Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice

Rita A. Busuttil, Ana Maria Garcia, Carlos Cabrera, Armando Rodriguez, Yousin Suh, Woo Ho Kim, Ting Ting Huang, Jan Vijg

Research output: Contribution to journalArticle

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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-stallied cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of ∼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.

Original languageEnglish (US)
Pages (from-to)11271-11275
Number of pages5
JournalCancer Research
Volume65
Issue number24
DOIs
StatePublished - Dec 15 2005
Externally publishedYes

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Superoxide Dismutase
Mutation Rate
Apoptosis
Mutation
Mammals
Liver
Oxidative Stress
Neoplasms
DNA Nucleotidylexotransferase
Liver Neoplasms
Reporter Genes
Caspase 3
Reactive Oxygen Species
Spleen
Antioxidants
Phenotype
Kidney
Mutation Accumulation
Incidence
Brain

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. / Busuttil, Rita A.; Garcia, Ana Maria; Cabrera, Carlos; Rodriguez, Armando; Suh, Yousin; Kim, Woo Ho; Huang, Ting Ting; Vijg, Jan.

In: Cancer Research, Vol. 65, No. 24, 15.12.2005, p. 11271-11275.

Research output: Contribution to journalArticle

Busuttil, RA, Garcia, AM, Cabrera, C, Rodriguez, A, Suh, Y, Kim, WH, Huang, TT & Vijg, J 2005, 'Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice', Cancer Research, vol. 65, no. 24, pp. 11271-11275. https://doi.org/10.1158/0008-5472.CAN-05-2980
Busuttil, Rita A. ; Garcia, Ana Maria ; Cabrera, Carlos ; Rodriguez, Armando ; Suh, Yousin ; Kim, Woo Ho ; Huang, Ting Ting ; Vijg, Jan. / Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. In: Cancer Research. 2005 ; Vol. 65, No. 24. pp. 11271-11275.
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