Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN.
Journal:
Mol. Cell. Biol. 2000 DecAuthors:
Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR
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 p
...[more]roduces 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.[less]
Mesh Headings:
Biological Transport, Cell Compartmentation, Cell Cycle, Cell Cycle Proteins, Cell Death, Cell Nucleus, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Half-Life, Microtubule-Associated Proteins, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases, Phosphorylation, Signal Transduction, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Tumor Cells, Cultured, Tumor Suppressor Proteins