title: Rapamycin blocks sexual development in fission yeast through inhibition of the cellular function of an FKBP12 homolog.
abstract: FKBP12 is a ubiquitous and a highly conserved prolyl isomerase that binds the immunosuppressive drugs FK506 and rapamycin. Members of the FKBP12 family have been implicated in many processes that include intracellular protein folding, transport, and assembly. In the budding yeast Saccharomyces cerevisiae and in human T cells, rapamycin forms a complex with FKBP12 that inhibits cell cycle progression by inhibition of the TOR kinases. We reported previously that rapamycin does not inhibit the vegetative growth of the fission yeast Schizosaccharomyces pombe; however, it specifically inhibits its sexual development. Here we show that disruption of the S. pombe FKBP12 homolog, fkh1(+), at its chromosomal locus results in a mating-deficient phenotype that is highly similar to that obtained by treatment of wild type cells with rapamycin. A screen for fkh1 mutants that can confer rapamycin resistance identified five amino acids in Fkh1 that are critical for the effect of rapamycin in S. pombe. All five amino acids are located in the putative rapamycin binding pocket. Together, our findings indicate that Fkh1 has an important role in sexual development and serves as the target for rapamycin action in S. pombe.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel. ronitt@post.tau.ac.il
authors.forename: R
authors.initials: R
authors.lastname: Weisman
authors.forename: S
authors.initials: S
authors.lastname: Finkelstein
authors.forename: M
authors.initials: M
authors.lastname: Choder
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D005656:Fungal Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D017510:Protein Folding; D012098:Reproduction / Q000187:drug effects; D029701:Saccharomyces cerevisiae Proteins; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D029702:Schizosaccharomyces pombe Proteins; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism; D022061:Tacrolimus Binding Protein 1A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D020123:Sirolimus; D022061:Tacrolimus Binding Protein 1A; C083324:TOR1 protein, S cerevisiae; C513100:tor2 protein, S pombe; C431935:Fkh1 protein, S pombe