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Drug-Induced Regulation of the MDR1 Promoter in Candida albicans

Jo Beth Harry,^2, Brian G. Oliver,^1,2 Jia L. Song,^1,2, Peter M. Silver,^1,2 John T. Little,^2, Jake Choiniere,² and Theodore C. White^1,2*

Department of Pathobiology, School of Public Health and Community Medicine, University of Washington,¹ Seattle Biomedical Research Institute, Seattle, Washington²

Received 31 December 2004/ Returned for modification 10 March 2005/ Accepted 8 April 2005

Resistance of Candida albicans to azole antifungal drugs is mediated by two types of efflux pumps, encoded by the MDR1 gene and the CDR gene family. MDR1 mRNA levels in a susceptible clinical isolate are induced by benomyl (BEN) but not by other drugs previously shown to induce MDR1. To monitor MDR1 expression under several conditions, the MDR1 promoter was fused to the Renilla reniformis luciferase reporter gene (RLUC). The promoter was monitored for its responses to four oxidizing agents, five toxic hydrophobic compounds, and an alkylating agent, all shown to induce major facilitator pumps in other organisms. Deletion constructs of the MDR1 promoter were used to analyze the basal transcription of the promoter and its responses to the toxic compound BEN and the oxidizing agent tert-butyl hydrogen peroxide (T-BHP). The cis-acting elements in the MDR1 promoter responsible for induction by BEN were localized between –399 and –299 upstream of the start codon. The cis-acting elements responsible for MDR1 induction by T-BHP were localized between –601 and –500 upstream of the start codon. The T-BHP induction region contains a sequence that resembles the YAP1-responsive element (YRE) in Saccharomyces cerevisiae. This Candida YRE was placed upstream of a noninducible promoter in the luciferase construct, resulting in an inducible promoter. Inversion or mutation of the 7-bp YRE eliminated induction. Many of the drugs used in this analysis induce the MDR1 promoter at concentrations that inhibit cell growth. These analyses define cis-acting elements responsible for drug induction of the MDR1 promoter.

Present address: National Institute on Aging, NIH, Baltimore, Md.

Present address: Brown University, Providence, R.I.

Present address: University of California at Santa Clara, Santa Clara, Calif.

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