PMID- 14691455
OWN - NLM
STAT- MEDLINE
DCOM- 20040318
LR  - 20111117
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 23
IP  - 8
DP  - 2004 Feb 26
TI  - NGF activation of TrkA decreases N-myc expression via MAPK path leading to a 
      decrease in neuroblastoma cell number.
PG  - 1522-30
AB  - 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.
FAU - Woo, Chan-Wook
AU  - Woo CW
AD  - Cell & Molecular Biology Section, Pediatric Oncology Branch, NCI, NIH, Bethesda, 
      MD 20892, USA.
FAU - Lucarelli, Enrico
AU  - Lucarelli E
FAU - Thiele, Carol J
AU  - Thiele CJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Carbazoles)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Cyclin E)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (E2F Transcription Factors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indole Alkaloids)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Transcription Factors)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - 97161-97-2 (staurosporine aglycone)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP3K1 protein, human)
SB  - IM
MH  - Carbazoles/pharmacology
MH  - Cell Count
MH  - Cell Cycle Proteins/drug effects/metabolism
MH  - Cell Division/drug effects
MH  - Cell Line, Tumor
MH  - Cyclin E
MH  - Cyclin-Dependent Kinases/drug effects/metabolism
MH  - *DNA-Binding Proteins
MH  - E2F Transcription Factors
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Indole Alkaloids
MH  - *MAP Kinase Kinase Kinase 1
MH  - MAP Kinase Kinase Kinases/metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Nerve Growth Factor/*pharmacology
MH  - Neuroblastoma
MH  - Proto-Oncogene Proteins c-myc/genetics/*metabolism
MH  - Receptor, trkA/genetics/*metabolism
MH  - Signal Transduction
MH  - Time Factors
MH  - Transcription Factors/drug effects/genetics/metabolism
MH  - Transfection
EDAT- 2003/12/24 05:00
MHDA- 2004/03/19 05:00
CRDT- 2003/12/24 05:00
PHST- 2003/12/24 05:00 [pubmed]
PHST- 2004/03/19 05:00 [medline]
PHST- 2003/12/24 05:00 [entrez]
AID - 1207267 [pii]
AID - 10.1038/sj.onc.1207267 [doi]
PST - ppublish
SO  - Oncogene. 2004 Feb 26;23(8):1522-30. doi: 10.1038/sj.onc.1207267.