A specific transcriptional mechanism compensates for defects in particular multidrug resistance transporters by induction of their homologues of overlapping specificity.
Marcin Kolaczkowski (1), Anna Kolaczkowska (2), André Goffeau (3), Scott Moye-Rowley (4)
(1) Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, Wroclaw, PL-50-368, Poland; (2) Institute of Biochemistry and Molecular Biology, University of Wroclaw, Tamka 2, PL-50-137 Wroclaw, Poland; (3) Unité de Biochimie Physiologique, Université Catholique de Louvain, Place Croix du Sud 2-20, B-1348 Louvain-la-Neuve, Belgium; (4) Department of Physiology and Biophysics, University of Iowa, 6-530 Bowen Science Bldg., Iowa City, IA 52242, USA
In Saccharomyces cerevisiae, detoxification of xenobiotics depends on the activation of the major ATP binding cassette multidrug resistance (MDR) transporters PDR5, SNQ2 and YOR1 by Pdr1p and Pdr3p. Our recent finding, that genes responsive to these homologous Zn 2 Cys 6 transcription factors cluster within the sphingolipid biosynthesis pathway suggests that the physiological role of the pleiotropic drug resistance- PDR network may not be limited to xenobiotic protection. We observed that resistance to growth inhibition by several Pdr5p substrates was elevated upon inactivation of homologous transporters of overlapping yet distinct substrate specificity, such as Yor1p and Snq2p. This correlates with an increased efflux activity of Pdr5p as measured by a newly developed fluorescence based assay. Similar behavior is observed with Yor1p or Snq2p when the other two homologues are not active. We will present data demonstrating that this increase in resistance and drug transport results from increased transcriptional activation and expression of corresponding proteins that occurs even in the absence of xenobiotics. Localization of promoter elements and identification of regulators involved in induction with a series of wild type and mutant promoters fused with the lacZ reporter will be shown. Our results identify a specific transcriptional mechanism of compensation to defects in particular MDR transporters, which supports a role for these proteins in addition to xenobiotic protection.