YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae

Abstract

In this study, we utilized a genetic approach to identify genes which render yeast cells resistant to cerulenin (Cer), a potent and noncompetitive inhibitor of fatty acid synthase (FAS). Overexpression of the yeast transcription factor Yap1p was found to confer Cer resistance (Cer(R)). This resistance was shown to be less pronounced in a strain deleted for YCF1, a multidrug resistance ABC transporter, supporting previous observations that implicated YCF1 in mediating Cer(R). However, isolation of YAP1 as a high-copy Cer(R) gene in a ycf1Δ strain suggested that YAP1-induced Cer(R) was mediated by additional downstream effecters. Overexpression of neither glutathione reductase nor a predicted aryl alcohol dehydrogenase (the products of two YAP1-regulated genes involved in detoxification) conferred Cer(R). Overexpression of ATR1, another YAP1-regulated gene previously implicated in conferring resistance to a number of cytotoxic drugs, was also incapable of making cells resistant to Cer. In contrast, overexpression of Flr1p, a yeast transporter of the major facilitator superfamily which is also under the control of YAP1, was sufficient to confer Cer(R) in an otherwise wild-type background. Moreover, Cer(R) was markedly diminished in a strain deleted for FLR1. These findings implicate members of both of the transporter superfamilies involved in multiple drug resistance (MDR) in the acquisition of Cer(R) in yeast. Furthermore, our studies indicate that yeast may be a useful model system in which to investigate the role of FAS in cancer biology and the effects of Cer on eukaryotic cell growth.