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Genomewide expression profiling of the cryptolepine-induced toxicity in Saccharomyces cerevisiae.

By M. Rojas, Colin W. Wright, B. Pina and J. Portugal

Abstract

noWe have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo\ud to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds\ud in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of\ud cryptolepine. Cryptolepine showed a relatively mild toxicity for wild-type strains, which was augmented by\ud either increasing cell permeability ( erg6 or ISE2 strains) or disrupting DNA damage repair ( rad52 strains).\ud These results are compatible with the ability of cryptolepine to intercalate into DNA and thus promote DNA\ud lesions. The effects of low concentrations of cryptolepine (20% and 40% inhibitory concentrations [IC20 and\ud IC40]) were analyzed by comparing the gene expression profiles of treated and untreated erg6 yeast cells.\ud Significant changes in expression levels were observed for 349 genes (117 upregulated and 232 downregulated).\ud General stress-related genes constituted the only recognizable functional cluster whose expression was increased\ud upon cryptolepine treatment, making up about 20% of upregulated genes. In contrast, analysis of the\ud characteristics of downregulated genes revealed a specific effect of cryptolepine on genes related to iron\ud transport or acid phosphatases, as well as a significant proportion of genes related to cell wall components. The\ud effects of cryptolepine on the transcription of iron transport-related genes were consistent with a loss of\ud function of the iron sensor Aft1p, indicating a possible disruption of iron metabolism in S. cerevisiae. Since the\ud interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this\ud finding supports the utility of S. cerevisiae in drug-developing schemes

Topics: Cryptolepine, Yeast cells, Saccharomyces cerevisiae, Antimalarial
Publisher: American Chemical Society
Year: 2008
DOI identifier: 10.1128/AAC.00532-08
OAI identifier: oai:bradscholars.brad.ac.uk:10454/4531
Provided by: Bradford Scholars
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