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Eukaryotic Cell, December 2004, p. 1639-1652, Vol. 3, No. 6
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.6.1639-1652.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

TAC1, Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2{dagger}

Alix T. Coste, Mahir Karababa, Françoise Ischer, Jacques Bille, and Dominique Sanglard*

Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland

Received 23 June 2004/ Accepted 2 September 2004

The ABC transporter genes CDR1 and CDR2 can be upregulated in Candida albicans developing resistance to azoles or can be upregulated by exposing cells transiently to drugs such as fluphenazine. The cis-acting drug-responsive element (DRE) present in the promoters of both genes and necessary for their upregulation contains 5'-CGG-3' triplets that are often recognized by transcriptional activators with Zn(2)-Cys(6) fingers. In order to isolate regulators of CDR1 and CDR2, the C. albicans genome was searched for genes encoding proteins with Zn(2)-Cys(6) fingers. Interestingly, three of these genes were tandemly arranged near the mating locus. Their involvement in CDR1 and CDR2 upregulation was addressed because a previous study demonstrated a link between mating locus homozygosity and azole resistance. The deletion of only one of these genes (orf19.3188) was sufficient to result in a loss of transient CDR1 and CDR2 upregulation by fluphenazine and was therefore named TAC1 (transcriptional activator of CDR genes). Tac1p has a nuclear localization, and a fusion of Tac1p with glutathione S-transferase could bind the cis-acting regulatory DRE in both the CDR1 and the CDR2 promoters. TAC1 is also relevant for azole resistance, since a TAC1 allele (TAC1-2) recovered from an azole-resistant strain could trigger constitutive upregulation of CDR1 and CDR2 in an azole-susceptible laboratory strain. Transcript profiling experiments performed with a TAC1 mutant and a revertant containing TAC1-2 revealed not only CDR1 and CDR2 as targets of TAC1 regulation but also other genes (RTA3, IFU5, and HSP12) that interestingly contained a DRE-like element in their promoters. In conclusion, TAC1 appears to be the first C. albicans transcription factor involved in the control of genes mediating antifungal resistance.

* Corresponding author. Mailing address: Institute of Microbiology, University Hospital Lausanne, Rue du Bugnon 48, CH-1011 Lausanne, Switzerland. Phone: 0041 21 3144083. Fax: 0041 21 3144060. E-mail: Dominique.Sanglard{at}chuv.hospvd.ch.

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

Eukaryotic Cell, December 2004, p. 1639-1652, Vol. 3, No. 6
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.6.1639-1652.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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