Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK signaling in human neuroblastoma cells

Exp Cell Res. 2005 Oct 15;310(1):218-28. doi: 10.1016/j.yexcr.2005.07.011.


Ras and Notch signaling have recently been shown to cooperate in the maintenance of neoplastic transformation. Here, we show that TGFalpha, a known activator of Ras signaling, can drive cell proliferation and at the same time induce the expression of the Notch target Hes-1 in the neuroblastoma cell line SK-N-BE(2)c. The up-regulation of Hes-1 occurred both at the transcriptional and protein levels and by use of EGFR and MEK inhibitors we could show that the Hes-1 response was dependent on activation of the MAP kinase ERK. Blocking Notch activation by gamma-secretase inhibition did not profoundly affect the Hes-1 levels, neither in untreated nor in TGFalpha treated cells. The up-regulation of Hes-1 was associated with down-regulation of its pro-neuronal target gene Hash-1. Taken together, these results show that TGFalpha is a potent mitogen of neuroblastoma cells and suggest a connection between activation of ERK and Hes-1, thus providing a link between the Ras and Notch signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Line, Tumor
  • Cell Proliferation
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Membrane Proteins / physiology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Receptors, Notch
  • Signal Transduction / drug effects
  • Transcription Factor HES-1
  • Transforming Growth Factor alpha / pharmacology
  • Transforming Growth Factor alpha / physiology*
  • Up-Regulation
  • ras Proteins / metabolism*


  • Basic Helix-Loop-Helix Transcription Factors
  • Enzyme Inhibitors
  • Homeodomain Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Transcription Factor HES-1
  • Transforming Growth Factor alpha
  • HES1 protein, human
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins