Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux

Leonard, Pat; Rathod, P K; Golin, John

doi:10.1128/aac.38.10.2492

Cited by 43 publications

(23 citation statements)

References 9 publications

(8 reference statements)

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“…The kinetic characterization of Pdr5p rhodamine 6G quenching inhibitors is consistent with the in vivo drug sensitivity assay results, showing that compounds whose toxicity is reduced by Pdr5p are competitive inhibitors of rhodamine transport including chloramphenicol, previously reported to be substrate of Pdr5p (40). There is one exception, however, Pdr5p clearly mediates trifluoperazine resistance which appears to be a noncompetitive inhibitor of rhodamine 6G transport.…”

Section: Resultssupporting

confidence: 69%

Anticancer Drugs, Ionophoric Peptides, and Steroids as Substrates of the Yeast Multidrug Transporter Pdr5p

Kołaczkowski

Rest

Cybularz-Kolaczkowska

et al. 1996

Journal of Biological Chemistry

300

288

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Pdr5p is the yeast Saccharomyces cerevisiae ATPbinding cassette transporter conferring resistance to several unrelated drugs. Its high overproduction in Pdr1p transcription factor mutants allows us to study the molecular mechanism of multidrug transport and substrate specificity. We have developed new in vivo and in vitro assays of Pdr5p-mediated drug transport. We show that in spite of little sequence homology, and inverted topology in respect to that of mammalian P-glycoproteins, Pdr5p shares with them common substrates. Pdr5p extrudes rhodamines 6G and 123, from intact yeast cells in an energy-dependent manner. Plasma membrane preparations from a Pdr5p-overproducing strain exhibit ATP hydrolysis-dependent, osmotically sensitive rhodamine 6G fluorescence quenching. The quenching is competitively inhibited by micromolar concentrations of many anticancer drugs, such as vinblastine, vincristine, taxol, and verapamil, and of ionophoric peptides as well as steroids. In contrast, other anticancer drugs, like colchicine and some multidrug resistance modifiers, such as quinidine, exert noncompetitive inhibition. Our experimental system opens new possibilities for the analysis of structure-function relationship of multidrug transporter substrates and inhibitors.

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Section: Resultssupporting

confidence: 69%

Anticancer Drugs, Ionophoric Peptides, and Steroids as Substrates of the Yeast Multidrug Transporter Pdr5p

Kołaczkowski

Rest

Cybularz-Kolaczkowska

et al. 1996

Journal of Biological Chemistry

300

288

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“…PDR5 (22), SNQ2 (14,28), and YOR1 (24) each encode an ABC pump which, upon overexpression, leads to resistance against a variety of structurally unrelated cytotoxic compounds. These ABC transporters are involved in a wide range of energy-dependent transport events across the plasma membrane and are thought to function as drug efflux pumps (27). The present work demonstrates that Pdr1p and Pdr3p can also activate expression of HXT11 and HXT9, two genes belonging to the MFS.…”

Section: Discussionmentioning

confidence: 50%

Multiple-Drug-Resistance Phenomenon in the Yeast Saccharomyces cerevisiae: Involvement of Two Hexose Transporters

Nourani

Wésolowski-Louvel

Delaveau

et al. 1997

Molecular and Cellular Biology

110

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In the yeast Saccharomyces cerevisiae, multidrug resistance to unrelated chemicals can result from overexpression of ATP-binding cassette (ABC) transporters such as Pdr5p, Snq2p, and Yor1p. Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p. Here, we describe the isolation, by an in vivo screen, of two new Pdr1p-Pdr3p target genes: HXT11 and HXT9. HXT11 and HXT9, encoding nearly identical proteins, have a high degree of identity to monosaccharide transporters of the major facilitator superfamily (MFS). In this study, we show that the HXT11 product, which allows glucose uptake in a glucose permease mutant (rag1) strain of Kluyveromyces lactis, is also involved in the pleiotropic drug resistance process. Loss of HXT11 and/or HXT9 confers cycloheximide, sulfomethuron methyl, and 4-NQO (4-nitroquinoline-N-oxide) resistance. Conversely, HXT11 overexpression increases sensitivity to these drugs in the wild-type strain, an effect which is more pronounced in a strain having both PDR1 and PDR3 deleted. These data show that the two putative hexose transporters Hxt11p and Hxt9p are transcriptionally regulated by the transcription factors Pdr1p and Pdr3p, which are known to regulate the production of ABC transporters required for drug resistance in yeast. We thus demonstrate the existence of genetic interactions between genes coding for two classes of transporters (ABC and MFS) to control the multidrug resistance process.Transmembrane solute transport is ensured in all eukaryotic cells by a set of proteins embedded in the plasma and the internal membranes. Most transport proteins characterized to date catalyze the uptake of solutes across the plasma membrane. Other plasma membrane transporters mediate extrusion of intracellular compounds into the medium, while others, located in intracellular membranes, catalyze efflux from or within the mitochondria, vacuole, peroxisomes, or secretion organelles. These membrane proteins are generally classified in three main categories: channels, facilitators (also named transporters, permeases, or carriers), and pumps (ATPases). Among them, one protein family of particular biological importance is the nonproton ATPase family encoding ATP-binding cassette (ABC) transporters, which appear to be conserved in all living organisms ranging from bacteria to humans (1, 13, 32). Alterations of certain ABC transporters can cause human genetic disorders such as cystic fibrosis (36), Zellweger syndrome (19), X-linked adrenoleukodystrophy (30), and the multidrug-resistance (MDR) phenotype shown by tumor cells which acquire resistance to a variety of chemotherapeutic agents. MDR phenotype is frequently linked to the increased expression, sometimes by gene amplification, of an integral membrane protein, a member of the ABC transporter family. This protein, called P-glycoprotein, functions as an ATP-dependent efflux pump for drugs (18).In the yeast Saccharomyces cerevisiae, a phenotype resembling the mammalian MDR exists and i...

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“…Subcellular localization will be a defining property in proposing models for how Yor1p might function in oligomycin resistance. Pdr5p is a plasma membrane protein that mediates the efflux of target drugs out of the cell (30). Hmt1p, a vacuolar ABC transporter from Schizosaccharomyces pombe, has recently been shown to confer cadmium resistance through pumping of phytochelatincadmium complexes into the vacuole (36).…”

Section: Discussionmentioning

confidence: 99%

Expression of an ATP-Binding Cassette Transporter-Encoding Gene (YOR1) Is Required for Oligomycin Resistance in Saccharomyces cerevisiae

Katzmann

Hallstrom

Voet

et al. 1995

Molecular and Cellular Biology

Self Cite

211

195

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Semidominant mutations in the PDR1 or PDR3 gene lead to elevated resistance to cycloheximide and oligomycin. PDR1 and PDR3 have been demonstrated to encode zinc cluster transcription factors. Cycloheximide resistance mediated by PDR1 and PDR3 requires the presence of the PDR5 membrane transporterencoding gene. However, PDR5 is not required for oligomycin resistance. Here, we isolated a gene that is necessary for PDR1-and PDR3-mediated oligomycin resistance. This locus, designated YOR1, causes a dramatic elevation in oligomycin resistance when present in multiple copies. A yor1 strain exhibits oligomycin hypersensitivity relative to an isogenic wild-type strain. In addition, loss of the YOR1 gene blocks the elevation in oligomycin resistance normally conferred by mutant forms of PDR1 or PDR3. The YOR1 gene product is predicted to be a member of the ATP-binding cassette transporter family of membrane proteins. Computer alignment indicates that Yor1p shows striking sequence similarity with multidrug resistance-associated protein, Saccharomyces cerevisiae Ycf1p, and the cystic fibrosis transmembrane conductance regulator. Use of a YOR1-lacZ fusion gene indicates that YOR1 expression is responsive to PDR1 and PDR3. While PDR5 expression is strictly dependent on the presence of PDR1 or PDR3, control of YOR1 expression has a significant PDR1/PDR3-independent component. Taken together, these data indicate that YOR1 provides the link between transcriptional regulation by PDR1 and PDR3 and oligomycin resistance of yeast cells.

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Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux

Cited by 43 publications

References 9 publications

Anticancer Drugs, Ionophoric Peptides, and Steroids as Substrates of the Yeast Multidrug Transporter Pdr5p

Anticancer Drugs, Ionophoric Peptides, and Steroids as Substrates of the Yeast Multidrug Transporter Pdr5p

Multiple-Drug-Resistance Phenomenon in the Yeast Saccharomyces cerevisiae: Involvement of Two Hexose Transporters

Expression of an ATP-Binding Cassette Transporter-Encoding Gene (YOR1) Is Required for Oligomycin Resistance in Saccharomyces cerevisiae

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