Adaptive response to the antimalarial drug artesunate in yeast involves Pdr1p/Pdr3p-mediated transcriptional activation of the resistance determinants TPO1 and PDR5.
The expression of the transcription regulator Pdr1p and its target genes PDR5 and TPO1 is required for Saccharomyces cerevisiae adaptation and resistance to artesunate, a promising antimalarial drug, also active against tumour cells and viruses. PDR5 and TPO1 encode plasma membrane multidrug transporters of the ATP-binding cassette and the major facilitator superfamilies, respectively. The transcriptional activation of TPO1 (10-fold) and PDR5 (13-fold) was registered after 30 min of exposure of the unadapted yeast population to acute artesunate-induced stress, being significantly reduced in the absence of Pdr1p and abolished in the absence of Pdr1p and Pdr3p. Maximum TPO1 mRNA levels were rapidly reduced to basal values following adaptation of the yeast population to artesunate, while high PDR5 levels were maintained during drug-stressed exponential growth.
Alenquer
Marta
M
Biological Sciences Research Group, Centro de Engenharia Biológica e Química, Instituto Superior Técnico, Lisbon, Portugal.
Tenreiro
Sandra
S
Sá-Correia
Isabel
I
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000222:Adaptation, Physiological; D000962:Antimalarials / Q000494:pharmacology*; D017920:Antiporters; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D004268:DNA-Binding Proteins / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000378:metabolism; D027701:Organic Cation Transport Proteins; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D017920:Antiporters; D037621:Artemisinins; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D027701:Organic Cation Transport Proteins; C085480:PDR1 protein, S cerevisiae; C089261:PDR3 protein, S cerevisiae; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D012717:Sesquiterpenes; C475058:TPO1 protein, S cerevisiae; D015534:Trans-Activators; D014157:Transcription Factors; D000077332:Artesunate