A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR
A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR
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DOI：
10.1016/s1535-6108(02)00086-7
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发表时间：
2002-07-01
期刊：
影响因子：
50.3
通讯作者：
Sellers, WR
中科院分区：
文献类型：
--
作者：
Ramaswamy, S;Nakamura, N;Sellers, WR
哺乳动物β 16样转录因子FKHR、FKHRL 1和AFX作为胰岛素信号传导、细胞周期进程和磷酸肌醇3-激酶下游细胞凋亡的关键调节因子发挥作用。通过与胰岛素反应序列（IRS）结合的基因激活被认为是介导这些功能所必需的。然而，使用转录谱分析，染色质免疫沉淀和功能实验，我们证明，而不是IRS调节基因（I类转录本）的激活，转录抑制D型细胞周期蛋白（111类）是FKHR介导的细胞周期进程和转化的抑制所必需的。这些数据表明，FKHR介导的基因调控的新机制与其作为肿瘤生长抑制剂的活性有关。
The mammalian DAF-16-like transcription factors, FKHR, FKHRL1, and AFX, function as key regulators of insulin signaling, cell cycle progression, and apoptosis downstream of phosphoinositide 3-kinase. Gene activation through binding to insulin response sequences (IRS) has been thought to be essential for mediating these functions. However, using transcriptional profiling, chromatin immunoprecipitation, and functional experiments, we demonstrate that rather than activation of IRS regulated genes (Class I transcripts), transcriptional repression of D-type cyclins (in Class 111) is required for FKHR mediated inhibition of cell cycle progression and transformation. These data suggest that a novel mechanism of FKHR-mediated gene regulation is linked to its activity as a suppressor of tumor growth.