Abstract
Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio- and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1(-/-), Nf1(+/-), and Nf1(+/+) MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.
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.
MeSH terms
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Animals
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Apoptosis* / drug effects
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Survival / drug effects
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Cyclic AMP / metabolism
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Embryo, Mammalian / cytology
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Embryo, Mammalian / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Farnesol / analogs & derivatives
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Farnesol / pharmacology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Gene Dosage / drug effects
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Genotype
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Humans
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Intercellular Signaling Peptides and Proteins / deficiency
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Mice
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Neurofibromin 1 / deficiency
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Neurofibromin 1 / metabolism*
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Phosphorylation / drug effects
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Salicylates / pharmacology
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Simian virus 40
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TOR Serine-Threonine Kinases
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ras Proteins / antagonists & inhibitors
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ras Proteins / metabolism*
Substances
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Intercellular Signaling Peptides and Proteins
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Neurofibromin 1
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Salicylates
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farnesylthiosalicylic acid
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Farnesol
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Cyclic AMP
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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ras Proteins