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dc.contributor.authorRojas, Marta-
dc.contributor.authorWright, Colin W.-
dc.contributor.authorPiña, Benjamín-
dc.contributor.authorPortugal, José-
dc.identifier.citationAntimicrobial Agents and Chemotherapy 52(11): 3844–3850 (2008)en_US
dc.description7 pages, 3 figures, 4 tables.-- PMID: 18710911 [PubMed].-- PMCID: PMC2573129.-- Printed version published Nov 2008.en_US
dc.description.abstractWe 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 (Deltaerg6 or ISE2 strains) or disrupting DNA damage repair (Deltarad52 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 [IC(20) and IC(40)]) were analyzed by comparing the gene expression profiles of treated and untreated Deltaerg6 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.en_US
dc.description.sponsorshipThis work has been supported by grants from the former Spanish Ministry of Education and Science (BIO2005-00840, BFU2007-60998/BMC, and AGL2000-0133-P4-03). The contribution of the Centre de Referencia en Biotecnologia of the Generalitat de Catalunya is also acknowledged.en_US
dc.format.extent426118 bytes-
dc.publisherAmerican Society for Microbiologyen_US
dc.titleGenomewide expression profiling of cryptolepine-induced toxicity in Saccharomyces cerevisiaeen_US
dc.description.peerreviewedPeer revieweden_US
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
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