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.