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The Candida albicans Lanosterol 14--Demethylase (ERG11) Gene Promoter Is Maximally Induced after Prolonged Growth with Antifungal Drugs

Jia L. Song, Jo Beth Harry, Richard T. Eastman, Brian G. Oliver, and Theodore C. White^*

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

Received 11 September 2003/ Returned for modification 14 October 2003/ Accepted 9 December 2003

The azole antifungal drugs that target lanosterol 14--demethylase, encoded by the ERG11 gene, are used to treat a variety of infections caused by Candida albicans. Azoles are known to induce expression of ERG11 mRNA. The ERG11 promoter was cloned 5' of the luciferase-coding region, and the induction of ERG11 expression by azoles was monitored by luciferase assays. Maximal induction of the ERG11 promoter by azoles occurs not during logarithmic growth but after the diauxic shift and requires azoles to be present throughout logarithmic growth. The effects of pH, carbon source, and aerobic or anaerobic growth on induction of the ERG11 promoter by azoles were analyzed. Treatment with terbinafine and fenpropimorph, which target other enzymes in the ergosterol biosynthetic pathway, also resulted in a delayed induction of ERG11 promoter activity. Nascent sterol synthesis was shown to parallel ERG11 promoter activity, and total sterols were reduced coincident with the timing of ERG11 promoter activation. These results as a whole suggest that expression of the ERG11 promoter is regulated in response to sterol depletion.

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

Present address: National Institute on Aging, National Institutes of Health, Baltimore, Md.

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