Introduction of nerve growth factor (NGF) receptors into a medulloblastoma cell line results in expression of high- and low-affinity NGF receptors but not NGF-mediated differentiation.

Pleasure, Samuel J.; Reddy, Usha R.; Venkatakrishnan, Gita; Roy, Amit; Chen, Jie; Ross, Alonzo H.; Trojanowski, John Q.; Pleasure, David E; Lee, Virginia M.‐Y.

doi:10.1073/pnas.87.21.8496

Cited by 54 publications

(41 citation statements)

References 38 publications

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“…MBs are thought to arise from granule cell progenitors in the external granule layer of the developing cerebellum (21), and it has been reported that the abundance of trkC mRNA expression correlates with a better response to therapy in pediatric patients with MB (22). Although our earlier studies failed to implicate NGF and low affinity NGF receptor in modulating the behavior of MB cells (23), a subsequent study of the same MB cells engineered to express TrkA on their cell surface yielded the unexpected finding that activation of these receptors led to extensive apoptosis (24). We hypothesized that NGF may induce apoptosis specifically through activation of specific signal transduction pathways.…”

Section: Ngfmentioning

confidence: 76%

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Chou

Trojanowski

Lee

2000

Journal of Biological Chemistry

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Nerve growth factor (NGF) induces apoptosis in a human medulloblastoma cell line (MED283) engineered to express TrkA (MED283-TrkA) (Muragaki, Y., Chou, T. T., Kaplan, D. R., Trojanowski, J. Q., and Lee, V. M. (1997) J. Neurosci. 17, 530 -542). To dissect the molecular signaling pathway that mediates this novel effect, specific receptor mutations in Trk have been employed. We showed that phosphorylation of tyrosine 490 is required for activation of phosphoinositide 3-OH kinase, whereas phosphorylation of tyrosine 785 is required for activation of phospholipase C-␥. TrkA-mediated apoptosis was abolished when either the ATP-binding site or both tyrosines 490 and 785 were mutated. Because tyrosines 490 and 785 mediate redundant signaling through the Rasextracellular signal-regulated kinase (Ras-ERK) pathway, we examined the role of Ras-ERK signaling in NGFinduced apoptosis. We found that MED283-TrkA cells expressing a dominant negative Ras inhibitor (N17Ras) failed to undergo ERK activation and apoptosis following NGF treatment, whereas the ERK kinase (mitogenactivated protein kinase kinase) inhibitors PD98059 and U0126 eliminated ERK activation but had no effect on apoptosis. We infer from these data that NGF-induced apoptosis is mediated by a novel Ras and/or Raf signaling pathway.

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Section: Ngfmentioning

confidence: 76%

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Chou

Trojanowski

Lee

2000

Journal of Biological Chemistry

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“…We and others have previously observed that the transfected gp75NGFR was able to signal an NGF response in several cell lines, although the molecular mechanisms have not been identified (16,37,43 (50). The trkA-mediated NGF signal pathway transcriptionally inactivated the N-myc oncogene in transfectants, although the gene shows a 20-fold amplification.…”

Section: Resultsmentioning

confidence: 99%

Expression of trkA cDNA in neuroblastomas mediates differentiation in vitro and in vivo.

Miyata

Bogenmann

1993

Mol. Cell. Biol.

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The human trkA cDNA was transfected into a malignant human neuroblastoma (NB) cell line (HTLA230) to investigate its role in NB growth and differentiation. This cell line lacks expression of both endogenous trkA and gp75NGFR genes. Transfectants expressing the trkA mRNA and surface-bound receptors transcriptionally activate immediate-early genes (c-fos, c-jun, and jun-B) following nerve growth factor (NGF) stimulation. NGF treatment induces growth arrest as well as down-regulation of the amplified N-myc oncogene. Genes selectively expressed in mature neurons (SCG-10, ret proto-oncogene, GAP-43, etc.) are transcriptionally activated, and neurite outgrowth further demonstrates differentiation of transfectants following NGF stimulation. trkA-expressing NB cells remain tumorigenic in nude mice; however, subcutaneous treatment of tumor-bearing mice with NGF induces Schwannian and neuronal cell differentiation similar to the induction seen in human ganglioneuroblastomas. Thus, trkA expression in HTLA230 cells is sufficient to generate a functional NGF receptor complex that leads to growth-arrested and differentiated NB cells in vitro and in vivo in the presence of NGF. Hence, NGF may play a crucial role in NB cell differentiation and regression in vivo.

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“…The p75 gene, when transfected into nonneuronal cells, was shown to generate low a nity NGF binding sites, while expression in neuronal cells induced NGF-mediated cell di erentiation (Hempstead et al, 1989;Johnson et al, 1986;Matsushima and Bogenmann, 1990;Pleasure et al, 1990). Complex formation between p75 and trkA was observed, thus enhancing the NGF signal (Hempstead et al, 1991;Verdi et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Regulation of NGF responsiveness in human neuroblastoma

et al. 1998

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Introduction of nerve growth factor (NGF) receptors into a medulloblastoma cell line results in expression of high- and low-affinity NGF receptors but not NGF-mediated differentiation.

Cited by 54 publications

References 38 publications

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Expression of trkA cDNA in neuroblastomas mediates differentiation in vitro and in vivo.

Regulation of NGF responsiveness in human neuroblastoma

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