NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number

Oncogene. 2004 Feb 26;23(8):1522-30. doi: 10.1038/sj.onc.1207267.


In neuroblastoma (NB), expression of the TrkA receptor is correlated with good prognosis while N-myc amplification is correlated with poor prognosis. Decreased N-myc levels are key to controlling growth and inducing differentiation in NB cells. In this report, we detail mechanisms by which nerve growth factor (NGF) decreases N-myc levels in TrkA-transfected NB cells and its effect on NB cell proliferation. NGF induced a decrease in N-myc mRNA within 1 h of treatment that occurred in the presence of cycloheximide. The stability of N-myc mRNA was not affected by NGF, indicating a transcriptional control of N-myc mRNA by NGF. NGF but not brain-derived neurotrophic factor (BDNF) decreased N-myc levels demonstrating that p75 alone was not involved. The NGF-induced decrease in N-myc expression was blocked by the Trk tyrosine kinase (TK) antagonist K252a indicating that signals transduced by Trk TK downstream targets were involved. Pharmacologic inhibitors implicated the mitogen-activated protein kinase (MAPK) path. This was supported by the finding that expression of a constitutively activated component of the MAPK path, MAPK kinase (MEK), decreased N-myc levels. Alterations in the level of N-myc are known to alter NB cell cycle progression by affecting the levels of E2Fs and p27(kip1). Consistent with these findings, NGF decreased NB cell number and decreased cyclin E-dependent kinase activity via an increase in p27(kip1). Thus, our results indicate that the MAP kinase is selectively involved in the NGF-induced N-myc downregulation through a transcriptional mechanism. Furthermore, NGF affects the time required for 15N TrkA cells to complete a replication cycle by decreasing N-myc, E2Fs, cyclin E kinase activity and increasing p27(kip1) binding to cyclin E kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbazoles / pharmacology
  • Cell Count
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cyclin E
  • Cyclin-Dependent Kinases / drug effects
  • Cyclin-Dependent Kinases / metabolism
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Indole Alkaloids
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nerve Growth Factor / pharmacology*
  • Neuroblastoma
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptor, trkA / genetics
  • Receptor, trkA / metabolism*
  • Signal Transduction
  • Time Factors
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection


  • Carbazoles
  • Cell Cycle Proteins
  • Cyclin E
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • Enzyme Inhibitors
  • Indole Alkaloids
  • Proto-Oncogene Proteins c-myc
  • Transcription Factors
  • Nerve Growth Factor
  • staurosporine aglycone
  • Receptor, trkA
  • Cyclin-Dependent Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP Kinase Kinase Kinases
  • MAP3K1 protein, human