Regulation of reactive oxygen species homoestasis by members of the peroxiredoxin family and c-Myc

1850 Peroxiredoxins (Prx’s) are a highly conserved family of proteins that are found in most organisms where they function primarily to scavenge reactive oxygen species (ROS). The most ubiquitous member of the family is Prx1, which has also been shown to function as a tumor suppressor. This occurs as a result of Prx1’s ability to interact with c-Myc and suppress the latter’s transforming potential (Mu ZM, et al. J Biol Chem. 277:43175-43184). prx1-/- mice demonstrate a predisposition to tumorigenesis, presumably due to genomic instability mediated by increased intracellular ROS. Moreover, prx1-/- embryonic fibroblasts (MEFs) show higher activity of c-Myc thus allowing them to be transformed by activated Ras oncogenes alone in comparison to wild type MEFs, which require both c-Myc + Ras. We previously demonstrated increased DNA damage in MEFs and other tissues of prx1-/- mice despite the fact that they show only modest increases in total levels of ROS levels compared to their wild-type counter parts (Egler RA, et al. Oncogene. 24:8038-8050). We postulated this to be consequential to a redistribution of the ROS within the cell. In fact, prx1-/- cells show a dramatic increase in nuclear ROS and reduced levels of cytoplasmic ROS, suggesting that another ROS scavenger may be active in prx1-/- cells. Consistent with this notion, examination of other Prx family members showed an approximate 5-10-fold up-regulation of Prx5 levels relative to prx1+/+ cells. Furthermore, depleting endogenous c-Myc in prx1-/- MEFs led to decreases in Prx5 and a subsequent increase in ROS levels. This study represents a heretofore unreported mechanism for the regulation one Prx family member by another, and identifies a novel means by which cells attempt to maintain ROS homeostasis when one of these family members is compromised.