Abstract
PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G(1) arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27(KIP1) protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Biological Transport
-
Cell Compartmentation
-
Cell Cycle / physiology*
-
Cell Cycle Proteins*
-
Cell Death / physiology*
-
Cell Nucleus
-
Cyclin-Dependent Kinase Inhibitor p27
-
Cyclin-Dependent Kinases / antagonists & inhibitors
-
DNA-Binding Proteins / metabolism*
-
Gene Expression Regulation, Neoplastic
-
Genes, Tumor Suppressor*
-
Half-Life
-
Microtubule-Associated Proteins / metabolism
-
PTEN Phosphohydrolase
-
Phosphoric Monoester Hydrolases / metabolism*
-
Phosphorylation
-
Signal Transduction
-
Transcription Factors / metabolism*
-
Transcription, Genetic
-
Transcriptional Activation
-
Tumor Cells, Cultured
-
Tumor Suppressor Proteins*
Substances
-
Cell Cycle Proteins
-
DNA-Binding Proteins
-
Microtubule-Associated Proteins
-
Transcription Factors
-
Tumor Suppressor Proteins
-
Cyclin-Dependent Kinase Inhibitor p27
-
Cyclin-Dependent Kinases
-
Phosphoric Monoester Hydrolases
-
PTEN Phosphohydrolase