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FBXL12 regulates G1 arrest via degradation of CaMKI
Author(s) -
Agassandian Marianna,
Kaercher Leah,
Snavely Courtney,
Pilijala Roopa,
Chen Beibei,
Coon Tiffany,
Mallampalli Rama
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.915.6
Subject(s) - microbiology and biotechnology , ubiquitin ligase , cyclin d1 , phosphorylation , cell cycle , proteasome , cyclin , cyclin a , cyclin d3 , biology , protein kinase b , cell cycle checkpoint , protein degradation , cyclin d , ubiquitin , cell , biochemistry , gene
Cell cycle progression through its regulatory control by changes in intracellular Ca 2+ levels at the G1/S transition controls the proliferation and viability of cells. Ca 2+ /CaM‐dependent kinase 1 (CaMKI) appears critical in regulating the assembly of the cyclin D1/cdk4 complex during G1 progression, but the molecular mechanisms are unknown. Here, we show that ectopic expression of 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 formation and G1 arrest in lung epithelia. Cyclin D1/cdk4 assembly in the early G1 phase is also regulated via binding to p27, a protein that has been shown previously to be phosphorylated by AKT, PKC, ERK 1/2 at Thr 157 and Thr 198 . Our studies demonstrate that i) CaMKI also phosphorylates p27 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 from other p27 phosphorylation events, an effect abrogated by FBXL12 overexpression in epithelia. Last, known inducers of G1 arrest significantly increased 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.