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 effectors. 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.