Redox regulation in mammalian signal transduction.

Abstract

DIOXYGEN AND OXYGEN METABOLITES Gene expression of any cell, be it a unicellular organism or constituent of a mammal, is regulated in response to extracellular cues. Among the many in uences to which respirating cells are exposed, oxygen and oxygen metabolites play a central role. That cells sense these components and convert the information into changes of gene expression, has been known formany years. How oxygen homeostasis is achieved, which ones the sensors are, and how gene programs are then regulated, is a matter of current study. One aspect of recent progress has been the recognition that, although the intracellular milieu is reductive, there are redox-sensitive pockets and macromolecules. Obviously, the program of gene expression is established by speciŽ c transcription factors. These are, however, not the direct targets of oxygen or oxygen metabolites. As an illustration to this point—lack of oxygen in the multicellular mammalian organism leads to enhanced angiogenesis, erythropoesis, altered metabolism, and, if persistant, to apoptosis of the most sensitive cells. Hypoxia-inducible factor (HIF) (1) seems to represent the most important responsive transcription factor affecting relevant gene expression [see review (2)]. The promoter speciŽ city determining subunit HIF ¤ is subjected to ubiquitination and degradation in normoxic conditions. During hypoxia, degradation is prevented. The sensor for dioxygen appears to be an enzyme that modiŽ es the ubiquitin conjugating enzyme (3, 4). The opposite to hypoxia, an increase of oxidative potential, results from a number of conditions. Reactive oxygen intermediates (ROI) can be normal products of oxygen consumption. Most evident is the generation of superoxide anions and ofH2O2, HOCl, and hydroxyl radicals during a respiratory burst of neutrophils. Its absence in chronic granulomatous disease results in life-threatening infections. TheROI are produced by anNADPH oxidase that is controlled by Rac2 (5). Small G protein-regulated NADPH oxidases have also been detected in other cells and it is assumed that low concentrations of ROIs can function as sec-