Effects of nitric oxide on the copper-responsive transcription factor Ace1in Saccharomyces cerevisiae: Cytotoxic and cytoprotective actions of nitric oxide

Previous studies indicate that nitric oxide (NO) can serve as a regulator/d isrupter of metal-metabolizing systems in cells and, indeed, this function may represent an important physiological and/or pathophysiological role for NO. In order to address possible mechanisms of this aspect of NO biology, the effect of NO on copper metabolism and toxicity in the yeast Saccharomyc es cerevisiae was examined. Exposure of S. cerevisiae to NO resulted in an alteration of the activity of the copper-responsive transcription factor Ac e1. Low concentrations of the NO donor DEA/NO were found to slightly enhanc e copper-mediated activation of Ace1. Since Ace1 regulates the expression o f genes responsible for the protection of S. cerevisiae from metal toxicity , the effect of NO on the toxicity of copper toward S. cerevisiae was also examined. Interestingly, low concentrations of NO were also found to protec t S. cerevisiae against the toxicity of copper. The effect of NO at high co ncentrations was, however, opposite. High concentrations of DEA/NO inhibite d copper-mediated Ace1 activity. Correspondingly, high concentrations of DE A/NO (1 mM) dramatically enhanced copper toxicity. An intermediate concentr ation of DEA/NO (0.5 mM) exhibited a dual effect, enhancing toxicity at low er copper concentrations (<0.5 mM) and protecting at higher (greater than o r equal to 0.5 mM) copper concentrations. Thus, it is proposed that the abi lity of NO to both protect against (at low concentrations) and enhance (at high concentration) copper toxicity in S. cerevisiae is, at least partially , a result of its effect on Ace1. The results of this study have implicatio ns for the role of NO as a mediator of metal metabolism. (C) 2000 Academic Press.