title: Identification of Saccharomyces cerevisiae ribosomal protein L3 as a target of curvularol, a G1-specific inhibitor of mammalian cells.
abstract: The cellular target of curvularol, a G1-specific cell-cycle inhibitor of mammalian cells, was identified by a genetic approach in Saccharomyces cerevisiae. Since the wild-type W303 strain was highly resistant to curvularol, a drug hypersensitive parental strain was constructed in which various genes implicated in general drug resistance had been disrupted. Curvularol resistant mutants were isolated, and strains that exhibited a semi-dominant, curvularol-specific resistance phenotype were selected. All five strains examined were classified into a single genetic complementation group designated YCR1. A mutant gene responsible for curvularol resistance was identified as an allele of the RPL3 gene encoding the ribosomal protein L3. Sequence analysis of the mutant genes revealed that Trp255Cys and Trp255Leu substitutions of Rpl3p are responsible for curvularol resistance. Rpl3p mutants in which Trp255 residue was replaced by other amino acids were constructed. All of these replacements led to varying degrees of increased resistance to curvularol and growth defects.
authors.affiliation: Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter (AdSM), Hiroshima University, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Mizunuma
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Tokichi
authors.initials: T
authors.lastname: Miyakawa
mesh_terms: D000818:Animals; D004351:Drug Resistance / Q000235:genetics*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008322:Mammals; D020125:Mutation, Missense; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014255:Trichothecenes / Q000494:pharmacology*
chemical_list: C000716547:RPL3 protein, human; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014255:Trichothecenes; C423645:curvularol