High impact information on PDR3

• Complementation cloning and linkage analysis led to the identification of the dominant mutation TPE1-1 as a new allele of PDR1 and the semidominant mutation tpe2-1 as a new allele of PDR3 [1].
• These data demonstrated that PDR1 and PDR3 regulate the net rate of M-C6-NBD-PE translocation (flip-flop) and the steady-state distribution of endogenous phosphatidylethanolamine across the plasma membrane [1].
• The putative consensus Yrr1p binding site deduced from these experiments, (T/A)CCG(C/T)(G/T)(G/T)(A/T)(A/T), is strikingly similar to the PDR element binding site sequence recognized by Pdr1p and Pdr3p [2].
• Overproduction of PDR3 suppresses mitochondrial import defects associated with a TOM70 null mutation by increasing the expression of TOM72 in Saccharomyces cerevisiae [3].
• The overproduction of PDR3 mediated this effect by increasing the import of Delta 1,2 pre-F(1)beta into mitochondria [3].

Biological context of PDR3

• A high-copy-number plasmid carrying the PDR3 gene elevated resistance to both oligomycin and cycloheximide [4].
• The presence of a functional copy of either PDR1 or PDR3 is essential for drug resistance and expression of a putative membrane transporter-encoding gene, PDR5 [4].
• Finally, we provide evidence in the absence of PDR1 for a PDR3-controlled transcriptional induction of the drug pump by cycloheximide and propose a model for the mechanism governing the transcriptional autoregulation of Pdr3p [5].
• The PDR3 gene is positively autoregulated in rho(0) cells by virtue of the presence of two binding sites for Pdr3p in its promoter [6].
• The resistant phenotype in these groups was found to be caused by allelic forms of the genes AFG2, PDR1, and PDR3 [7].

Anatomical context of PDR3

• These results indicate that pdr3-1 and pdr3-2 are alleles of the same pleiotropic drug resistance locus PDR3 which is involved in the control of the plasma membrane permeability in yeast [8].
• The transcription regulators, PDR1 and PDR3, have been shown to activate the transcription of numerous genes involved in a wide range of functions, including resistance to physical and chemical stress, membrane transport, and organelle function in Saccharomyces cerevisiae [1].
• These data suggest that Pdr1p and Pdr3p may act to modulate the lipid composition of membranes in S. cerevisiae through activation of sphingolipid biosynthesis along with other target genes [9].

Associations of PDR3 with chemical compounds

• Feeding glucose to starved cells rapidly re-induces both PDR5 and PDR3 transcription [10].
• After in vitro mutagenesis of the PDR3 gene six single amino acid substitutions were identified and resulted in resistance to cycloheximide, sulfomethuron methyl, 4-nitroquinoline oxide, fluconazole, mucidin, chloramphenicol and oligomycin [11].
• The SNQ2 gene of Saccharomyces cerevisiae, which encodes an ATP binding cassette protein responsible for resistance to the mutagen 4-nitroquinoline oxide, is regulated by the DNA-binding proteins PDR1 and PDR3 [12].
• Different missense mutations in PDR1 and PDR3 genes from clotrimazole-resistant sake yeast are responsible for pleiotropic drug resistance and improved fermentative activity [13].
• FLR1 gene (ORF YBR008c) is required for benomyl and methotrexate resistance in Saccharomyces cerevisiae and its benomyl-induced expression is dependent on pdr3 transcriptional regulator [14].

Physical interactions of PDR3

• Finally, DNA footprint analysis revealed that the SNQ2 promoter contains three binding sites for Pdr3 [15].
• An overlapping region of the related transcriptional activator PDR3p was also found to interact with NGG1p [16].
• Multiple Pdr1p/Pdr3p binding sites are essential for normal expression of the ATP binding cassette transporter protein-encoding gene PDR5 [17].

Regulatory relationships of PDR3

• Indeed, PDR3 deletion severely reduces benomyl-induced activation of FLR1 gene expression (by 85%), while the homologous Pdr1p transcription factor is apparently not involved in this activation [14].
• Interestingly, rho(0) strains lacking Lge1p failed to induce PDR3 transcription, but induction was still seen in Deltarad6, Deltabre1, and H2B-K123R mutant strains [6].
• These pleiotropic drug resistance loci are under the control of the key transcription factors Pdr1p and Pdr3p [18].
• Pdr3p is involved in a retrograde response in which mitochondrial dysfunctions activate PDR5, a gene encoding an ABC membrane transporter [19].

Other interactions of PDR3

• Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p [20].
• Transcriptional control of the yeast PDR5 gene by the PDR3 gene product [4].
• Conversely, HXT11 overexpression increases sensitivity to these drugs in the wild-type strain, an effect which is more pronounced in a strain having both PDR1 and PDR3 deleted [20].
• The screening is based on the ability to abrogate the growth defect of cells suffering from the galactose induced Pdr3p driven over-expression of a dominant-lethal allele of the PMA1 gene placed under the control of the PDR5 promoter [21].
• We show that HSF activates expression of PDR3, encoding a multidrug resistance (MDR) transcription factor that also directly activates RPN4 gene expression [22].

Analytical, diagnostic and therapeutic context of PDR3

• Isoelectric focusing indicated that transformed yeast cells secreted one major form of AMY2 and four dominant forms of AMY1 [23].
• The cDNA from activated mutants of the homologous transcription factors Pdr1p and Pdr3p was used to screen DNA microarrays of the Saccharomyces cerevisiae complete genome [24].
• The low yield of AMY2 practically excludes mutational analysis of structure-function relationships and protein engineering [25].

References