Nature Genetics
3, 62 - 66 (1993)
doi:10.1038/ng0193-62
Neurofibromatosis type 1 gene mutations in neuroblastomaInge The1, 2, Anita E. Murthy1, Gregory E. Hannigan1, Lee B. Jacoby1, Anil G. Menon1, 3, James F. Gusella1
& Andre Bernards1, 2
1Molecular Neurogenetics Unit, Massachusetts General Hospital, MGH East, Building 149, 13th St. Charlestown Massachusetts 02129, USA
2Massachusetts General Hospital Cancer Center, MGH East, Building 149, 13th St. Charlestown, Massachusetts 02129, USA
3Present address: Dept. of Molecular Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0524, USA Correspondence should be addressed to A.B. The introduction of human chromosome 17 suppresses the tumourigenicity of a neuroblastoma cell line in the absence of any effects on in vitro growth and the neurofibromatosis type 1 (NF1) gene may be responsible. Here we report that 4 out of 10 human neuroblastoma lines express little or no neurofibromin and that two of these lines show evidence of NF1 mutations, providing further proof that NF1 mutations occur in tumours that are not commonly found in NF1 patients. We also show that NF1 deficient neuroblastomas show only moderately elevated ras−GTP levels, in contrast to NF1 tumour cells, indicating that neurofibromin contributes differently to the negative regulation of ras in different cell types
REFERENCES
- Riccardi, V.M. Von Recklinghausen neurofibromatosis. New Engl. J. Med. 305, 1617−1627 (1981).
- Barker, D. et al. Gene for von Recklinghausen neurofibromatosis is in the pericentric region of chromosome 17. Science 236, 1100−1102 (1987).
- Seizinger, B.R. et al. Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell 49, 589−594 (1987).
- Viskochil, D. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187−192 (1990).
- Cawthon, R.M. et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193−201 (1990).
- Wallace, M.R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 240, 181−186 (1990).
- Xu, G. et al. The neurofibromatosis type-1 gene encodes a protein related to GAP. Cell 62, 599−608 (1990).
- Buchberg, A.M., Cleveland, L.S., Jenkins, N.A. & Copeland, N.G. Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway. Nature 347, 291−294 (1990).
- De Clue, J.E. et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265−273 (1992).
- Basu, T.N. et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713−715 (1992).
- Nishi, T. et al. Differential expression of two types of the neurofibromatosis type 1 (NF1) gene transcripts related to neuronal differentiation. Oncogene 6, 1555−1559 (1991).
- Bernards, A. et al. Complete human NF1 cDNA sequence: two alternatively spliced mRNAs and absence of expression in a neuroblastoma line. DNA cell Biol. (in the press).
- Daston, M.M. et al. The product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron 8, 1−14 (1992).
- Fong, C.T. et al. Loss of heterozygosity for chromosome 1p in human neuroblastomas: correlation with N-myc amplification. Proc. natn. Acad. Sci. U.S.A. 6, 3753−3757 (1989).
- Gilbert, F. et al. Human neuroblastomas and abnormalities of chromosomes 1 and 17. Cancer Res. 4, 5444−5449 (1984).
- Bader, S.A., Fasching, C., Brodeur, G.M. & Stanbridge, E.J. Dissociation of suppression of tumorigenicity and differentiation in vitro effected by transfer of single human chromosomes into human neuroblastoma cells. Cell Growth Diff. 2, 245−255 (1991).
- Bernards, A., Rubin, C.M., Westbrook, C.A., Paskind, M. & Baltimore, D. The first intron in the human c-abl gene is at least 200 kilobases long and is a target for translocations in chronic myelogenous leukemia. Molec. cell. Biol. 7, 3231−3236 (1987).
- Bernards, A. & de la Monte, S. M. The ltk receptor tyrosine kinase is expressed in pre-B lymphocytes and cerebral neurons and uses a non-AUG translational initiator. EMBO J. 9, 2279−2287 (1990).
- Furth, M.E., Davis, L.J., Fleurdelys, B & Scolnick, E.M. Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family. J. Virol. 43, 294−304 (1982).
- Burgering, B.M.T. et al. Insulin stimulation of gene expression mediated by p21ras activation. EMBO J. 10, 1103−1109 (1991).
- Trahey, M. & McCormick, F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542−545 (1987).
- Gibbs, J.B., Schaber, M.D., Allard, W.J., Sigal, I.S. & Scolnick, E.M. Purification of ras GTPase activating protein from bovine brain. Proc. natn. Acad. Sci. U.S.A. 85, 5026−5030 (1988).
- Taparowski, E., Shimizu, K., Goldfarb, M. & Wigler, M. Structure and activation of the human N-ras gene. Cell 34, 581−586 (1983).
- Bos, J.L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682−4689 (1989).
- Moley, J.F. et al. Low frequency of ras gene mutations in neuroblastomas, pheochromocytomas, and medullary thyroid cancers. Cancer Res. 51, 1596−1599 (1991).
- Thomas, S.M., DeMarco, M., D'Arcangelo, G., Halegoua, S. & Brugge, J.S. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell 68, 1031−1040 (1992).
- Wood, K.W., Sarnecki, C., Roberts, T.M. & Blenis, J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 68, 1041−1050 (1992).
- Kushner, B.H., Hajdu, S.I. & Helson, L. Synchronous neuroblastoma and von Recklinghausen's disease: a review of the literature. J. clin. Oncol. 3, 117−120 (1985).
- Clausen, N., Andersson, P. & Tommerup, N. Familial occurrence of neuroblastoma, von Recklinghausen's neurofibromatosis, Hirschsprung's agangliosis and jaw-winking syndrome. Acta Paediatr. Scand. 78, 736−741 (1989).
- Li, Y. et al. Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 69, 275−281 (1992).
- Shimada, H. et al. Histopathological prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastoma. JNCI 73, 405−416 (1984).
- Brodeur, G.M., Seeger, R.C., Schwab, M., Varmus, H.E. & Bishop, J.M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224, 1121−1124 (1984).
- Harlow, E. & Lane, D. Antibodies. A laboratory manual (Cold Spring Harbor Laboratory, New York, 1988).
- Solomon, E. et al. Human gene mapping using an X/autosome translocation. Som. Cell Genetics 2, 125−140 (1976).
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