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doi:10.1534/genetics.106.057596
A more recent version of this article appeared on August 1, 2006.
REGULAR RESEARCH PAPERS |
ELM1 is required for multidrug resistance in Saccharomyces cerevisiae
Abdul-Kader Souid 1, Chen Gao 2, Luming Wang 2, Elena Milgrom 2 and Wu-Cheng Winston Shen 2*
1 SUNY Upstate Medical University, Department of Pediatrics
2 SUNY Upstate Medical University, Department of Biochemistry and Molecular Biology
* To whom correspondence should be addressed. E-mail: shenw{at}upstate.edu.
Submitted on February 24, 2006
Revised on March 30, 2006
Accepted on 30 May 2006
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 anti-cancer 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 elm1D mutations in a pdr1-3 strain also caused elongated bud morphology (indicating a G2/M delay), and reduction of PDR5 transcription under induced and non-induced conditions. Interestingly, mutations in several genes functionally related to ELM1, including cla4D, gin4D and cdc28-C127Y, also caused drastic reductions in drug resistance and PDR5 transcription. Collectively, these data show that ELM1, and genes encoding related protein serine/threonine kinases, are required for regulation of multidrug resistance involving, at least in part, control of PDR5 transcription.
Key Words: ELM1, PDR5, cell cycle, multidrug resistance, transcription
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