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Vol. 18, Issue 12, 4932-4944, December 2007

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Membrane-active Compounds Activate the Transcription Factors Pdr1 and Pdr3 Connecting Pleiotropic Drug Resistance and Membrane Lipid Homeostasis in Saccharomyces cerevisiae

Christoph Schüller^*,,, Yasmine M. Mamnun^*,,, Hubert Wolfger^*,||, Nathan Rockwell^¶,#, Jeremy Thorner^¶, and Karl Kuchler^*

*Medical University Vienna, Max F. Perutz Laboratories, Department of Medical Biochemistry, A-1030 Vienna, Austria; and ^¶Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720

Submitted June 27, 2007; Revised August 31, 2007; Accepted September 7, 2007
Monitoring Editor: John York

The Saccharomyces cerevisiae zinc cluster transcription factors Pdr1 and Pdr3 mediate general drug resistance to many cytotoxic substances also known as pleiotropic drug resistance (PDR). The regulatory mechanisms that activate Pdr1 and Pdr3 in response to the various xenobiotics are poorly understood. In this study, we report that exposure of yeast cells to 2,4-dichlorophenol (DCP), benzyl alcohol, nonionic detergents, and lysophospholipids causes rapid activation of Pdr1 and Pdr3. Furthermore, Pdr1/Pdr3 target genes encoding the ATP-binding cassette proteins Pdr5 and Pdr15 confer resistance against these compounds. Genome-wide transcript analysis of wild-type and pdr1 pdr3 cells treated with DCP reveals most prominently the activation of the PDR response but also other stress response pathways. Polyoxyethylene-9-laurylether treatment produced a similar profile with regard to activation of Pdr1 and Pdr3, suggesting activation of these by detergents. The Pdr1/Pdr3 response element is sufficient to confer regulation to a reporter gene by these substances in a Pdr1/Pdr3-dependent manner. Our data indicate that compounds with potential membrane-damaging or -perturbing effects might function as an activating signal for Pdr1 and Pdr3, and they suggest a role for their target genes in membrane lipid organization or remodeling.

These authors contributed equally to this work.

Present addresses: Max F. Perutz Laboratories, Department of Biochemistry, University of Vienna, A-1030 Vienna, Austria;

Max F. Perutz Laboratories, Department for Chromosome Biology, University of Vienna, A-1030 Vienna, Austria;

^|| Konrad Lorenz Institute for Ethology, Austrian Academy of Sciences, A-1160 Vienna, Austria;

^# Section of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616.

Address correspondence to: Karl Kuchler (karl.kuchler{at}meduniwien.ac.at).