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Eukaryotic Cell, July 2008, p. 1180-1190, Vol. 7, No. 7
1535-9778/08/$08.00+0     doi:10.1128/EC.00103-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Gain-of-Function Mutation in the Transcription Factor Upc2p Causes Upregulation of Ergosterol Biosynthesis Genes and Increased Fluconazole Resistance in a Clinical Candida albicans Isolate{triangledown} ,{dagger}

Nico Dunkel,1,§ Teresa T. Liu,2,4,§ Katherine S. Barker,2,6 Ramin Homayouni,7,8 Joachim Morschhäuser,1*,{ddagger} and P. David Rogers2,3,4,5,6*,{ddagger}

Institut für Molekulare Infektionsbiologie, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany,1 Departments of Clinical Pharmacy,2 Pharmaceutical Sciences,3 Molecular Sciences,4 Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38163,5 Children's Foundation Research Center of Memphis, Le Bonheur Children's Medical Center, Memphis, Tennessee 38103,6 Bioinformatics Program, University of Memphis, Memphis, Tennessee 38152,7 Department of Biology, University of Memphis, Memphis, Tennessee 381528

Received 22 March 2008/ Accepted 8 May 2008

In the pathogenic yeast Candida albicans, the zinc cluster transcription factor Upc2p has been shown to regulate the expression of ERG11 and other genes involved in ergosterol biosynthesis upon exposure to azole antifungals. ERG11 encodes lanosterol demethylase, the target enzyme of this antifungal class. Overexpression of UPC2 reduces azole susceptibility, whereas its disruption results in hypersusceptibility to azoles and reduced accumulation of exogenous sterols. Overexpression of ERG11 leads to the increased production of lanosterol demethylase, which contributes to azole resistance in clinical isolates of C. albicans, but the mechanism for this has yet to be determined. Using genome-wide gene expression profiling, we found UPC2 and other genes involved in ergosterol biosynthesis to be coordinately upregulated with ERG11 in a fluconazole-resistant clinical isolate compared with a matched susceptible isolate from the same patient. Sequence analysis of the UPC2 alleles of these isolates revealed that the resistant isolate contained a single-nucleotide substitution in one UPC2 allele that resulted in a G648D exchange in the encoded protein. Introduction of the mutated allele into a drug-susceptible strain resulted in constitutive upregulation of ERG11 and increased resistance to fluconazole. By comparing the gene expression profiles of the fluconazole-resistant isolate and of strains carrying wild-type and mutated UPC2 alleles, we identified target genes that are controlled by Upc2p. Here we show for the first time that a gain-of-function mutation in UPC2 leads to the increased expression of ERG11 and imparts resistance to fluconazole in clinical isolates of C. albicans.

* Corresponding author. Mailing address for Joachim Morschhäuser: Institut für Molekulare Infektionsbiologie, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany. Phone: 49-931-31 21 52. Fax: 49-931-31 25 78. E-mail: joachim.morschhaeuser{at}mail.uni-wuerzburg.de. Mailing address for P. David Rogers: Le Bonheur Children's Medical Center, Room 304 West Patient Tower, Children's Foundation Research Center, 50 North Dunlap Street, Memphis, TN 38103. Phone: (901) 287-5387. Fax: (901) 287-5036. E-mail: drogers{at}utmem.edu

{triangledown} Published ahead of print on 16 May 2008.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

§ These two authors contributed equally to this work.

{ddagger} These two authors share senior authorship of this paper.

Eukaryotic Cell, July 2008, p. 1180-1190, Vol. 7, No. 7
1535-9778/08/$08.00+0     doi:10.1128/EC.00103-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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