The kinase mTOR (mammalian target of rapamycin) promotes translation as well as cell survival and proliferation under nutrient- rich conditions. Whereas mTOR activates translation through ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP), how it facilitates cell proliferation has remained unclear. We have now identified p19Arf, an inhibitor of cell cycle progression, as a novel substrate of S6K that is targeted to promote cell proliferation. Serum stimulation induced activation of the mTOR-S6K axis and consequent phosphorylation of p19Arf at Ser75. Phosphorylated p19Arf was then recognized by the F-box protein β-TrCP2 and degraded by the proteasome. Ablation of β-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19Arf. The β-TrCP2 paralog β-TrCP1 had no effect on p19Arf stability, suggesting that phosphorylated p19Arf is a specific substrate of β-TrCP2. Mice deficient in β-TrCP2 manifested accumulation of p19Arf in the yolk sac and died in utero. Our results suggest that the mTOR pathway promotes cell proliferation via β-TrCP2-dependent p19Arf degradation under nutrient-rich conditions.
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