ELM1 is required for multidrug resistance in Saccharomyces cerevisiae.
In Saccharomyces cerevisiae, transcription of several drug transporter genes, including the major transporter gene PDR5, has been shown to peak during mitosis. The significance of this observation, however, remains unclear. PDR1 encodes the primary transcription activator of multiple drug transporter genes in S. cerevisiae, including PDR5. Here, we show that in synchronized PDR1 and pdr1-3 (multidrug resistant) strains, cellular efflux of a known substrate of ATP-binding-cassette transporters, doxorubicin (a fluorescent anticancer drug), is highest during mitosis when PDR5 transcription peaks. A genetic screen performed to identify regulators of multidrug resistance revealed that a truncation mutation in ELM1 (elm1-300) suppressed the multidrug resistance of pdr1-3. ELM1 encodes a serine/threonine protein kinase required for proper regulation of multiple cellular kinases, including those involved in mitosis, cytokinesis, and cellular morphogenesis. elm1-300 as well as elm1Delta mutations in a pdr1-3 strain also caused elongated bud morphology (indicating a G2/M delay) and reduction of PDR5 transcription under induced and noninduced conditions. Interestingly, mutations in several genes functionally related to ELM1, including cla4Delta, gin4Delta, and cdc28-C127Y, also caused drastic reductions in drug resistance and PDR5 transcription. Collectively, these data show that ELM1, and genes encoding related serine/threonine protein kinases, are required for regulation of multidrug resistance involving, at least in part, control of PDR5 transcription.
Souid
Abdul-Kader
AK
Department of Biochemistry and Molecular Biology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
Gao
Chen
C
Wang
Luming
L
Milgrom
Elena
E
Shen
W-C Winston
WC
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000595:Amino Acid Sequence; D002455:Cell Division / Q000235:genetics; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics*; D016195:G2 Phase / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D013045:Species Specificity; D014158:Transcription, Genetic
D018528:ATP-Binding Cassette Transporters; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C411302:ELM1 protein, S cerevisiae