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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / drug effects*
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Animals
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Benzimidazoles / pharmacology
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Benzothiazoles / pharmacology
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Calmodulin / metabolism
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Cell Nucleus / metabolism
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DNA-Binding Proteins / metabolism*
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Drug Design*
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Enzyme Inhibitors / pharmacology*
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Exportin 1 Protein
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Karyopherins / metabolism
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Models, Molecular
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / deficiency
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Phosphoric Monoester Hydrolases / genetics
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Phosphorylation
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Receptors, Cytoplasmic and Nuclear*
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Signal Transduction / drug effects
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
Substances
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5233705 compound
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Benzimidazoles
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Benzothiazoles
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Calmodulin
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DNA-Binding Proteins
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Enzyme Inhibitors
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Karyopherins
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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Phosphoric Monoester Hydrolases