Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(19):2851-2858; doi:10.1093/hmg/ddi317
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Pas1, a G1 cyclin, regulates amino acid uptake and rescues a delay in G1 arrest in Tsc1 and Tsc2 mutants in Schizosaccharomyces pombe
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
* To whom correspondence should be addressed at: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, Tel: +1 2157282428; Fax: +1 2152141623; Email: elizabeth.henske{at}fccc.edu
Received June 16, 2005; Accepted August 11, 2005
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 
tsc1. Disruption of pas1+ causes defects in arginine and leucine uptake that are remarkably similar to tsc1 and tsc2, whereas pas1tsc1 and pas1tsc2 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 tsc1 yeast, but not in pas1 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, tsc1 and tsc2 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.
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