Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation

Cell. 2004 Apr 16;117(2):211-23. doi: 10.1016/s0092-8674(04)00298-3.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Division / genetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics
  • Cyclins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fetus
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Developmental / genetics*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Binding / genetics
  • Signal Transduction / genetics
  • Smad Proteins
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Telencephalon / cytology
  • Telencephalon / embryology*
  • Telencephalon / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Smad Proteins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Phosphatidylinositol 3-Kinases