title: Pas1, a G1 cyclin, regulates amino acid uptake and rescues a delay in G1 arrest in Tsc1 and Tsc2 mutants in Schizosaccharomyces pombe.
abstract: Tuberous sclerosis complex is a tumor suppressor syndrome caused by mutations in either the TSC1 or the TSC2 gene. Previous studies have shown that deletion of the TSC1 or TSC2 ortholog in Schizosaccharomyces pombe results in an amino acid uptake defect, with conditional lethality. We identified a G1 cyclin, pas1+, as a high-copy suppressor of this defect in Deltatsc1. Disruption of pas1+ causes defects in arginine and leucine uptake that are remarkably similar to Deltatsc1 and Deltatsc2, whereas Deltapas1Deltatsc1 and Deltapas1Deltatsc2 double mutants have more severe amino acid uptake defects. In a second screen, we identified a novel G63D/S165 N mutant of the small GTPase Rhb1, the target of the Tsc1/Tsc2 protein complex. The Rhb1 mutant suppresses amino acid uptake in Deltatsc1 yeast, but not in Deltapas1 yeast. Hence, Pas1 does not regulate amino acid uptake through Rhb1. To determine whether Pas1 links nutrient availability to cell cycle progression downstream of the Tsc1/Tsc2 complex, we examined the kinetics of G1 arrest in single and double mutant strains. After nitrogen starvation, Deltatsc1 and Deltatsc2 yeast had a delay in G1 arrest when compared with wild-type, which was rescued by deletion of pas1+. In summary, we identified the G1 cyclin, Pas1, as a novel regulator of amino acid uptake. Our data support a model in which Pas1 inhibits G1 arrest downstream of Tsc1 and Tsc2, linking nutrient uptake and cell cycle progression in yeast.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Marjon
authors.initials: M
authors.lastname: van Slegtenhorst
authors.forename: Aladdin
authors.initials: A
authors.lastname: Mustafa
authors.forename: Elizabeth Petri
authors.initials: EP
authors.lastname: Henske
mesh_terms: D000251:Adenosine Triphosphatases; D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics; D002172:Canavanine / Q000494:pharmacology; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics; D017353:Gene Deletion; D005804:Genes, Lethal; D007930:Leucine / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016213:Cyclins; D005656:Fungal Proteins; D008565:Membrane Proteins; D029702:Schizosaccharomyces pombe Proteins; C471572:Tsc1 protein, S pombe; C471573:Tsc2 protein, S pombe; C511587:pas1 protein, S pombe; D002172:Canavanine; D001120:Arginine; D000251:Adenosine Triphosphatases; D020558:GTP Phosphohydrolases; C412832:Rhb1 protein, S pombe; D007930:Leucine