title: Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I.
abstract: Cell cycle progression through its regulatory control by changes in intracellular Ca(2+) levels at the G1/S transition mediates cellular proliferation and viability. Ca(2+)/CaM-dependent kinase 1 (CaMKI) appears critical in regulating the assembly of the cyclin D1/cdk4 complex essential for G1 progression, but how this occurs is unknown. Cyclin D1/cdk4 assembly in the early G1 phase is also regulated via binding to p27. Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex assembly and resultant G1 arrest in lung epithelia. We also demonstrate that i) CaMKI phosphorylates p27 at Thr(157) and Thr(198) in human cells and at Thr(170) and Thr(197) in mouse cells to modulate its subcellular localization; ii) Fbxl12-induced CaMKI degradation attenuates p27 phosphorylation at these sites in early G1 and iii) activation of CaMKI during G1 transition followed by p27 phosphorylation appears to be upstream to other p27 phosphorylation events, an effect abrogated by Fbxl12 overexpression. Lastly, known inducers of G1 arrest significantly increase Fbxl12 levels in cells. Thus, Fbxl12 may be a previously uncharacterized, functional growth inhibitor regulating cell cycle progression that might be used for mechanism-based therapy.
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, The University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.forename: Leah
authors.initials: L
authors.lastname: Kaercher
authors.forename: Courtney
authors.initials: C
authors.lastname: Snavely
authors.forename: Roopa
authors.initials: R
authors.lastname: Pulijala
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.forename: Tiffany
authors.initials: T
authors.lastname: Coon
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Marianna
authors.initials: M
authors.lastname: Agassandian
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis
chemical_list: D044783:F-Box Proteins; C586673:Fbxl12 protein, human; D019938:Cyclin D1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051358:Cyclin-Dependent Kinase 4; D046988:Proteasome Endopeptidase Complex
keywords: CaMKI; Calcium signaling; F-box protein; PKB/AKT; Proteasome degradation; cdk4/cyclin D1; p27(kip1)