title: Genomewide expression profile analysis of the Candida glabrata Pdr1 regulon.
abstract: The ABC transporters Candida glabrata Cdr1 (CgCdr1), CgPdh1, and CgSnq2 are known to mediate azole resistance in the pathogenic fungus C. glabrata. Activating mutations in CgPDR1, a zinc cluster transcription factor, result in constitutive upregulation of these ABC transporter genes but to various degrees. We examined the genomewide gene expression profiles of two matched azole-susceptible and -resistant C. glabrata clinical isolate pairs. Of the differentially expressed genes identified in the gene expression profiles for these two matched pairs, there were 28 genes commonly upregulated with CgCDR1 in both isolate sets including YOR1, LCB5, RTA1, POG1, HFD1, and several members of the FLO gene family of flocculation genes. We then sequenced CgPDR1 from each susceptible and resistant isolate and found two novel activating mutations that conferred increased resistance when they were expressed in a common background strain in which CgPDR1 had been disrupted. Microarray analysis comparing these reengineered strains to their respective parent strains identified a set of commonly differentially expressed genes, including CgCDR1, YOR1, and YIM1, as well as genes uniquely regulated by specific mutations. Our results demonstrate that while CgPdr1 activates a broad repertoire of genes, specific activating mutations result in the activation of discrete subsets of this repertoire.
authors.affiliation: Children's Foundation Research Center, Le Bonheur Children's Hospital, 50 North Dunlap Street, Memphis, TN 38103, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Caudle
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Barker
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Lijing
authors.initials: L
authors.lastname: Xu
authors.forename: Ramin
authors.initials: R
authors.lastname: Homayouni
authors.forename: P David
authors.initials: PD
authors.lastname: Rogers
mesh_terms: D001393:Azoles / Q000494:pharmacology; D041221:Candida glabrata / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002177:Candidiasis / Q000382:microbiology; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D006801:Humans; D018085:Regulon; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001393:Azoles; D005656:Fungal Proteins; D014157:Transcription Factors