Abstract
Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Child, Preschool
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Enzyme Activation
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Female
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Humans
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Infant
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Male
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Medulloblastoma / enzymology
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Medulloblastoma / pathology*
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Medulloblastoma / ultrastructure
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Mice
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Mice, Nude
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Nerve Growth Factors / pharmacology
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Neurotrophin 3
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Phosphatidylinositol 3-Kinases / metabolism
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Prognosis
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / physiology*
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Receptor, trkC
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Receptors, Nerve Growth Factor / biosynthesis
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Receptors, Nerve Growth Factor / metabolism
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Receptors, Nerve Growth Factor / physiology*
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Signal Transduction / physiology
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Stimulation, Chemical
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Tumor Cells, Cultured
Substances
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Nerve Growth Factors
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Neurotrophin 3
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Proto-Oncogene Proteins c-fos
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Receptors, Nerve Growth Factor
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Phosphatidylinositol 3-Kinases
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Receptor Protein-Tyrosine Kinases
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Receptor, trkC
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Calcium-Calmodulin-Dependent Protein Kinases