title: Upregulation of the Saccharomyces cerevisiae efflux pump Tpo1 rescues an Imp2 transcription factor-deficient mutant from bleomycin toxicity.
abstract: Yeast mutants lacking the transcriptional co-activator Imp2 are hypersensitive to the anticancer drug bleomycin, although the gene targets involved in this process remain elusive. A search for multicopy suppressors that rescue the imp2Δ mutant from bleomycin toxicity revealed the transcriptional activator Yap1, which can turn on many target genes such as transporters involved in regulating drug resistance. We show that YAP1 overexpression stimulated the expression of the TPO1 gene encoding a polyamine efflux pump, and that Yap1 failed to rescue the imp2Δ mutant from bleomycin toxicity in the absence of the TPO1 gene. Moreover, TPO1 overexpression, and not the related transporter gene QDR3, conferred upon the tpo1Δ imp2Δ double mutant parental resistance to bleomycin. We conclude that YAP1 overexpression rescues the imp2Δ mutant from bleomycin toxicity by triggering Tpo1 expression to expel the drug. Our data provide the first evidence that bleomycin could be a substrate for the Tpo1 efflux pump.
authors.affiliation: Maisonneuve-Rosemont Hospital, Research Center, University of Montreal, 2nd Floor J.A DeSeve, 5415 de L'Assomption, Montreal, QC, Canada.
authors.forename: Siham
authors.initials: S
authors.lastname: Berra
authors.forename: Sami
authors.initials: S
authors.lastname: Ayachi
authors.forename: Dindial
authors.initials: D
authors.lastname: Ramotar
mesh_terms: D017920:Antiporters / Q000378:metabolism*; D001761:Bleomycin / Q000633:toxicity*; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013095:Spermidine / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017920:Antiporters; D017931:DNA Primers; C096739:IMP2 protein, S cerevisiae; D009687:Nuclear Proteins; D027701:Organic Cation Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; C475058:TPO1 protein, S cerevisiae; D015534:Trans-Activators; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; D001761:Bleomycin; D013095:Spermidine
keywords: drug efflux pumps; drug responses; transcription factors; yeast