Characterization of the Saccharomyces cerevisiae RTA1 gene involved in 7-aminocholesterol resistance

Soustre, Isabelle; Letourneux, Yves; Karst, Francis

doi:10.1007/s002940050110

Cited by 54 publications

(57 citation statements)

References 19 publications

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“…Overexpression of RTA1 confers resistance to 7-aminocholesterol, a drug that leads to the production of toxic analogues of oxysterols in yeast (41). RTM1 overexpression confers resistance to molasses and is present in multiple copies in industrial strains of yeast but is not present in strains derived from S. cerevisiae S288C (22).…”

Section: Resultsmentioning

confidence: 99%

“…RTA1 was identified in a screen for genes that, when overexpressed, confer resistance to 7-aminocholesterol, a drug that is a substrate for enzymes in the ergosterol biosynthetic pathway (41). Treatment of cells with 7-aminocholesterol results in the accumulation of aberrant sterols that are toxic to the cell, and overexpression of Rta1p reduces the accumulation of at least one of the aberrant sterols.…”

Section: Discussionmentioning

confidence: 99%

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Role of PUG1 in Inducible Porphyrin and Heme Transport in Saccharomyces cerevisiae

et al. 2008

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Unlike pathogenic fungi, the budding yeast Saccharomyces cerevisiae is not efficient at using heme as a nutritional source of iron. Here we report that for this yeast, heme uptake is induced under conditions of heme starvation. Heme synthesis requires oxygen, and yeast grown anaerobically exhibited an increased uptake of hemin. Similarly, a strain lacking aminolevulinate synthase exhibited a sixfold increase in hemin uptake when grown without 2-aminolevulinic acid. We used microarray analysis of cells grown under reduced oxygen tension or reduced intracellular heme conditions to identify candidate genes involved in heme uptake. Surprisingly, overexpression of PUG1 (protoporphyrin uptake gene 1) resulted in reduced utilization of exogenous heme by a heme-deficient strain and, conversely, increased the utilization of protoporphyrin IX. Pug1p was localized to the plasma membrane by indirect immunofluorescence and subcellular fractionation. Strains overexpressing PUG1 exhibited decreased accumulation of [ 55 Fe]hemin but increased accumulation of protoporphyrin IX compared to the wild-type strain. To measure the effect of PUG1 overexpression on intracellular heme pools, we used a CYC1-lacZ reporter, which is activated in the presence of heme, and we monitored the activity of a heme-containing metalloreductase, Fre1p, expressed from a constitutive promoter. The data from these experiments were consistent with a role for Pug1p in inducible protoporphyrin IX influx and heme efflux.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of PUG1 in Inducible Porphyrin and Heme Transport in Saccharomyces cerevisiae

et al. 2008

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“…However, as noted earlier, it is homologous to ScRTA1, which has been implicated in resistance to 7-aminocholesterol (47). Up-regulation of RTA3 may also contribute to the azole-resistant phenotype.…”

Section: Downloaded Frommentioning

confidence: 99%

Genome-Wide Expression Profile Analysis Reveals Coordinately Regulated Genes Associated with Stepwise Acquisition of Azole Resistance in Candida albicans Clinical Isolates

Rogers

Barker²

2003

Antimicrob Agents Chemother

151

131

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Candida albicans is an opportunistic human fungal pathogen and a causative agent of oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients with AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC; however, with increased use of these agents treatment failures have occurred. Such failures have been associated with the emergence of azoleresistant strains of C. albicans. In the present study we examined changes in the genome-wide gene expression profile of a series of C. albicans clinical isolates representing the stepwise acquisition of azole resistance. In addition to genes previously associated with azole resistance, we identified many genes whose differential expression was for the first time associated with this phenotype. Furthermore, the expression of these genes was correlated with that of the known resistance genes CDR1, CDR2, and CaMDR1. Genes coordinately regulated with the up-regulation of CDR1 and CDR2 included the up-regulation of GPX1 and RTA3 and the downregulation of EBP1. Genes coordinately regulated with the up-regulation of CaMDR1 included the up-regulation of IFD1, IFD4, IFD5, IFD7, GRP2, DPP1, CRD2, and INO1 and the down-regulation of FET34, OPI3, and IPF1222. Several of these appeared to be coordinately regulated with both the CDR genes and CaMDR1. Many of these genes are involved in the oxidative stress response, suggesting that reduced susceptibility to oxidative damage may contribute to azole resistance. Further evaluation of the role these genes and their respective gene products play in azole antifungal resistance is warranted.The human fungal pathogen Candida albicans is a cause of mucosal, cutaneous, and systemic infections, including oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among AIDS patients (11, 21). The azole antifungal agents, particularly fluconazole, have proven effective for the management of OPC. The repetition and lengthy duration of therapy for OPC in this patient population has led to an increased incidence of treatment failures secondary to the emergence of azole resistance in this pathogenic fungus (33, 42, 55;

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“…RTA3 is a gene of unknown function that is coregulated with CDR1, CDR2, and ERG2 in azole-resistant isolates (28). It is homologous to RTA1 in S. cerevisiae, which has been implicated in resistance to the ergosterol biosynthesis inhibitor 7-aminocholoesterol (34). IFD4 (also known as CSH1) is a member of a family of homologs of YPL088w in S. cerevisiae (31).…”

Section: Gene Expression Responses To Ktz Genes Responsive To Ktz Inmentioning

confidence: 99%

Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents inCandida albicans

Liu

Lee²,

Barker

et al. 2005

Antimicrob Agents Chemother

300

266

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Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the ␤-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.Candida albicans is the most common human fungal pathogen and is the fourth leading cause of bloodstream infections in the United States (6,14,24). Currently only four antifungal drug classes are available for the management of systemic infections due to Candida species. Recently we examined changes in the genome-wide expression profile of Saccharomyces cerevisiae in response to representatives of the polyene, pyrimidine, azole, and echinocandin antifungal agents in an effort to identify class-specific and mechanism-independent changes in gene expression (1). In the present study, we extend this analysis to the pathogenic fungus C. albicans. By using the same representative drugs and similar growth conditions as in our previous study, we are able to show similarities and differences in the responses to these antifungal agents between S. cerevisiae and C. albicans. Gene expression profiling experiments revealed drug-specific responses consistent with their mechanisms of action, responses indicative of other pathways that may be affected by these agents, and responses that reflect known and potential mechanisms of resistance to these antifungal drugs. MATERIALS AND METHODSAntifungal agents. Ketoconazole (KTZ) and flucytosine (5-FC) were obtained from Sigma (St. Louis, MO). Amphotericin B (AMB) was obtained from ICN Biomedicals (Aurora, OH). The commercially available preparation of caspofungin (CPF) acetate for injection (Cancidas) was used. Stock solutions of various concentrations were made in dimethyl sulfoxide (DMS...

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Characterization of the Saccharomyces cerevisiae RTA1 gene involved in 7-aminocholesterol resistance

Cited by 54 publications

References 19 publications

Role of PUG1 in Inducible Porphyrin and Heme Transport in Saccharomyces cerevisiae

Role of PUG1 in Inducible Porphyrin and Heme Transport in Saccharomyces cerevisiae

Genome-Wide Expression Profile Analysis Reveals Coordinately Regulated Genes Associated with Stepwise Acquisition of Azole Resistance in Candida albicans Clinical Isolates

Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents inCandida albicans

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