Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I.
Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I.
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DOI：
10.1016/j.cellsig.2013.05.012
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发表时间：
2013-10
影响因子：
4.8
通讯作者：
Agassandian M
中科院分区：
文献类型：
--
作者：
Mallampalli RK;Kaercher L;Snavely C;Pulijala R;Chen BB;Coon T;Zhao J;Agassandian M
细胞周期进程通过其在G1/S转换时细胞内Ca 2+水平的变化的调节控制介导细胞增殖和活力。Ca 2 +/CaM依赖性激酶1（CaMKI）在调节G1期进展所必需的细胞周期蛋白D1/cdk 4复合物的组装中似乎至关重要，但这是如何发生的尚不清楚。细胞周期蛋白D1/cdk 4在早期G1期的组装也通过与p27的结合来调节。在这里，我们表明，泛素E3连接酶的组成部分，F-box蛋白Fbxl 12，介导的CaMKI降解通过蛋白酶体介导的途径，导致细胞周期蛋白D1/cdk 4复合物组装和G1期阻滞在肺上皮细胞的破坏。我们还证明了i）CaMKI在人细胞中在Thr 157和Thr 198处以及在小鼠细胞中在Thr 170和Thr 197处磷酸化p27以调节其亚细胞定位; ii）Fbxl 12诱导的CaMKI降解减弱G1早期这些位点的p27磷酸化，和iii）在G1转换期间CaMKI的活化，随后是p27磷酸化，似乎是其它p27磷酸化事件的上游，Fbx 112过表达消除了这种效应。最后，已知的G1阻滞诱导剂显著增加细胞中的Fbxl 12水平。因此，Fbxl 12可能是一种以前未表征的功能性生长抑制剂，调节细胞周期进程，可用于基于机制的治疗。
Cell cycle progression through its regulatory control by changes in intracellular Ca2+ levels at the G1/S transition mediates cellular proliferation and viability. Ca2+/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 Thr157 and Thr198 in human cells and at Thr170 and Thr197 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.
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影响因子：
4.8
作者：
Agassandian, Marianna;Chen, Bill B.;Mallampalli, Rama K.
通讯作者：
Mallampalli, Rama K.
影响因子：
3.7
作者：
Hsu, SL;Hsu, JW;Chang, CD
通讯作者：
Chang, CD
影响因子：
5.3
作者：
Chen, Bill B.;Mallampalli, Rama K.
通讯作者：
Mallampalli, Rama K.
影响因子：
4.3
作者：
De Vita, Fernanda;Riccardi, Miriam;Viglietto, Giuseppe
通讯作者：
Viglietto, Giuseppe
影响因子：
11.4
作者：
Cheng, MG;Olivier, P;Sherr, CJ
通讯作者：
Sherr, CJ