INACTIVATION OF THE NF1 GENE IN HUMAN-MELANOMA AND NEUROBLASTOMA CELL-LINES WITHOUT IMPAIRED REGULATION OF GTP.RAS

The NF1 gene, which is altered in patients with type 1 neurofibromatos is, encodes neurofibromin, a protein whose GTPase-activating function can negatively regulate GTP.Ras by accelerating its conversion to inac tive GDP.Ras. In schwannoma cell lines from patients with neurofibroma tosis, loss of neurofibromin was previously shown to be associated wit h impaired regulation of GTP-Ras. Our analysis of other neural crest-d erived tumor cell lines has shown that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neur ofibromatosis contain reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, GTP.Ras was appropriately regulated in t he melanoma and neuroblastoma lines that were deficient in neurofibrom in, even when c-H-ras was overexpressed in the lines. These results de monstrate that some neural crest tumors not associated with neurofibro matosis have acquired somatically inactivated NF1 genes and suggest a tumor-suppressor function for neurofibromin that is independent of Ras GTPase activation.