Redox-sensitive kinases of the nuclear factor-kappaB signaling pathway

Abstract

NF-kappaB is an inducible transcription factor that plays a role in the expression of over one hundred genes involved in immunity, inflammation, proliferation, and in defense against apoptosis. NF-kappaB has been known to be redox regulated for some time and is a direct target for oxidation that can affect its ability to bind to DNA. Reactive oxygen species (ROS) have been identified as second messengers in cells, and play a role in receptor signaling and posttranslation modification of signaling molecules. These posttranslation modifications include oxidations of critical cysteines to sulfenic acids or mixed disulfides, which can affect the activity of proteins. Many kinases involved in direct or indirect activation of NF-kappaB are affected by oxidants and therefore, have the potential to alter NF-kappaB activity. This review will provide a summary of the NF-kappaB family, their activation and regulation, followed by a summary of cytoplasmic and nuclear kinases in this pathway whose activity is affected by oxidants. Additionally, recent investigations have revealed that the JNK signaling pathway, which is known to be redox regulated, and pro-apoptotic, is inhibited by NF-kappaB signaling. The crosstalk of NF-kappaB with other signaling pathways is therefore critical for cellular fate, notably survival or cell death under oxidative conditions, and will also be reviewed.