The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

Cell Death Differ. 2007 May;14(5):895-906. doi: 10.1038/sj.cdd.4402057. Epub 2006 Nov 10.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclic AMP / metabolism
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Farnesol / analogs & derivatives
  • Farnesol / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Gene Dosage / drug effects
  • Genotype
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Mice
  • Neurofibromin 1 / deficiency
  • Neurofibromin 1 / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Salicylates / pharmacology
  • Simian virus 40
  • TOR Serine-Threonine Kinases
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / metabolism*

Substances

  • Intercellular Signaling Peptides and Proteins
  • Neurofibromin 1
  • Salicylates
  • farnesylthiosalicylic acid
  • Farnesol
  • Cyclic AMP
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins