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J. Biol. Chem., Vol. 281, Issue 9, 5677-5685, March 3, 2006

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Expression of FLR1 Transporter Requires Phospholipase C and Is Repressed by Mediator^*

From the Department of Biological Sciences, St. John's University, Queens, New York 11439

In budding yeast, phosphoinositide-specific phospholipase C (Plc1p encoded by PLC1 gene) is important for function of kinetochores. Deletion of PLC1 results in benomyl sensitivity, alterations in chromatin structure of centromeres, mitotic delay, and a higher frequency of chromosome loss. Here we intended to utilize benomyl sensitivity as a phenotype that would allow us to identify genes that are important for kinetochore function and are downstream of Plc1p. However, our screen identified SIN4, encoding a component of the Mediator complex of RNA polymerase II. Deletion of SIN4 gene (sin4) does not suppress benomyl sensitivity of plc1 cells by improving the function of kinetochores. Instead, benomyl sensitivity of plc1 cells is caused by a defect in expression of FLR1, and the suppression of benomyl sensitivity in plc1 sin4 cells occurs by derepression of FLR1 transcription. FLR1 encodes a plasma membrane transporter that mediates resistance to benomyl. Several other mutations in the Mediator complex also result in significant derepression of FLR1 and greatly increased resistance to benomyl. Thus, benomyl sensitivity is not a phenotype exclusively associated with mitotic spindle defect. These results demonstrate that in addition to promoter-specific transcription factors that are components of the pleiotropic drug resistance network, expression of the membrane transporters can be regulated by Plc1p, a component of a signal transduction pathway, and by Mediator, a general transcription factor. The results thus suggest another layer of complexity in regulation of pleiotropic drug resistance.

Received for publication, June 21, 2005 , and in revised form, December 1, 2005.

^* This work was supported in part by National Institutes of Health Grant GM62183 and the American Cancer Society Grant RSG-01-145-01-CCG (to A. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Dept. of Education Grant P200A010130.

² To whom correspondence should be addressed: Dept. of Biological Sciences, St. John's University, 8000 Utopia Pkwy., Queens, NY 11439. Tel.: 718-990-6287; Fax: 718-990-5958; E-mail: vancuraa{at}stjohns.edu.

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