Disease relevance of PDR5

• In this study, we demonstrate that relief of estradiol toxicity in yeast cells expressing VEO requires functional PDR5 and SNQ2 genes, since a Deltapdr5 Deltasnq2 double deletion leads to an increased estradiol toxicity [1].
• Loss of function mutations in PDR5 result in chloramphenicol hypersensitivity [2].
• Functional analysis demonstrated that cDNA of atrB can complement the drug hypersensitivity associated with PDR5 deficiency in S. cerevisiae [3].

High impact information on PDR5

• Furthermore, YDR1 overexpression impaired cell growth, an effect that could be rescued by overexpression of TBP [4].
• The repressor complex is encoded by two essential genes, designated YDR1 and BUR6 [4].
• We isolated a yeast mutant, lem1, with increased sensitivity to dexamethasone and triamcinolone acetonide; responsiveness to a third agonist, deoxycorticosterone, is unaffected [5].
• We propose that transporters like LEM1 can selectively modulate the intracellular levels of steroid hormones [5].
• Genetic analysis of the YDR1-BUR6 repressor complex reveals an intricate balance among transcriptional regulatory proteins in yeast [6].

Chemical compound and disease context of PDR5

• Pregnenolone toxicity is more pronounced when the atf2-Delta mutation is introduced in a yeast strain devoid of the ATP-binding cassette transporters, PDR5 and SNQ2 [7].
• We demonstrate that disruption of PDR5 causes marked hypersensitivity not only to cycloheximide but also to sulphometuron methyl and the mitochondrial inhibitors chloramphenicol, lincomycin, erythromycin and antimycin [8].
• In addition, activation of Ras2, a regulator of cAMP generation, results in some protection from fluconazole toxicity in a fashion independent of the efflux transporter Pdr5p [9].
• The mode of Pdr5p inhibition of enniatin was competitive against FK506, and its inhibitory activity was more potent with less toxicity than that of FK506 [10].
• Disruption of YDR1 resulted in hypersensitivity to cycloheximide, cerulenin, compactin, staurosporine and fluphenazine, indicating that YDR1 is an important determinant of cross resistance to apparently-unrelated drugs [11].

Biological context of PDR5

• Overexpression of Pdr13p leads to an increase in both the expression of PDR5 and YOR1 and a corresponding enhancement in drug resistance [12].
• The yeast PDR5 gene encodes an efflux pump that confers multidrug resistance [13].
• Loss of previously described nuclear-mitochondrial signaling genes like RTG1 reduce the level of PDR5 expression and drug resistance seen in rho(o) cells but has no effect on oxa1-induced phenotypes [14].
• Disruption of both PDR5 and SNQ2 in a pdr1 mutant decreases the cell growth rate and reveals the presence of at least two other ATP binding cassette proteins in the 160-kDa overexpressed band that have been identified by amino-terminal microsequencing [15].
• We have carried out a genetic screen to identify negative regulators of PDR5 expression and found that loss of the mitochondrial genome (rho(o) cells) causes up-regulation of Pdr3p but not Pdr1p function [14].

Anatomical context of PDR5

• The SNQ2 protein was solubilized with n-dodecyl beta-D-maltoside from the plasma membranes of a PDR5-deleted strain and separated from the PMA1 H(+/-)ATPase by sucrose gradient centrifugation [15].
• Homologues of three of these genes have been implicated in azole and/or drug resistance in Saccharomyces cerevisiae: two of these belong to the family of ABC transporters (PDR5 and PDR16), and one is involved in retrograde signaling from mitochondria to nucleus (RTG2) [16].
• These results reinforce the emerging evidence in both S. cerevisiae and Candida albicans that sterols could serve as substrates for Pdr5p for transport across membranes [17].
• However, unlike in yeast cells, ecdysone agonist RH5992 could not be excluded by PDR5, probably because of low expression levels or imperfect incorporation of the recombinant protein in these transformed cell lines [18].
• Immunofluorescence analysis revealed that vacuolar delivery of Pdr5 is blocked in conditional end4 endocytosis mutants at the restrictive temperature, showing that endocytosis delivers Pdr5 from the plasma membrane to the vacuole [19].

Associations of PDR5 with chemical compounds

• The ATP binding cassette transporter-encoding genes regulated by Pdrlp include PDR5 and YOR1, which are required for normal cycloheximide and oligomycin tolerances, respectively [12].
• The enzyme shows a nucleoside triphosphatase activity that differs biochemically from that of PDR5 (Decottignies, A., Kolaczkowski, M., Balzi, E., and Goffeau, A. (1994) J. Biol. Chem. 269, 12797-12803) and is sensitive to vanadate, erythrosine B, and Triton X-100 but not to oligomycin, which inhibits the PDR5 activity only [15].
• Library deconvolution identified the 4-methoxy-2,3,6-trimethylbenzensulfonyl-substituted D-octapeptide KN20 as a potent Pdr5p ATPase inhibitor (concentration of drug causing 50% inhibition of enzyme activity [IC(50)], 4 microM) which chemosensitized AD/PDR5(+) to FLC, itraconazole, and ketoconazole [20].
• Here, we show that PDR5 promoter activity is dramatically reduced when cells stop growing due to a limitation of glucose or nitrogen or when they approach stationary phase [21].
• Although the protective role of TPO1 and PDR5 genes was confirmed, the majority of the responsive genes encoding multidrug resistance do not confer resistance to 2,4-D [22].

Physical interactions of PDR5

• Loss of the mitochondrial genome (rho(0) cell) or elimination of the mitochondrial inner membrane protein Oxa1p causes a dramatic increase in expression of the ATP binding cassette transporter-encoding gene PDR5 in the yeast Saccharomyces cerevisiae [23].
• Overexpression of the yeast Pdr5 ATP-binding cassette transporter leads to pleiotropic drug resistance to a variety of structurally unrelated cytotoxic compounds [24].
• Interestingly, yeast Pdr5p interacted with flavonoids recently found to bind to cancer cell P-glycoprotein and to the protozoan parasite multidrug transporter [25].

Regulatory relationships of PDR5

• However, the camptothecin resistance accompanying GAL1-promoted overexpression of PDR5 suggests some substrate promiscuity among the ATP-binding cassette transporters [26].
• FDR-1 has been found to be an activated allele of the Pleiotropic Drug Resistance-1 (PDR-1) gene (termed PDR1-100) and to upregulate PDR5 transcription [17].
• Pdr3p is involved in a retrograde response in which mitochondrial dysfunctions activate PDR5, a gene encoding an ABC membrane transporter [27].
• A PDR5-independent pathway of multi-drug resistance regulated by the SIN4 gene product [28].

Other interactions of PDR5

• Transcriptional control of the yeast PDR5 gene by the PDR3 gene product [29].
• The PDR1 T879M mutant increased PDR5 transcription compared with wild-type PDR1 strains [26].
• The ATP binding cassette transporters Pdr5 and Snq2 of Saccharomyces cerevisiae can mediate transport of steroids in vivo [1].
• We also analyzed the interaction between PDR5 and YAP1 [30].
• Zinc cluster protein Rdr1p is a transcriptional repressor of the PDR5 gene encoding a multidrug transporter [13].

Analytical, diagnostic and therapeutic context of PDR5

• Indirect immunofluorescence showed that a pdr1-3 mutant massively overexpresses Pdr5 at the plasma membrane, suggesting that estradiol efflux from the cells occurs across the plasma membrane [1].
• Immunoblotting demonstrates that Pdr5p levels are high in the logarithmic growth phase, while its levels decrease sharply when cells exit exponential growth [21].
• Analyzed by chromatin immunoprecipitations, loss of contacts between histones and DNA occurs at both promoter and coding sequences of PDR5 [31].
• Here, we described a novel drug screening system designated to detect compounds that inhibit the function of Pdr5 [32].
• Sequence analysis revealed significant amino acid homology to the primary structures of PMR1 (protein encoded by the PMR1 gene) and ABC transporters of Saccharomyces cerevisiae (PDR5 and SNQ2), Schizosaccharomyces pombe (HBA2), Candida albicans (CDR1), and Aspergillus nidulans (AtrA and AtrB) [33].

References