Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors
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Cell Line, Tumor
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Cell Proliferation
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Neoplastic*
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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Membrane Proteins / physiology*
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Mitogen-Activated Protein Kinases / metabolism*
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Neuroblastoma / metabolism*
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Neuroblastoma / pathology
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Receptors, Notch
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Signal Transduction / drug effects
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Transcription Factor HES-1
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Transforming Growth Factor alpha / pharmacology
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Transforming Growth Factor alpha / physiology*
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Up-Regulation
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ras Proteins / metabolism*
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Enzyme Inhibitors
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Homeodomain Proteins
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Membrane Proteins
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Receptors, Notch
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Transcription Factor HES-1
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Transforming Growth Factor alpha
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HES1 protein, human
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ErbB Receptors
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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ras Proteins