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

Chan Wook Woo, Enrico Lucarelli, Carol J. Thiele

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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. Pharmacologie 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 p27kip1. Consistent with these findings, NGF decreased NB cell number and decreased cyclin E-dependent kinase activity via an increase in p27kip1. 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 p27kip1 binding to cyclin E kinase.

Original languageEnglish (US)
Pages (from-to)1522-1530
Number of pages9
JournalOncogene
Volume23
Issue number8
DOIs
StatePublished - Feb 26 2004

Keywords

  • Cell cycle
  • E2F
  • MAPK
  • N-myc
  • NGF
  • Neuroblastoma
  • TrkA
  • p27

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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