Journal
CANCER CELL
Volume 4, Issue 6, Pages 463-476Publisher
CELL PRESS
DOI: 10.1016/S1535-6108(03)00303-9
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Funding
- NCI NIH HHS [CA85912, CA67786, CA30002, CA89021, 2T32 CA09361-21A1, 5T32CA09361-22] Funding Source: Medline
- NIAID NIH HHS [AI07386-11] Funding Source: Medline
- NIGMS NIH HHS [GM36373] Funding Source: Medline
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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.
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