Two Nuclear Proteins, Cin5 and Ydr259c, Confer Resistance to Cisplatin in Saccharomyces cerevisiae (original) (raw)
Research ArticleArticle
, Hirohide Ishikawa, Nobuhiko Miura, Miki Ishizuka, Kazuki Kajiya, Shusuke Kuge and Akira Naganuma
Molecular Pharmacology March 2001, 59 (3) 470-474; DOI: https://doi.org/10.1124/mol.59.3.470
Abstract
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.
Footnotes
Received August 28, 2000.
Accepted November 20, 2000.
Send reprint requests to: Akira Naganuma, Ph.D., Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. E-mail: naganuma{at}mail.pharm.tohoku.ac.jp
This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (Diagnosis and Treatment of Cancer) from the Ministry of Education, Science, Sports and Culture of Japan.
The American Society for Pharmacology and Experimental Therapeutics
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