Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation.
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.
Seoane
Joan
J
Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, 1300 York Avenue, New York, NY 1002, USA.
Le
Hong-Van
HV
Shen
Lijian
L
Anderson
Stewart A
SA
Massagué
Joan
J
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005333:Fetus; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases