NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number.
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.[1]References
- NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number. Woo, C.W., Lucarelli, E., Thiele, C.J. Oncogene (2004) [Pubmed]
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