Reactive oxygen species and regulation of gene expression.
In eucaryotic cells reactive oxygen species (ROS) are produced in the reactions catalyzed by NAD(P)H oxidase and by some other specialized oxidases and also as an inevitable by-product of many redox reactions. Intracellular ROS synthesis is regulated by various hormones, cytokines, and growth factors. An increase in the ROS levels above a certain threshold (so-called oxidative stress) is accompanied by processes that are harmful for cell survival, such as lipid peroxidation and oxidative modification of proteins and nucleic acids. However, at low concentrations ROS act as secondary messengers responsible for a signal transduction from extracellular signaling molecules and their membrane receptors to the intracellular regulatory systems which control gene expression. Cellular transcriptional response to ROS is mediated mainly by activation of MAP protein kinases and submitted transcription factors AP-1, ATF, and NF-kappaB. A number of specific genes is also induced under hypoxia, i.e., under conditions opposite to oxidative stress. Cellular transcriptional response on hypoxia is mediated by activation of transcription factors HIF-1 and AP-1. Together with ROS, nitric oxide fulfills the role of a mobile and highly reactive redox-sensitive signaling molecule. Chemical reactions of NO with the superoxide anion and with other free radicals leads to production of highly reactive intermediates. Depending on the ratio of their intracellular concentrations, NO and ROS can either enhance or attenuate their reciprocal effects on cells.