TGF-alpha induces upregulation and nuclear translocation of Hes1 in glioma cell

Cell Biochem Funct. 2008 Aug;26(6):692-700. doi: 10.1002/cbf.1494.


Both the Notch-signaling pathway and extracellular signal regulated kinase (ERK) cascade are involved in a wide variety of biological processes, such as proliferation, differentiation, survival, and tumorigenesis. Their dysregulation in recent studies have been shown to be associated with glioma formation. Here, we show that transforming growth factor-alpha (TGF-alpha) stimulated glioma cell line U251 growth and can partly compensate for the inhibitory effect of Notch-signaling inhibitor DAPT. The effect of TGF-alpha on ERK1/2 phosphorylation was prompt and transient and could be inhibited by mitogen-activated/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) specific inhibitor PD98059. Moreover, TGF-alpha was capable of up-regulating Hairy-enhancer of split1 (Hes1) expression which was independent of Notch1 activation, and of introducing Hes1 nuclear import in the presence of ERK1/2 activation. Collectively, our data suggest a potential linkage between ERK activation and the Notch-signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Dipeptides / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Phosphorylation / drug effects
  • Protease Inhibitors / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport / drug effects
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Transcription Factor HES-1
  • Transforming Growth Factor alpha / pharmacology*
  • Up-Regulation / drug effects*


  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Dipeptides
  • Flavonoids
  • Homeodomain Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Protease Inhibitors
  • Protein Kinase Inhibitors
  • RBPJ protein, human
  • Receptors, Notch
  • Transcription Factor HES-1
  • Transforming Growth Factor alpha
  • HES1 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • Amyloid Precursor Protein Secretases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one