Faculty Publications

van Slegtenhorst M, Mustafa A, Henske EP

Pas1, a G(1) cyclin, regulates amino acid uptake and rescues a delay in G(1) arrest in Tsc1 and Tsc2 mutants in Schizosaccharomyces pombe

Hum Mol Genet. 2005 Oct 1;14(19):2851-8.

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 G(1) cyclin, pas1(+), as a high-copy suppressor of this defect in Delta tsc1. Disruption of pas1(+) causes defects in arginine and leucine uptake that are remarkably similar to Delta tsc1 and Delta tsc2, whereas Delta pas1 Delta tsc1 and Delta pas1 Delta tsc2 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 Delta tsc1 yeast, but not in Delta pas1 yeast. Hence, Pas1 does not regulate amino acid uptake through Rhb1. To determine whether Pas1 links nutrient availability to cell cycle progression do wnstream of the Tsc1/Tsc2 complex, we examined the kinetics of G(1) arrest in single and double mutant strains. After nitrogen starvation, Delta tsc1 and Delta tsc2 yeast had a delay in G(1) arrest when compared with wild-type, which was rescued by deletion of pas1(+). In summary, we identified the G(1) cyclin, Pas1, as a novel regulator of amino acid uptake. Our data support a model in which Pas1 inhibits G(1) arrest downstream of Tsc1 and Tsc2, linking nutrient uptake and cell cycle progression in yeast.