title: Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans.
abstract: Constitutive overexpression of the Mdr1 efflux pump is an important mechanism of acquired drug resistance in the yeast Candida albicans. The zinc cluster transcription factor Mrr1 is a central regulator of MDR1 expression, but other transcription factors have also been implicated in MDR1 regulation. To better understand how MDR1-mediated drug resistance is achieved in this fungal pathogen, we studied the interdependence of Mrr1 and two other MDR1 regulators, Upc2 and Cap1, in the control of MDR1 expression. A mutated, constitutively active Mrr1 could upregulate MDR1 and confer drug resistance in the absence of Upc2 or Cap1. On the other hand, Upc2 containing a gain-of-function mutation only slightly activated the MDR1 promoter, and this activation depended on the presence of a functional MRR1 gene. In contrast, a C-terminally truncated, activated form of Cap1 could upregulate MDR1 in a partially Mrr1-independent fashion. The induction of MDR1 expression by toxic chemicals occurred independently of Upc2 but required the presence of Mrr1 and also partially depended on Cap1. Transcriptional profiling and in vivo DNA binding studies showed that a constitutively active Mrr1 binds to and upregulates most of its direct target genes in the presence or absence of Cap1. Therefore, Mrr1 and Cap1 cooperate in the environmental induction of MDR1 expression in wild-type C. albicans, but gain-of-function mutations in either of the two transcription factors can independently mediate efflux pump overexpression and drug resistance.
authors.affiliation: Institut für Molekulare Infektionsbiologie, Universität Würzburg, Josef-Schneider-Str. 2, Bau D15, D-97080 Würzburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schubert
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Barker
authors.forename: Sadri
authors.initials: S
authors.lastname: Znaidi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schneider
authors.forename: Franziska
authors.initials: F
authors.lastname: Dierolf
authors.forename: Nico
authors.initials: N
authors.lastname: Dunkel
authors.forename: Malika
authors.initials: M
authors.lastname: Aïd
authors.forename: Geneviève
authors.initials: G
authors.lastname: Boucher
authors.forename: P David
authors.initials: PD
authors.lastname: Rogers
authors.forename: Martine
authors.initials: M
authors.lastname: Raymond
authors.forename: Joachim
authors.initials: J
authors.lastname: Morschhäuser
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors; D015139:Blotting, Southern; D015153:Blotting, Western; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002569:Cerulenin / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D025141:Drug Resistance, Fungal; D005434:Flow Cytometry; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050976:Basic-Leucine Zipper Transcription Factors; C426523:CAP1 protein, Candida albicans; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D014157:Transcription Factors; D002569:Cerulenin; D015725:Fluconazole