ABSTRACT
All organisms have evolved cellular responses to combat adverse and abrupt environmental changes, which in most cases involve the in creased synthesis and activation of molecules or enzymes that serve a protective function (1). One such response mechanism is triggered by oxidative stress which, through the generation of reactive oxygen spe cies (ROS), can induce considerable macromolecular damage (2). As a result, all aerobic organisms have defense mechanisms to protect against such oxidants. The mechanisms that underlie the oxidative stress re sponse have been well characterized in the prokaryotes (3), but in eu karyotes, the mechanisms are far less clear. Most progress has been made in the budding yeast S accharom yces cerevisiae (4), where the response is dependent upon the transcription factor yAP-1 (6,7). This factor was initially identified and cloned by virtue of its ability to spe cifically bind to AP-1 sites. It is a bZIP-containing factor that shows homology within its DNA-binding domain to members of the mamma-
lian Jun family of proteins (8). Consistent with the importance of this factor to the oxidative stress response, its activity is induced by oxida tive stress (6,7), and disruption of the YAP1 gene causes significant increased sensitivity to oxidative stress generated by agents such as hydrogen peroxide, diamide, and diethyl maleate (4,5). However, the factor is also important in the response of cells to other stress condi tions, its overexpression conferring pleiotropic drug and cadmium re sistance (6,9-11). A number of target genes that are activated by stress conditions in a yAP-1-dependent manner have now been identified, including the TRX2 gene, which encodes thioredoxin that confers in creased resistance to hydroperoxides (6,12); TRR1, which encodes thio redoxin reductase (12); YCF1, which encodes a GS-X transporter (13); one type of ATP-binding cassette transporter gene essential for cadmium tolerance (11); GSH1 (14), which encodes γ-glutamylcysteine synthetase involved in glutathione biosynthesis; GLR1, which encodes glutathione reductase (15), and the additional ABC transporter proteins encoded by PDR5 and SNQ2 (16). These results indicate that, as well as having a key role in the oxidative stress response, yAP-1 is also a key factor in drug metabolism including modification and efflux of drugs. In this review, we present recent data that address the mechanism of yAP-1 activation by oxidative stress (17).
