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S6 Kinase- and β-TrCP2-Dependent Degradation of p19Arf Is Required for Cell Proliferation.
- Source :
-
Molecular & Cellular Biology . October 2015, Vol. 35 Issue 20, p3517-3527. 11p. - Publication Year :
- 2015
-
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 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *RAPAMYCIN
*CELL proliferation
*CELL cycle
*DISEASE progression
*SERUM
Subjects
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 35
- Issue :
- 20
- Database :
- Academic Search Index
- Journal :
- Molecular & Cellular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 162635741
- Full Text :
- https://doi.org/10.1128/MCB.00343-15