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

Oncogene volume 23, pages 1522–1530 (2004)Cite this article

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. 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 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.

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Acknowledgements

We thank Natalie G Ahn (Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA) for the gift of the mutant MEK (MAPKK) plasmids; Uimook Choi for assistance with the transfection experiments; Tatsuya Matsuo for assistance with cell cycle experiment; Kim Mott for helpful assistance; Mitsunari Nakamura, Xuezhong Yang, Jimmy Stauffer, Jerry Jaboin and Arvind Ingle for technical assistance; and David Kaplan for helpful discussion. Dr Woo received partial support from the Department of Pediatrics of the Korea University Hospital and the Korea University College of Medicine Alumni Association of USA.

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  1. Enrico Lucarelli

    Present address: Laboratorio De Ricerca Onologica, Instituti Ortopedici Rizzoli, Instituto Codavilla Putti, Via di Barbiano 1/10, 40136, Bologna (BO), Italy

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  1. Cell & Molecular Biology Section, Pediatric Oncology Branch, NCI, NIH, Bethesda, 20892, MD, USA

    Chan-Wook Woo, Enrico Lucarelli & Carol J Thiele

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Correspondence to Carol J Thiele.

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Woo, CW., Lucarelli, E. & Thiele, C. NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number. Oncogene 23, 1522–1530 (2004). https://doi.org/10.1038/sj.onc.1207267

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