A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells.
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.
Kau
Tweeny R
TR
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Schroeder
Frank
F
Ramaswamy
Shivapriya
S
Wojciechowski
Cheryl L
CL
Zhao
Jean J
JJ
Roberts
Thomas M
TM
Clardy
Jon
J
Sellers
William R
WR
Silver
Pamela A
PA
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002147:Calmodulin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097606:Exportin 1 Protein
D001562:Benzimidazoles; D052160:Benzothiazoles; D002147:Calmodulin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D028884:Karyopherins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C000604115:5233705 compound; C085126:FOXO1 protein, human