan
Issue Date
2005-12-17
Publisher
American Association for Cancer Research
Citation
Cancer Res 2005;65:11271-5
Abstract
Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apoptotic cells, as indicated by an increase in both terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling- and caspase 3-stained cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of approximately 2.5-fold was found not earlier than at 6 months. No increased mutation accumulation was observed in brain or spleen. These results support the hypothesis, that oxidative stress is an important causal factor of cancer in mammals.
ISSN
0008-5472 (print)
1538-7445 (online)
Language
English
URI
http://hdl.handle.net/10371/9937
DOI
https://doi.org/10.1158/0008-5472.CAN-05-2980
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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