Redox regulation of cellular signalling.

ABSTRACT

Extracellular stimuli elicit a variety of responses, such as cell proliferation and differentiation, through the cellular signalling system. Binding of growth factors to the respective receptor leads to the activation of receptor tyrosine kinases, which in turn stimulate downstream signalling systems such as mitogen-activated protein (MAP) kinases, phospholipase Cgamma (PLCgamma) and phosphatidylinositol 3-kinase. These biochemical reactions finally reach the nucleus, resulting in gene expression mediated by the activation of several transcription factors. Recent studies have revealed that cellular signalling pathways are regulated by the intracellular redox state. Generation of reactive oxygen species (ROS), such as H2O2, leads to the activation of protein tyrosine kinases followed by the stimulation of downstream signalling systems including MAP kinase and PLCgamma. The activation of PLCgamma by oxidative radical stress elevates the cellular Ca2+ levels by flux from the intracellular Ca2+ pool and from the extracellular space. Such reactions in the upstream signalling cascade, in concert, result in the activation of several transcription factors. On the other hand, reductants generally suppress the upstream signalling cascade resulting in the suppression of transcription factors. However, it is well known that cysteine residues in a reduced state are essential for the activity of many transcription factors. In fact, in vitro, oxidation of NFkappaB results in its activation, whereas reductants promote its activity. Thus, cellular signalling pathways are generally subjected to dual redox regulation in which redox has opposite effects on upstream signalling systems and downstream transcription factors. Not only are the cellular signalling pathways subjected to redox regulation, but also the signalling systems regulate the cellular redox state. When cells are activated by extracellular stimuli, the cells produce ROS, which in turn stimulate other cellular signalling pathways, indicating that ROS act as second messengers. It is thus evident that there is cross talk between the cellular signalling system and the cellular redox state. Cell death and life also are subjected to such dual redox regulation and cross talk. Death signals induce apoptosis through the activation of caspases in the cells. Oxidative radical stress induces the activation of caspases, whereas the oxidation of caspases results in their inactivation. Furthermore, some cell-death signals induce the production of ROS in the cells, and the ROS produced in turn stimulate the cell-death machinery. All this evidence shows that the cell's fate is determined by cross talk between the cellular signalling pathways and the cellular redox state through a complicated regulation mechanism.