A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells
A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells
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DOI：
10.1016/s1535-6108(03)00303-9
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发表时间：
2003-12-01
期刊：
影响因子：
50.3
通讯作者：
Silver, PA
中科院分区：
文献类型：
--
作者：
Kau, TR;Schroeder, F;Silver, PA
PI3K/PTEN/Akt信号转导通路在许多肿瘤中起关键作用。该途径的下游靶点包括Forkhead转录因子家族(FOXO1a、FOXO3a、FOXO4)。在PTEN缺失的细胞中，FOXO1a被依赖于PI3K的磷酸化和错误定位到细胞质而失活，但仍经历核质穿梭。由于FOXO1a强制定位到细胞核可以逆转PTEN缺失细胞的致瘤性，因此进行了高含量的FOXO1a核输出抑制剂的化学遗传筛选。在第一次筛选中检测到的化合物在二次分析中重新测试，并确定了结构-功能关系。发现了新的与CRM1反应的通用出口抑制剂以及一些抑制PI3K/Akt信号转导的化合物，其中包括多种钙调蛋白信号转导的拮抗剂。
The PI3K/PTEN/Akt signal transduction pathway plays a key role in many tumors. Downstream targets of this pathway include the Forkhead family of transcription factors (FOXO1a, FOXO3a, FOXO4). In PTEN null cells, FOXO1a is inactivated by PI3K-dependent phosphorylation and mislocalization to the cytoplasm, yet still undergoes nucleocytoplasmic shuttling. Since forcible localization of FOXO1a to the nucleus can reverse tumorigenicity of PTEN null cells, a high-content, chemical genetic screen for inhibitors of FOXO1a nuclear export was performed. The compounds detected in the primary screen were retested in secondary assays, and structure-function relationships were identified. Novel general export inhibitors were found that react with CRM1 as well as a number of compounds that inhibit PI3K/Akt signaling, among which are included multiple antagonists of calmodulin signaling.