Yeast gene YRR1, which is required for resistance to 4‐nitroquinoline N‐oxide, mediates transcriptional activation of the multidrug resistance transporter gene SNQ2

Cui, Zhifeng; Shiraki, Toshiyuki; Hirata, Dai; Miyakawa, Tokichi

doi:10.1046/j.1365-2958.1998.01027.x

Cited by 71 publications

(72 citation statements)

References 28 publications

(51 reference statements)

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“…However, Wehrschutz et al (23) have shown that the deletion of both PDR1 and PDR3, despite strongly reducing PDR5 basal expression, does not abolish the induction of this gene upon cycloheximide or diazaborine treatment. Similar results have been reported for the ABC transporter Snq2p, the expression of which is slightly up-regulated by 4-nitroquinoline (4-NQO) independent of PDR1 and PDR3 (24).…”

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confidence: 86%

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

Fardeau

Lelandais

Oldfield

et al. 2007

Journal of Biological Chemistry

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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...

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supporting

confidence: 86%

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

Fardeau

Lelandais

Oldfield

et al. 2007

Journal of Biological Chemistry

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“…was originally cloned by its ability to confer reveromycin A resistance (17). Our data previously implicated YOR1 in resistance to both reveromycin A (7) and the mitochondrial ATPase inhibitor oligomycin (6).…”

Section: Yrr1 Confers Oligomycin Resistance In S Cerevisiae-yrr1mentioning

confidence: 95%

“…PB4 is a pdr1⌬ and pdr3⌬ mutant yeast strain as previously described (19). XZY1 and XZY2 were made by transforming a yrr1-⌬1::TRP1 gene disruption plasmid (17) digested with BamHI and PstI into SEY6210 and PB4, respectively. Trp ϩ transformants were selected and analyzed by Southern blotting analysis to confirm introduction of the disruption allele.…”

Section: Methodsmentioning

confidence: 99%

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Cross-talk between Transcriptional Regulators of Multidrug Resistance in Saccharomyces cerevisiae

Zhang

Cui

Miyakawa

et al. 2001

Journal of Biological Chemistry

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Multiple or pleiotropic drug resistance often arises in the yeast Saccharomyces cerevisiae due to genetic alterations of the functional state of the Cys 6 -Zn(II) 2 transcription factors Pdr1p and Pdr3p. Single amino acid substitutions give rise to hyperactive forms of these regulatory proteins, which in turn cause overproduction of downstream target genes that directly mediate multidrug resistance. Previous work has identified a novel Cys 6 -Zn(II) 2 transcription factor designated Yrr1p as mutant forms of this protein confer high level resistance to the cell cycle inhibitor reveromycin A and DNA damaging agent 4-nitroquinoline-N-oxide. In the present study, we demonstrate that Yrr1p also mediates oligomycin resistance through activation of the ATP-binding cassette transporter-encoding gene YOR1. Additionally, insertion of triplicated copies of the hemagglutinin epitope in the C-terminal region of Yrr1p causes the protein to behave as a hyperactive regulator of transcription. We have found that YRR1 expression is both controlled in a Pdr1p/Pdr3p-dependent manner and autoregulated. Chromatin immunoprecipitation experiments also show that Yrr1p associates with target promoters in vivo. Together these data argue that the signal generated by activation of Pdr1p and/or Pdr3p can be amplified through the action of these transcriptional regulatory proteins on downstream target genes, like YRR1, that also encode transcription factors.A common feature underlying acquisition of multiple or pleiotropic drug resistance is the overexpression of genes encoding ATP-binding cassette (ABC) 1 transporters. Multidrug resistant tumor cells often exhibit amplification of the gene encoding the Mdr1p, a prototypical drug efflux pump (1). Gene amplification is typically not seen associated with pleiotropic drug resistance (Pdr) of the yeast Saccharomyces cerevisiae (2), yet these highly drug-resistant strains commonly possess high level transcription of ABC transporter genes like PDR5 (3-5) or YOR1 (6, 7). Overexpression of these ABC transporters is required for the Pdr phenotype and most commonly results from genetic lesions that activate function of the Cys 6 -Zn(II) 2 transcription factors Pdr1p and Pdr3p (8,9).PDR1 was isolated as the first locus that could be mutated to confer a Pdr phenotype in S. cerevisiae (10). Cloning and analysis of this gene indicated that Pdr1p likely acted as a transcriptional regulator (11). Hyperactive alleles of PDR1 led to marked overproduction of target genes, which in turn allowed cells to tolerate otherwise toxic levels of drugs (12). Mutant forms of a PDR1 homologue (PDR3) produce a similar effect on both drug resistance and ABC transporter expression (13,14). Biochemical experiments indicated that Pdr1p and Pdr3p bind to the same DNA element that was designated the Pdr1p/ Pdr3p response element (PDRE) (15). Interestingly, the PDR3 structural gene contains two PDREs and is regulated by Pdr1p and autoregulated at the transcriptional level (16). The presence of at least one PDRE has been found asso...

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“…Transcription of PDR5, SNQ2, PDR10 and PDR15, as well as YOR1 (Table 2) is controlled by Pdr1p/Pdr3p and Yrr1p, the latter modulating expression of both SNQ2 and YOR1 [63,64]. PDR3 and YRR1 are also autoregulated via PDREs in their own promoters [63][64][65].…”

Section: Regulation Of Abc Gene Expression In S Cerevisiaementioning

confidence: 99%

Yeast ABC transporters – A tale of sex, stress, drugs and aging

2005

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Yeast ATP-binding cassette (ABC) proteins are implicated in many biological phenomena, often acting at crossroads of vital cellular processes. Their functions encompass peptide pheromone secretion, regulation of mitochondrial function, vacuolar detoxification, as well as pleiotropic drug resistance and stress adaptation. Because yeast harbors several homologues of mammalian ABC proteins with medical importance, understanding their molecular mechanisms, substrate interaction and three-dimensional structure of yeast ABC proteins might help identifying new approaches aimed at combating drug resistance or other ABC-mediated diseases. This review provides a comprehensive discussion on the functions of the ABC protein family in the yeast Saccharomyces cerevisiae.

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Yeast gene YRR1, which is required for resistance to 4‐nitroquinoline N‐oxide, mediates transcriptional activation of the multidrug resistance transporter gene SNQ2

Cited by 71 publications

References 28 publications

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

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

Cross-talk between Transcriptional Regulators of Multidrug Resistance in Saccharomyces cerevisiae

Yeast ABC transporters – A tale of sex, stress, drugs and aging

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