Abstract
Substrates of pleiotropic drug resistance (PDR) transporters can induce the expression of corresponding transporter genes by binding to their transcription factors. Penetrating cations are substrates of PDR transporters and theoretically may also activate the expression of transporter genes. However, the accumulation of penetrating cations inside mitochondria may prevent the sensing of these molecules. Thus, whether penetrating cations induce PDR is unclear. Using Saccharomyces cerevisiae as a model, we studied the effects of penetrating cations on the activation of PDR. We found that the lipophilic cation dodecyltriphenylphosphonium (C12TPP) induced the expression of the plasma membrane PDR transporter genes PDR5, SNQ2 and YOR1. Moreover, a 1-hour incubation with C12TPP increased the concentration of Pdr5p and Snq2p and prevented the accumulation of the PDR transporter substrate Nile red. The transcription factor PDR1 was required to mediate these effects, while PDR3 was dispensable. The deletion of the YAP1 or RTG2 genes encoding components of the mitochondria-to-nucleus signalling pathway did not prevent the C12TPP-induced increase in Pdr5-GFP. Taken together, our data suggest (i) that the sequestration of lipophilic cations inside mitochondria does not significantly inhibit sensing by PDR activators and (ii) that the activation mechanisms do not require mitochondria as a signalling module.
Highlights
Living cells are capable of resisting toxic compounds due to the activity of plasma membrane pumps with broad substrate specificity
Treating rat liver cells with the MDR transporter substrate doxorubicin upregulates the expression of the corresponding P-glycoprotein gene9. 2-methyl-4-chlorophenoxyacetic has been shown to be a substrate of yeast pleiotropic pumps (Pdr5p and Tpo1p), inducing the expression of the corresponding genes[5]
We measured the dynamics of C12R1 accumulation in a strain with deleted PDR1 and PDR3 transcription factors
Summary
Living cells are capable of resisting toxic compounds due to the activity of plasma membrane pumps with broad substrate specificity. Cycloheximide D can induce the expression of PDR5 in yeast by binding directly to the upstream transcription factor Pdr1p11 Another mechanism of pleiotropic drug resistance pumps activation that relies on mitochondria was revealed for some yeast species[12,13,14]. In Saccharomyces cerevisiae, the loss of mitochondrial DNA or the deletion of nuclear encoded genes essential for mitochondrial functioning (e.g., FZO1) upregulates unspecific drug resistance[15,16,17] This effect requires the Pdr3p transcription factor and the components of the mitochondria-to-nucleus retrograde signalling pathway RTG1 and RTG215. We found that C12TPP induces MDR in yeast This activation requires the Pdr1p transcription factor, whereas the deletion of the PDR3 gene or the genes encoding components of the mitochondria-to-nucleus retrograde signalling pathways did not abolish the induction
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