Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK signaling in human neuroblastoma cells.
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.
Stockhausen
Marie-Thérése
MT
Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, Entrance 78, S-205 02 Malmö, Sweden.
Sjölund
Jonas
J
Axelson
Håkan
H
D051792:Basic Helix-Loop-Helix Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1; D016211:Transforming Growth Factor alpha / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D016211:Transforming Growth Factor alpha; D018631:ras Proteins; C078493:HES1 protein, human