Abstract
FoxO Forkhead transcription factors are shown here to act as signal transducers at the confluence of Smad, PI3K, and FoxG1 pathways. Smad proteins activated by TGF-beta form a complex with FoxO proteins to turn on the growth inhibitory gene p21Cip1. This process is negatively controlled by the PI3K pathway, a known inhibitor of FoxO localization in the nucleus, and by the telencephalic development factor FoxG1, which we show binds to FoxO-Smad complexes and blocks p21Cip1 expression. We suggest that the activity of this network confers resistance to TGF-beta-mediated cytostasis during the development of the telencephalic neuroepithelium and in glioblastoma brain tumor cells.
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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Animals
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Cell Division / genetics
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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Cyclins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Fetus
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Gene Expression Regulation, Developmental / genetics*
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Glioblastoma / genetics
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Glioblastoma / metabolism*
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Binding / genetics
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Signal Transduction / genetics
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Smad Proteins
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Stem Cells / cytology
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Stem Cells / metabolism*
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Telencephalon / cytology
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Telencephalon / embryology*
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Telencephalon / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Smad Proteins
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Phosphatidylinositol 3-Kinases