A possible mechanism of mutagenesis : oxidative stress and nuclear translocation of superoxide dismutase.

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Extracellular superoxide dismutase(EC-SOD) is the only known secretory SOD isoenzyme. EC-SOD has a positively-charged heparin-binding domain at the C-terminus and it has been thought that this domain could allow the enzyme characteristic distribution in tissues after the secretion.Histochemical examination of mouse tissues showed nuclear staining of extracellular superoxide dismutase(EC-SOD),and the nuclear translocation of EC-SOD was also confirmed in cultured cells that had been transfected with its gene, as shown by immunohistochemistry and Western blot analysis. The EC-SOD which was secreted into the medium was incorporated into 3T3-LI cells and a significant fraction of the material taken up was localized in the nucleus. Site-directed mutagenesis indicated that the heparin-binding domain of EC-SOD functions as the nuclear localization signal. These results suggest that the mechanism of the nuclear transport of EC-SOD involves a series of N-terminal signal peptide-and C-terminal he … More parin-binding domain-dependent processes of secretion, re-uptake and the subsequent nuclear translocation. The findings herein provide support for the view that the role of EC-SOD is to protect of genome DNA from damage by reactive oxygen species and/or the transcriptional regulation of redox-sensitive gene expression. Moreover, the effect of oxidative stress on the cellular uptake and nuclear translocation of EC-SOD was investigated. Treatment of the 3T3-LI cells with H_2O_2,(5mM for 5min) followed by incubation with CHO-EK medium downregulated the uptake of EC-SOD. Nuclear translocation of the incorporated EC-SOD was clearly enhanced by H_2O_2 treatment following incubation with the CHO-EK medium. EC-SOD is the only anti-oxidant enzyme which is known at this time to be actively transported into nuclei. The results suggest that the upregulation of the nuclear translocation of EC-SOD by oxidative stress might play a role in the mechanism by which the nucleus is protected against oxidative damage of genomic DNA. Less