The Central Role of PDR1 in the Foundation of Yeast Drug Resistance

Abstract

The widespread pleiotropic drug resistance (PDR) phenomenon is well described as the long term selection of genetic variants expressing constitutively high levels of membrane transporters involved in drug efflux. However, the transcriptional cascades leading to the PDR phenotype in wild-type cells are largely unknown, and the first steps of this phenomenon are poorly understood. We investigated the transcriptional mechanisms underlying the establishment of an efficient PDR response in budding yeast. We show that within a few minutes of drug sensing yeast elicits an effective PDR response, involving tens of PDR genes. This early PDR response (ePDR) is highly dependent on the Pdr1p transcription factor, which is also one of the major genetic determinants of long term PDR acquisition. The activity of Pdr1p in early drug response is not drug-specific, as two chemically unrelated drugs, benomyl and fluphenazine, elicit identical, Pdr1p-dependent, ePDR patterns. Our data also demonstrate that Pdr1p is an original stress response factor, the DNA binding properties of which do not depend on the presence of drugs. Thus, Pdr1p is a promoter-resident regulator involved in both basal expression and rapid drug-dependent induction of PDR genes.All living organisms have developed complex transcriptional responses for rapidly adapting genome expression to the presence of toxic compounds in the environment. These responses involve various types of cellular pathway. Genome-wide studies of drug responses in microorganisms have revealed that these responses comprise both specific effects depending on the precise chemical nature and cellular targets of the toxic compound and a general stress response (environmental stress response (ESR) 5 in the yeast Saccharomyces cerevisiae), reflecting cell adaptation to growth defects and cellular damages, regardless of the type of stress encountered by the cell (1). Inbetween these very specific and very general responses, prokaryotic and eukaryotic cells have evolved multidrug resistance (MDR) pathways, which confer resistance to a broad spectrum of unrelated chemicals, but which are restricted to the stress responses associated with organic drugs. From bacteria to humans, MDR is essentially based on the overexpression of membrane transporters able to export a large number of chemically different compounds (2-4). MDR is a major concern for human health, as it leads to antibiotic resistance in pathogens and enables cancer cells to survive chemotherapy.In the model yeast S. cerevisiae, MDR is referred to as PDR (pleiotropic drug response). The PDR network currently comprise 10 transcription factors regulating about 70 different target genes reviewed in Ref. 18). In this network, the Pdr1p transcription factor has the largest set of potential targets (about 50). Pdr1p and its functional homologue, Pdr3p, were identified in the early 1990s as regulators of the basal level of drug resistance in yeast cells (19,20). Gain-or loss-of-function alleles of PDR1 and PDR3 confer resistance or sensitivit...

Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation

“…The rapid weak acid-triggered activation of War1 is accompanied by the concomitant appearance of several phosphorylated War1 isoforms (7,21,22). As reported recently, exposure to the drug fluphenazine causes transient activation of the zinc cluster proteins Pdr1/Pdr3 on a similar time scale (23).…”

“…They often control small and specific regulons representing a particular task in the cell metabolism. Only few members, like the drug resistance regulators Pdr1 and Pdr3, seem to play more than one distinct role (23,32). War1 is another highly specific member of this class, even conserved beyond the yeast S. cerevisiae.…”

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

“…Fluphenazine is a drug interfering with the calmodulin functions in yeast and is also an efficient inductor of Cdr1 and Cdr2 in C. albicans. This drug helped to identity in susceptibility assays the effect of TFs involved in the regulation of these transporters (14,51).…”

Site‐directed mutagenesis of Asp853 in Pdr3p transcriptional activator from Saccharomyces cerevisiae

“…In the yeast Saccharomyces cerevisiae, two transcriptional activators, Pdr1p and Pdr3p, belong to the master regulators of the entire PDR gene network, including the PDR5 gene coding for the main multidrug ABC transporter in the cytoplasmic membrane (Moye-Rowley, 2003;Fardeau et al, 2006;Jungwirth and Kuchler, 2006). Like Pdr1p (Balzi et al, 1994), Pdr3p is a zinc cluster protein recognizing pleiotropic drug response elements (PDREs) in promoters of the target genes (Delaveau et al, 1994;Katzmann et al, 1994).…”

“…Both transcription factors are constitutively bound to the PDR5 promoter (Mamnun et al, 2002;Fardeau et al, 2006). Unlike PDR1, the PDR3 gene is autoregulated by its own gene product (Delahodde et al, 1995) and activated by Hsf1p heat shock transcription factor (Hahn et al, 2006).…”