The immunosuppressant SR 31747 blocks cell proliferation by inhibiting a steroid isomerase in Saccharomyces cerevisiae.
SR 31747 is a novel immunosuppressant agent that arrests cell proliferation in the yeast Saccharomyces cerevisiae, SR 31747-treated cells accumulate the same aberrant sterols as those found in a mutant impaired in delta 8- delta 7-sterol isomerase. Sterol isomerase activity is also inhibited by SR 31747 in in vitro assays. Overexpression of the sterol isomerase-encoding gene, ERG2, confers enhanced SR resistance. Cells growing anaerobically on ergosterol-containing medium are not sensitive to SR. Disruption of the sterol isomerase-encoding gene is lethal in cells growing in the absence of exogenous ergosterol, except in SR-resistant mutants lacking either the SUR4 or the FEN1 gene product. The results suggest that sterol isomerase is the target of SR 31747 and that both the SUR4 and FEN1 gene products are required to mediate the proliferation arrest induced by ergosterol depletion.
Silve
S
S
Department of Microbiology, Sanofi-Recherche, Labège, France.
Leplatois
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Josse
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Dupuy
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Lanau
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Kaghad
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Dhers
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Picard
C
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Rahier
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Taton
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Le Fur
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Caput
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Ferrara
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Loison
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D000595:Amino Acid Sequence; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004875:Ergosterol / Q000096:biosynthesis; D005656:Fungal Proteins / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression; D005800:Genes, Fungal; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics; D014170:Transformation, Genetic
D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D007166:Immunosuppressive Agents; C088447:SR 31747; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase; D004875:Ergosterol