Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients.
Defects in the NF1 gene have been implicated in the inherited disorder neurofibromatosis type 1, which is characterized by several developmental abnormalities including an increased frequency of benign and malignant tumours of neural crest origin (neurofibromas and neurofibrosarcomas respectively). The NF1 gene encodes a ubiquitous protein homologous to p120GAP, the GTPase-activating protein (GAP) for the products of the ras protooncogenes. When expressed in non-mammalian systems, the region of the NF1 gene homologous to p120GAP produces a protein with GAP-like activity. Here we present evidence that the ras proteins in malignant tumour cell lines from patients with type 1 neurofibromatosis are in a constitutively activated state, as judged by the guanine nucleotide bound to them, and are necessary for cellular proliferation. These cells contain p21ras and p120GAP that are both functionally wild type, but barely any functional NF1 protein. Our results show that the NF1 protein is normally essential for correct negative regulation of ras proteins in the cell, even in the presence of normal p120GAP, and they support the hypothesis that NF1 is a tumour-suppressor gene whose product acts upstream of ras.
Basu
T N
TN
Signal Transduction Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, UK.
Gutmann
D H
DH
Fletcher
J A
JA
Glover
T W
TW
Collins
F S
FS
Downward
J
J
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D020690:GTPase-Activating Proteins; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D009456:Neurofibromatosis 1 / Q000188:drug therapy / Q000378:metabolism*; D011233:Precipitin Tests; D011506:Proteins / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D020703:ras GTPase-Activating Proteins
D000911:Antibodies, Monoclonal; D020690:GTPase-Activating Proteins; D011506:Proteins; D020703:ras GTPase-Activating Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)