P120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via β-catenin and Kaiso respectively.
P120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via β-catenin and Kaiso respectively.
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DOI：
10.1371/journal.pone.0030303
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang E
中科院分区：
文献类型：
--
作者：
Jiang G;Wang Y;Dai S;Liu Y;Stoecker M;Wang E;Wang E
P120-连环蛋白(P120ctn)亚型1/3调控细胞周期进程的不同机制至今仍不清楚。我们发现，在p120ctn耗竭的肺癌细胞中，通过p120ctn-1A或p120ctn-3A的修复，可以有效地恢复细胞周期蛋白D1和细胞周期蛋白E。在p120ctn缺失的p120ctn-1A或3A细胞中，当与siRNA-cyClinD1共转染阻断细胞周期蛋白D1的表达时，细胞周期蛋白E的表达略有下降，而不是增加，提示p120ctn亚型1和3不能直接上调细胞周期蛋白E，而可能是通过上调细胞周期蛋白D1实现的。有趣的是，p120ctn-1A的过表达增加了β-catenin和细胞周期蛋白D1的表达，而与针对β-catenin的siRNA共转染可取消p120ctn-1A上调细胞周期蛋白d1的作用，提示β-catenin可能参与了p120ctn-1A对细胞周期蛋白d1表达的调节作用。另一方面，p120ctn异构体3A的过表达减少了细胞核Kaiso的定位，从而减少了Kaiso与Cyclin D1启动子上KBS的结合，从而通过解除Kaiso的抑制作用而增强了Cyclin D1基因的表达。由于过度表达NLS-p120ctn-3A(p120ctn-3A核靶向定位质粒)或抑制LMB对p120ctn-3的核输出导致Kaiso转位到核内，Kaiso的核输出可能是p120ctn-3依赖的。我们的结果提示，p120ctn异构体1和3上调细胞周期蛋白D1，进而上调细胞周期蛋白E，从而促进肺癌细胞的细胞增殖和细胞周期进程，这可能是通过不同的蛋白介质实现的，即异构体1的β-连环蛋白和异构体3的Cyclin D1的负转录因子Kaiso。
The different mechanisms involved in p120-catenin (p120ctn) isoforms' 1/3 regulation of cell cycle progression are still not elucidated to date. We found that both cyclin D1 and cyclin E could be effectively restored by restitution of p120ctn-1A or p120ctn-3A in p120ctn depleted lung cancer cells. When the expression of cyclin D1 was blocked by co-transfection with siRNA-cyclin D1 in p120ctn depleted cells restoring p120ctn-1A or 3A, the expression of cyclin E was slightly decreased, not increased, implying that p120ctn isoforms 1 and 3 cannot up-regulate cyclin E directly but may do so through up-regulation of cyclin D1. Interestingly, overexpression of p120ctn-1A increased β-catenin and cyclin D1 expression, while co-transfection with siRNA targeting β-catenin abolishes the effect of p120ctn-1A on up-regulation of cyclin D1, suggesting a role of β-catenin in mediating p120ctn-1A's regulatory function on cyclin D1 expression. On the other hand, overexpression of p120ctn isoform 3A reduced nuclear Kaiso localization, thus decreasing the binding of Kaiso to KBS on the cyclin D1 promoter and thereby enhancing the expression of cyclin D1 gene by relieving the repressor effect of Kaiso. Because overexpressing NLS-p120ctn-3A (p120ctn-3A nuclear target localization plasmids) or inhibiting nuclear export of p120ctn-3 by Leptomycin B (LMB) caused translocation of Kaiso to the nucleus, it is plausible that the nuclear export of Kaiso is p120ctn-3-dependent. Our results suggest that p120ctn isoforms 1 and 3 up-regulate cyclin D1, and thereby cyclin E, resulting in the promotion of cell proliferation and cell cycle progression in lung cancer cells probably via different protein mediators, namely, β-catenin for isoform 1 and Kaiso, a negative transcriptional factor of cyclin D1, for isoform 3.
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