Genomewide expression profiling of the cryptolepine-induced toxicity in Saccharomyces cerevisiae.
Rojas, M. Wright, Colin W. Pina, B. Portugal, J.
Rojas, M.
Wright, Colin W.
Pina, B.
Portugal, J.
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2008
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Abstract
We have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo
to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds
in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of
cryptolepine. Cryptolepine showed a relatively mild toxicity for wild-type strains, which was augmented by
either increasing cell permeability ( erg6 or ISE2 strains) or disrupting DNA damage repair ( rad52 strains).
These results are compatible with the ability of cryptolepine to intercalate into DNA and thus promote DNA
lesions. The effects of low concentrations of cryptolepine (20% and 40% inhibitory concentrations [IC20 and
IC40]) were analyzed by comparing the gene expression profiles of treated and untreated erg6 yeast cells.
Significant changes in expression levels were observed for 349 genes (117 upregulated and 232 downregulated).
General stress-related genes constituted the only recognizable functional cluster whose expression was increased
upon cryptolepine treatment, making up about 20% of upregulated genes. In contrast, analysis of the
characteristics of downregulated genes revealed a specific effect of cryptolepine on genes related to iron
transport or acid phosphatases, as well as a significant proportion of genes related to cell wall components. The
effects of cryptolepine on the transcription of iron transport-related genes were consistent with a loss of
function of the iron sensor Aft1p, indicating a possible disruption of iron metabolism in S. cerevisiae. Since the
interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this
finding supports the utility of S. cerevisiae in drug-developing schemes.
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Rojas, M., Wright, C. W., Pina, B. and Portugal, J. (2008). Genomewide expression profiling of the cryptolepine-induced toxicity in Saccharomyces cerevisiae. Antimicrobial Agents and Chemotherapy. Vol. 52, No. 11, pp. 3844-3850.
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