title: Cross-talk between transcriptional regulators of multidrug resistance in Saccharomyces cerevisiae.
abstract: 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.
authors.affiliation: Molecular Biology Program and Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242 , USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Cui
authors.forename: T
authors.initials: T
authors.lastname: Miyakawa
authors.forename: W S
authors.initials: WS
authors.lastname: Moye-Rowley
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers; D004271:DNA, Fungal; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D014158:Transcription, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D004271:DNA, Fungal; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; C097077:YOR1 protein, S cerevisiae