Review ArticleRegulation of Nox and Duox enzymatic activity and expression
Section snippets
The respiratory burst
The “respiratory burst” refers to the early observation that when professional phagocytes such as neutrophils and macrophages are exposed to microbes, they consume large amounts of oxygen. Unexpectedly, this oxygen consumption was not inhibited by cyanide, an inhibitor of mitochondrial electron transport. This observation led to a more than 25 year search for the enzymatic origin of the respiratory burst and to the eventual discovery and molecular characterization of the phagocytic NADPH
Reactive oxygen in nonphagocytic cells
During the 1990s, probably as a result of more sensitive methods for detection of H2O2 and O2-, several groups reported the occurrence of ROS in a wide variety of cell types other than professional phagocytes [70], [71], [72], [73], [74], [75], [76]. Although frequently attributed to mitochondrial respiration, in many cases ROS generation was inhibited by diphenylene iodonium (DPI), an inhibitor of the phagocyte NADPH oxidase and some other flavoprotein dehydrogenases [77]. However, although
Regulation of the activity of nonphagocytic Nox/Duox enzymes
A summary of the known modes of regulation of Nox and Duox enzymes is shown in Table 1, and is detailed below.
Regulation of Nox/Duox expression
Although the activity of Nox and Duox enzymes is acutely regulated by subunits or calcium, the maximum capacity of a cell to generate ROS will be determined not only by the activation state, but also by the protein expression of Nox/Duox enzymes and their regulatory subunits. Misregulation of Nox protein expression is a component of certain disease states and stress responses, as discussed in the accompanying review. Therefore, the transcriptional and perhaps translational regulation of Nox
Conclusions
This review of the mechanism and regulation of ROS generation by Nox and Duox enzymes makes evident that ROS levels in cells and tissues are carefully controlled, both by tissue- and stimulus-specific expression of Nox and Duox proteins and their regulatory subunits, and by acute regulation via calcium, protein phosphorylation, guanine nucleotide exchange on Rac, and the assembly of regulatory subunits. Both the expression and the acute activation are regulated by complex mechanisms, and much
Acknowledgments
This work was supported by NIH Grants CA105116 and CA084138.
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