title: S6 Kinase- and β-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation.
abstract: 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 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 p19(Arf). The β-TrCP2 paralog β-TrCP1 had no effect on p19(Arf) stability, suggesting that phosphorylated p19(Arf) is a specific substrate of β-TrCP2. Mice deficient in β-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 β-TrCP2-dependent p19(Arf) degradation under nutrient-rich conditions.
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Araki
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Division of Molecular Genetics, Cancer and Stem Cell Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.affiliation: Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan nakayak2@med.tohoku.ac.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D044844:beta-Transducin Repeat-Containing Proteins / Q000502:physiology*
chemical_list: C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; C486774:Fbxw1b protein, mouse; D044844:beta-Transducin Repeat-Containing Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse