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Originally published as Genetics Published Articles Ahead of Print on June 4, 2006.
Genetics, Vol. 173, 1919-1937, August 2006, Copyright © 2006
doi:10.1534/genetics.106.057596
ELM1 Is Required for Multidrug Resistance in Saccharomyces cerevisiae
Abdul-Kader Souid*,1,
Chen Gao
,1,
Luming Wang,1,
Elena Milgrom,1 and
W.-C. Winston Shen,2
Department of Biochemistry and Molecular Biology and * Department of Pediatrics, State University of New York Upstate Medical University, Syracuse, New York 13210
2 Corresponding author: Department of Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, 750 E. Adams St., WHA Room 4281, Syracuse, NY 13210.
E-mail: winston.shen{at}uspto.gov
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 elm1
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 cla4, gin4, 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.
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