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J. Biol. Chem., Vol. 282, Issue 37, 26822-26831, September 14, 2007

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Negative Transcriptional Regulation of Multidrug Resistance Gene Expression by an Hsp70 Protein^*

From the Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

One of the most common origins of multidrug resistance occurs via the overproduction of ATP-binding cassette (ABC) transporter proteins. These ABC transporters then act as broad specificity drug pumps and efflux a wide range of toxic agents out of the cell. The yeast Saccharomyces cerevisiae exhibits multiple or pleiotropic drug resistance (Pdr) often through the over-production of a plasma membrane-localized ABC transporter protein called Pdr5p. Expression of the PDR5 gene is controlled by two zinc cluster-containing transcription factors called Pdr1p and Pdr3p. Cells that lack their mitochondrial genome (⁰ cells) strongly induce PDR5 transcription in a Pdr3p-dependent fashion. To identify proteins associated with Pdr3p that might act to regulate this factor, a tandem affinity purification (TAP) moiety was fused to Pdr3p, and this recombinant protein was purified from yeast cells. The cytosolic Hsp70 chaperone Ssa1p co-purified with TAP-Pdr3p. Overexpression of Ssa1p repressed expression of PDR5 but had no effect on expression of other genes involved in the Pdr phenotype. This Ssa1p-mediated repression required the presence of Pdr3p and did not influence Pdr1p-dependent gene expression. Loss of the nucleotide exchange factor Fes1p mimicked Ssa1p-mediated repression of PDR5. Co-immunoprecipitation experiments indicated that Ssa1p was associated with Pdr3p but not Pdr1p in yeast cells. Finally, ⁰ cells had less Ssa1p bound to Pdr3p than ⁺ cells, consistent with Ssa1p-mediated repression of Pdr3p activity serving as a key regulatory step in control of multidrug resistance in yeast.

Received for publication, June 11, 2007 , and in revised form, July 16, 2007.

^* This work was supported by National Institutes of Health Grant GM49825. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Physiology and Biophysics, 6-530 Bowen Science Bldg., 51 Newton Road, Iowa City, IA 52242. Tel.: 319-335-7874; Fax: 319-335-7330; E-mail: scott-moyerowley{at}uiowa.edu.

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