Abstract
Apoptosis is induced by reactive oxygen species (ROS) and nitrogen species (RNS) which are produced under inflammatory conditions. Antioxidative enzymes such as superoxide dismutases and glutathione peroxidases (GPx) are known to prevent apoptosis through scavenging cytotoxic ROS. We found that nitric oxide (NO) specifically inhibits GPx activity, resulting in augmentation of peroxides. This suggests that dysfunction of GPx by binding of NO to the active site, selenocysteine, is at leaset in part responsible for the cellular damage. Since imbalance of a redox state caused by overexpression of aldose reductase also induces apoptosis, a significant role of redox system in controlling apoptosis is implicated. We have cloned and analyzed five members of the peroxiredoxin (Prx) gene family, which detoxify peroxides with thioredoxin and/or glutathione as electron donors. Analysis of the fourth member, Prx IV, indicates that it is a secretable form and exerts its protective role outside of the cells. We also demonstrated the essential role of selenocysteine residue in thioredoxin reductase by site specific mutagenesis as well as by deletion analysis of the selenocysteine insertion sequence element located at the 3' -untranslated region of the gene. Possible roles of these redox systems in protection against apoptotic stimuli are discussed.
