Membrane-active compounds activate the transcription factors Pdr1 and Pdr3 connecting pleiotropic drug resistance and membrane lipid homeostasis in saccharomyces cerevisiae.
The Saccharomyces cerevisiae zinc cluster transcription factors Pdr1 and Pdr3 mediate general drug resistance to many cytotoxic substances also known as pleiotropic drug resistance (PDR). The regulatory mechanisms that activate Pdr1 and Pdr3 in response to the various xenobiotics are poorly understood. In this study, we report that exposure of yeast cells to 2,4-dichlorophenol (DCP), benzyl alcohol, nonionic detergents, and lysophospholipids causes rapid activation of Pdr1 and Pdr3. Furthermore, Pdr1/Pdr3 target genes encoding the ATP-binding cassette proteins Pdr5 and Pdr15 confer resistance against these compounds. Genome-wide transcript analysis of wild-type and pdr1Delta pdr3Delta cells treated with DCP reveals most prominently the activation of the PDR response but also other stress response pathways. Polyoxyethylene-9-laurylether treatment produced a similar profile with regard to activation of Pdr1 and Pdr3, suggesting activation of these by detergents. The Pdr1/Pdr3 response element is sufficient to confer regulation to a reporter gene by these substances in a Pdr1/Pdr3-dependent manner. Our data indicate that compounds with potential membrane-damaging or -perturbing effects might function as an activating signal for Pdr1 and Pdr3, and they suggest a role for their target genes in membrane lipid organization or remodeling.
Schüller
Christoph
C
Medical University Vienna, Max F. Perutz Laboratories, Department of Medical Biochemistry, A-1030 Vienna, Austria.
Mamnun
Yasmine M
YM
Wolfger
Hubert
H
Rockwell
Nathan
N
Thorner
Jeremy
J
Kuchler
Karl
K
D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002733:Chlorophenols / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003902:Detergents / Q000737:chemistry / Q000494:pharmacology; D025141:Drug Resistance, Fungal; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D016681:Genome, Fungal / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects; D007477:Ions / Q000737:chemistry; D008563:Membrane Lipids / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
D002733:Chlorophenols; D004268:DNA-Binding Proteins; D003902:Detergents; D007477:Ions; D008563:Membrane Lipids; C085480:PDR1 protein, S cerevisiae; C089261:PDR3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C004762:2,4-dichlorophenol