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首页> 外文期刊>Cellular Signalling >Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I
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Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I

机译：Fbxl12通过介导钙调蛋白激酶I降解来触发G1阻滞

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摘要

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.
机译：细胞周期通过其在G1 / S过渡期细胞内Ca〜（2+）水平变化的调控控制来进行，介导细胞增殖和生存能力。 Ca〜（2 +）/ CaM依赖性激酶1（CaMKI）在调节G1进程必不可少的细胞周期蛋白D1 / cdk4复合物的组装中似乎至关重要，但如何发生尚不清楚。 G1早期的细胞周期蛋白D1 / cdk4装配也通过与p27结合来调节。在这里，我们显示泛素E3连接酶成分F-box蛋白Fbxl12通过蛋白酶体定向途径介导CaMKI降解，导致细胞周期蛋白D1 / cdk4复合物装配体破坏和肺上皮中的G1阻滞。我们还证明：i）CaMKI使人细胞中的Thr_（157）和Thr_（198）以及小鼠细胞中的Thr_（170）和Thr_（197）磷酸化p27，以调节其亚细胞定位。 ii）Fbxl12诱导的CaMKI降解减弱了G1早期这些位点的p27磷酸化，并且iii）CaMKI在G1过渡期间激活，随后p27磷酸化似乎是其他p27磷酸化事件的上游，这一作用因Fbxl12过表达而被废除。最后，已知的G1阻滞诱导剂显着增加细胞中Fbxl12的水平。因此，Fbxl12可能是以前无法表征的功能性生长抑制剂，可调节细胞周期进程，可用于基于机制的治疗。

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