Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells
Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells
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DOI：
10.1158/0008-5472.can-06-4484
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Schneider, Guenter
中科院分区：
文献类型：
--
作者：
Reichert, Maximilian;Saur, Dieter;Schneider, Guenter
磷酸肌醇-3-激酶（PI 3 K）/AKT信号通路控制癌细胞生物学的基本过程，如增殖和细胞存活。PI 3 K/AKT通路在胰腺导管腺癌（PDAC）细胞中被激活。在PDAC细胞中将PI 3 K信号传导与细胞周期机制联系起来的分子机制尚未详细研究。使用PI 3 K抑制剂Ly 294002以及靶向AKT 1表达的小干扰RNA，我们显示PI 3 K控制PDAC细胞的增殖和G（1）期进展。基因分析揭示了PI 3 K信号转导控制的GI-S期进展的几个重要调节因子，如p21（Cip 1）、S期激酶相关蛋白2（SKP 2）、CDC 25 a、细胞周期蛋白A、细胞周期蛋白D2、CDK 2和细胞周期蛋白E。我们发现，F-box蛋白SKP 2，一个在PDAC中上调的癌基因，在PDAC细胞中受PI 3 K/AKT 1通路的转录调控。在分子水平上，PI 3 K对SKP 2基因的控制是由于E2 F1与SKP 2基因启动子近端结合的调节。PI 3 K/AKT 1的复杂和深刻的联系。向细胞周期的信号传导使该途径成为PDAC中治疗性干预的合适靶点。
The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G(1) phase progression of PDAC cells. Gene profiling revealed several important regulators of GI-S phase progression controlled by PI3K signaling like p21(Cip1), S-phase kinase-associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/ AKT1. signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC.