| First Author | Nakagawa T | Year | 2015 |
| Journal | Mol Cell Biol | Volume | 35 |
| Issue | 20 | Pages | 3517-27 |
| PubMed ID | 26240281 | Mgi Jnum | J:228222 |
| Mgi Id | MGI:5705684 | Doi | 10.1128/MCB.00343-15 |
| Citation | Nakagawa T, et al. (2015) S6 Kinase- and beta-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation. Mol Cell Biol 35(20):3517-27 |
| abstractText | 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 p19(Arf), 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 p19(Arf) at Ser(75). Phosphorylated p19(Arf) was then recognized by the F-box protein beta-TrCP2 and degraded by the proteasome. Ablation of beta-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19(Arf). The beta-TrCP2 paralog beta-TrCP1 had no effect on p19(Arf) stability, suggesting that phosphorylated p19(Arf) is a specific substrate of beta-TrCP2. Mice deficient in beta-TrCP2 manifested accumulation of p19(Arf) in the yolk sac and died in utero. Our results suggest that the mTOR pathway promotes cell proliferation via beta-TrCP2-dependent p19(Arf) degradation under nutrient-rich conditions. |
