AKT Activation by Pdcd4 Knockdown Up-Regulates Cyclin D1 Expression and Promotes Cell Proliferation.
AKT Activation by Pdcd4 Knockdown Up-Regulates Cyclin D1 Expression and Promotes Cell Proliferation.
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DOI：
10.1177/1947601911431082
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发表时间：
2011-08-01
期刊：
影响因子：
--
通讯作者：
Yang, Hsin-Sheng
中科院分区：
文献类型：
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作者：
Guo, Xiaoling;Li, Wenjuan;Yang, Hsin-Sheng
程序性细胞死亡4(Pdcd4)是一种新的肿瘤抑制因子，可抑制肿瘤转化和肿瘤侵袭。在这项研究中，作者发现Pdcd4基因的敲除促进了细胞的增殖，上调了细胞周期蛋白D1的表达。此前，作者证明了Pdcd4基因敲除激活了依赖于NF-kappaB的转录。细胞周期蛋白D1启动子上的核因子-kappaB结合位点的突变减弱了Pdcd4基因敲除所诱导的细胞周期蛋白D1启动子活性。此外，抑制调节NF-kappaB激活的激酶--KappaB/IkappaB-α或IKKβ的表达，抑制了细胞周期蛋白D1启动子的活性和细胞周期蛋白D1的表达，表明Pdcd4基因敲除对细胞周期蛋白D1的上调至少部分是通过核因子-kappaB的激活来实现的。为了探讨Pdcd4基因敲除细胞激活核因子-kappaB的机制，作者发现Pdcd4基因敲除细胞中AKT磷酸化水平和AKT激酶活性增加。相反，Pdcd4的异位表达抑制了AKT的磷酸化和细胞周期蛋白D1的表达，提示Pdcd4调节AKT活性和细胞周期蛋白D1的表达。此外，在Pdcd4基因敲除的细胞中，AKT的敲除抑制了IKK的磷酸化、核因子-kappaB的激活、细胞周期蛋白D1启动子的活性、细胞周期蛋白D1的表达以及细胞的增殖。综上所述，这些发现表明，通过AKT敲除Pdcd4而激活的NF-kappaB有助于提高细胞周期蛋白D1的表达，从而为Pdcd4的表达缺失如何促进肿瘤的发展提供了新的见解。
Programmed cell death 4 (Pdcd4), a novel tumor suppressor, inhibits neoplastic transformation and tumor invasion. In this study, the authors found that knockdown of Pdcd4 promoted cell proliferation and up-regulated cyclin D1 expression. Previously, the authors demonstrated that Pdcd4 knockdown activated NF-kappaB-dependent transcription. Mutations of NF-kappaB binding sites on the cyclin D1 promoter attenuated the cyclin D1 promoter activity induced by Pdcd4 knockdown. In addition, knockdown of NF-kappaB/IkappaB kinase (IKK) alpha or IKKbeta, the kinase regulating NF-kappaB activation, inhibited cyclin D1 promoter activity and cyclin D1 expression, indicating that up-regulation of cyclin D1 by Pdcd4 knockdown is contributed, at least in part, by NF-kappaB activation. To investigate the mechanism of how Pdcd4 knockdown activates NF-kappaB, the authors found that the levels of AKT phosphorylation and AKT kinase activity were increased in the Pdcd4 knockdown cells. Conversely, ectopic expression of Pdcd4 inhibited AKT phosphorylation and cyclin D1 expression, suggesting that Pdcd4 regulates AKT activity and cyclin D1 expression. Furthermore, knockdown of AKT in the Pdcd4 knockdown cells inhibited IKK phosphorylation, NF-kappaB activation, cyclin D1 promoter activity, and cyclin D1 expression as well as cell proliferation. Taken together, these findings suggest that activation of NF-kappaB by Pdcd4 knockdown through AKT contributes to the elevated expression of cyclin D1, thus providing new insights into how loss of Pdcd4 expression promotes tumor development.