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Vol. 59, Issue 3, 470-474, March 2001
Laboratory of Molecular and Biochemical Toxicology, Graduate School
of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (T.F.,
H.I., N.M., M.I., K.K., A.N.); and the Department of Microbiology,
Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo,
Japan (S.K.)
In an attempt to identify genes that can confer resistance to
cisplatin, we introduced a yeast genomic library into
Saccharomyces cerevisiae and selected for transformants
that grew in the presence of a normally toxic concentration of
cisplatin. Plasmids were rescued from the transformants and were
analyzed for the presence of individual open reading frames that
conferred resistance to cisplatin. We isolated two genes,
CIN5 and YDR259c, that increased resistance to cisplatin when overexpressed in Saccharomyces
cerevisiae. These genes encoded two proteins, Cin5 and Ydr259c,
that were homologous to yAP-1, a basic leucine zipper transcriptional
factor that is known to mediate cellular resistance to various toxic agents. The two proteins exhibited stronger homology to each other (33.2% identity, 49.2% similarity) than to all other gene products in
S. cerevisiae. Overexpression of each of these proteins
also conferred resistance to two DNA-alkylating agents,
methylmethanesulfonate and mitomycin C. An experiment with fusion
proteins with green fluorescent protein revealed that Cin5 and Ydr259c
were localized constitutively in the nuclei of yeast cells. Our results
suggest that Cin5 and Ydr259c might be involved in pleiotropic
drug-resistance and might protect yeast against the toxicity of
cisplatin and other alkylating agents via a single mechanism. These two
nuclear proteins might act as transcriptional factors, regulating the expression of certain genes that confer resistance to DNA-alkylating agents.
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