Abstract
Loss of axonal contact characterizes Schwann cells in benign and malignant peripheral nerve sheath tumors (MPNST) from neurofibromatosis type 1 (NF1) patients. Tumor Schwann cells demonstrate NF1 mutations, elevated Ras activity, and aberrant epidermal growth factor receptor (EGFR) expression. Using cDNA microarrays, we found that brain lipid binding protein (BLBP) is elevated in an EGFR-positive subpopulation of Nf1 mutant mouse Schwann cells (Nf1(-/-) TXF) that grows away from axons; BLBP expression was not affected by farnesyltransferase inhibitor, an inhibitor of H-Ras. BLBP was also detected in EGFR-positive cell lines derived from Nf1:p53 double mutant mice and human MPNST. BLBP expression was induced in normal Schwann cells following transfection with EGFR but not H-Ras12V. Furthermore, EGFR-mediated BLBP expression was not inhibited by dominant-negative H-Ras, indicating that BLBP expression is downstream of Ras-independent EGFR signaling. BLBP-blocking antibodies enabled process outgrowth from Nf1(-/-) TXF cells and restored interaction with axons, without affecting cell proliferation or migration. Following injury, BLBP expression was induced in normal sciatic nerves when nonmyelinating Schwann cells remodeled their processes. These data suggest that BLBP, stimulated by Ras-independent pathways, regulates Schwann cell-axon interactions in normal peripheral nerve and peripheral nerve tumors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Axons / metabolism*
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Movement
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Cells, Cultured / cytology
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Cells, Cultured / metabolism
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Cytoplasm / metabolism
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Genes, Dominant
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Genes, Neurofibromatosis 1
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Genes, ras
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Humans
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Nerve Crush
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Nerve Regeneration
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Nerve Sheath Neoplasms / etiology*
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Nerve Sheath Neoplasms / metabolism
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Nerve Sheath Neoplasms / pathology
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Neural Crest / cytology
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Neurofibromin 1 / physiology
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Recombinant Fusion Proteins / physiology
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Schwann Cells / cytology
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Schwann Cells / metabolism*
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Sciatic Nerve / injuries
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Signal Transduction
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / metabolism
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Tumor Suppressor Proteins*
Substances
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Carrier Proteins
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FABP7 protein, human
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Fabp7 protein, mouse
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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Membrane Proteins
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Neoplasm Proteins
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Nerve Tissue Proteins
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Neurofibromin 1
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RNA, Messenger
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RNA, Neoplasm
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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ErbB Receptors