Transcriptional Regulation of
            <i>MDR1</i>
            , Encoding a Drug Efflux Determinant, in Fluconazole-Resistant
            <i>Candida albicans</i>
            Strains through an Mcm1p Binding Site

Riggle, Perry J.; Kumamoto, Carol A.

doi:10.1128/ec.00243-06

Cited by 52 publications

(71 citation statements)

References 58 publications

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“…Pdr1p and Pdr3p target a sequence motif or PDRE (59-TCCG/aC/tGG/cA/G-39), where variable bases in the consensus motif are shown in lower case (DeRisi et al, 2000). This motif is not equivalent to the DRE [59-CGGA(A/T)ATCGGATATTTTTTTT-39] common to CDR1 and CDR2 (De Micheli et al, 2002) or to the benomyl-responsive element (BRE) described recently in MDR1 (Rognon et al, 2006) and also by other studies (Harry et al, 2005;Hiller et al, 2006b;Riggle & Kumamoto, 2006). Even though CTA4, ASG1 and CTF1 (as well as FCR1) show little similarity to PDR1 and PDR3, there may still be sufficient similarity to enable the activation of PDR5 through a PDRE.…”

Section: Discussionmentioning

confidence: 96%

Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae

et al. 2008

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One of the mediators of pleiotropic drug resistance in Saccharomyces cerevisiae is the ABC-transporter gene PDR5. This gene is regulated by at least two transcription factors with Zn(2)-Cys(6) finger DNA-binding motifs, Pdr1p and Pdr3p. In this work, we searched for functional homologues of these transcription factors in Candida albicans. A C. albicans gene library was screened in a S. cerevisiae mutant lacking PDR1 and PDR3 and clones resistant to azole antifungals were isolated. From these clones, three genes responsible for azole resistance were identified. These genes (CTA4, ASG1 and CTF1) encode proteins with Zn(2)-Cys(6)-type zinc finger motifs in their N-terminal domains. The C. albicans genes expressed in S. cerevisiae could activate the transcription of a PDR5-lacZ reporter system and this reporter activity was PDRE-dependent. They could also confer resistance to azoles in a S. cerevisiae strain lacking PDR1, PDR3 and PDR5, suggesting that CTA4-, ASG1-and CTF1-dependent azole resistance can be caused by genes other than PDR5 in S. cerevisiae. Deletion of CTA4, ASG1 and CTF1 in C. albicans had no effect on fluconazole susceptibility and did not alter the expression of the ABC-transporter genes CDR1 and CDR2 or the major facilitator gene MDR1, which encode multidrug transporters known as mediators of azole resistance in C. albicans. However, additional phenotypic screening tests on the C. albicans mutants revealed that the presence of ASG1 was necessary to sustain growth on nonfermentative carbon sources (sodium acetate, acetic acid, ethanol). In conclusion, C. albicans possesses functional homologues of the S. cerevisiae Pdr1p and Pdr3p transcription factors; however, their properties in C. albicans have been rewired to other functions. INTRODUCTIONMultidrug transporters are widely distributed proteins in living organisms and are responsible for the transport of a large variety of compounds. Two types of transporters, the ATP-binding cassette (ABC) and the major facilitator superfamily (MFS) transporters have been described in lower eukaryotes such as Saccharomyces cerevisiae and have several functions, including phospholipid translocation in the plasma membrane, pheromone transport and the efflux of different classes of antifungal agents. Multidrug transporters are important for the human pathogen Candida albicans, as they have been found to be responsible for the development of resistance to azoles, which are important antifungal agents.In C. albicans, two ABC transporters, Cdr1p and Cdr2p (for Candida drug resistance) and one MFS transporter, Mdr1p (multidrug resistance) were shown to be upregulated in several azole-resistant isolates (Sanglard et al., 1995). Each of the genes encoding these proteins can be upregulated in distinct clinical azole-resistant strains. The transcription of the gene encoding Mdr1p, MDR1, is almost absent in azole-susceptible isolates, but is measurable in specific azole-resistant cells. The gene encoding Cdr1p, CDR1, shows basal transcriptional activity in azolesusceptible...

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Section: Discussionmentioning

confidence: 96%

Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae

et al. 2008

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show abstract

“…Constitutive upregulation of Mdr1, a member of the major facilitator superfamily of transporters, confers resistance to fluconazole (67,163,230). Multiple cis-regulatory sequences governing the upregulation of Mdr1 have recently been identified (75,182,188), as have key residues in the transporter required for drug efflux VOL. 7, 2008 MINIREVIEWS 749 (159).…”

Section: Resistance To Drugs Exerting Cell Membrane Stress: the Triazmentioning

confidence: 99%

Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance

2008

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“…Detailed deletion mapping experiments have been described in several publications (47,49,96,99). These studies have identified several different regions in the CaMDR1 promoter that are involved in basal, oxidant-or drug-induced expression.…”

Section: Candida Albicansmentioning

confidence: 99%

Multidrug Resistance in Fungi

2007

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Transcriptional Regulation of MDR1 , Encoding a Drug Efflux Determinant, in Fluconazole-Resistant Candida albicans Strains through an Mcm1p Binding Site

Cited by 52 publications

References 58 publications

Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae

Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae

Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance

Multidrug Resistance in Fungi

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