Author/Authors :
Kau، نويسنده , , Tweeny R and Schroeder، نويسنده , , Frank and Ramaswamy، نويسنده , , Shivapriya and Wojciechowski، نويسنده , , Cheryl L and Zhao، نويسنده , , Jean J and Roberts، نويسنده , , Thomas M and Clardy، نويسنده , , Jon and Sellers، نويسنده , , William R and Silver، نويسنده , , Pamela A، نويسنده ,
Abstract :
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.
