Functional analysis of the Kluyveromyces lactis PDR1 gene

In Saccharomyces cerevisiae, the simultaneous resistance to various cytotoxic compounds known as multidrug resistance (MDR) is caused by overexpression of membrane efflux pumps under the control of two main transcriptional activators Pdr1p and Pdr3p. In this work we describe the results of functional analysis of a single Kluyveromyces lactis homolog of the PDR1 gene, which encodes a zinc finger Zn(2) Cys(6)-containing transcription factor. The KlPDR1 deletion generated a strain hypersusceptible to oligomycin, antimycin A and azole antifungals. Overexpression of KlPDR1 from a multicopy plasmid in the Klpdr1 Delta mutant strain increased the tolerance of transformants to all the drugs tested (oligomycin, antimycin A and azole antifungals). The plasmid-borne KlPDR1 gene was able to complement drug hypersensitivity of the S. cerevisiae pdr1 Delta pdr3 Delta mutant strain. The KlPDR1 was found to be necessary for upregulation of the ATP-binding cassette transporter encoded by the KlPDR5 gene and rhodamine 6G efflux out of the cells. The KlPDR5 and some other K. lactis pleiotropic drug resistance (PDR) orthologues were found to contain putative PDR-responsive elements in their promoters. These results demonstrate that KlPdr1p is involved in K. lactis MDR and is required for cell's tolerance to various cytotoxic compounds.