The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways.
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.
Shapira
S
S
Department of Neurobiochemistry, George S Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
Barkan
B
B
Friedman
E
E
Fridman
E
E
Kloog
Y
Y
Stein
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018628:Gene Dosage / Q000187:drug effects; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency; D051379:Mice; D025542:Neurofibromin 1 / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology; D013539:Simian virus 40; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D036341:Intercellular Signaling Peptides and Proteins; D025542:Neurofibromin 1; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D000242:Cyclic AMP; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins