Hyperactive Ras as a therapeutic target in neurofibromatosis type 1.
The NF1 gene encodes neurofibromin, a GTPase-activating protein (GAP) for members of the p21(ras) (Ras) family, which negatively regulates Ras output by accelerating the conversion of active Ras. GTP to inactive Ras.GDP. Analysis of tumors from patients with neurofibromatosis type 1 (NF1) has shown biochemical evidence of hyperactive Ras as well as frequent loss of the normal NF1 allele, consistent with its role as a tumor suppressor gene. Taken together, these data suggest that novel therapeutics directed against components of the Ras signaling cascade might provide effective treatments for certain pathological complications of NF1. Here we summarize data that support a role for hyperactive Ras in NF1 disease, including Ras processing, activation, and down-regulation. We review targets for rational drug design, provide preliminary results, and discuss implications for future studies. Am. J. Med. Genet. (Semin. Med. Genet.) 89:14-22, 1999.
Weiss
B
B
Department of Pediatrics, University of California, San Francisco 94143-0519, USA.
Bollag
G
G
Shannon
K
K
D015195:Drug Design; D020690:GTPase-Activating Proteins; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000628:therapy*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D020690:GTPase-Activating Proteins; D011506:Proteins; D020703:ras GTPase-Activating Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins