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Ras Activation in Astrocytomas and Neurofibromas

Published online by Cambridge University Press:  18 September 2015

Abhijit Guha
Abhijit Guha*
Affiliation:
Division of Neurosurgery, The Toronto Hospital, University of Toronto, Toronto and theLunenfeld Research Institute Mt. Sinai Hospital, University of Toronto, Toronto
*
2-415 McLaughlin Pavilion, The Toronto Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8
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Abstract:

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Oncogenic mutations resulting in activated Ras Guanosine Triphosphate (GTP) are prevalent in 30% of all human cancers, but not primary nervous system tumors. Several growth factors/receptors are implicated in the pathogenesis of malignant astrocytomas including epidermal growth factor (EGFR) and platelet derived growth factor (PDGF-R) receptors, plus the highly potent and specific angiogenic vascular endothelial growth factor (VEGF). A significant proportion of these tumors also express a truncated EGFR, which is constitutively activated. Our work demonstrates that the mitogenic signals from both the normal PDGF-R and EGFR and the truncated EGFR activate Ras. Inhibition of Ras by genetic or pharmacological strategies leads to decreased astrocytoma tumorgenic growth in vitro and decreased expression of VEGF. This suggests that these agents may be potentially important as novel anti-proliferative and anti-angiogenic therapies for human malignant astrocytomas.

In contrast to astrocytomas, where increased levels of activated Ras GTP results from transmitted signals from activated growth factor receptors, the loss of neurofibromin is postulated to lead to functional up-regulation of the Ras pathway in neurofibromatosis-1(NF-1). We have demonstrated that NF-1 neurofibromas and neurogenic sarcomas, compared to non-NF-1 Schwannomas, have markedly elevated levels of activated Ras GTP. Increased Ras GTP was associated with increased tumor vascularity in the NF-1 neurogenic sarcomas, perhaps related to increased VEGF secretion. The role of Ras inhibitors as potential therapy in this tumor is also under study.

Résumé:

RÉSUMÉ:

). Les mutations d'oncogènes provoquant une activation de Ras-GTP ont une prévalence de 30% dans tous les cancers humains, mais non dans les tumeurs primitives du système nerveux. Plusieurs facteurs de croissance / récepteurs sont impliqués dans la pathogenèse des astrocytomes malins dont le récepteur du facteur de croissance épidermique (EGF-R) et celui du facteur de croissance plaquettaire (PDGF-R), ainsi que le facteur de croissance endothélial vasculaire (VEGF), un facteur de croissance très puissant et hautement spécifique. Une grande proportion des astrocytomes malins expriment un EGF-R tronqué qui est activé constitutivement. Nos travaux démontrent que les signaux mitogènes du PDGF-R normal et du EGFR normal et du EGFR tronqué activent Ras. L'inhibition de Ras par des stratégies génétiques ou pharmacologiques provoque la diminution de la croissance tumorale astrocytaire in vitro et diminue l'expression du VEGF. Ceci indique que ces agents pourraient être importants comme traitements antipro-lifératifs et antiangiogéniques dans les astrocytomes malins humains. Contrairement aux astrocytomes où des niveaux augmentés de Ras.GTP activé résultent de signaux transmis provenant de récepteurs de facteurs de croissance activés, on pense que la perte de la neurofibromine amène une régulation fonctionnelle à la hausse de la voie Ras dans la neu-rofibromatose I (NFI). Nous avons démontré que les neurofibromes de la NFI et les sarcomes neurogéniques non-NFI ont des niveaux très élevés de Ras.GTP activé comparés aux Schwannomes. Un Ras.GTP augmenté était associé à une vascularité tumorale augmentée dans les sarcomes neurogéniques de la NFI, possiblement en relation avec une augmentation de la sécrétion du VEGF. Le rôle des inhibiteurs de Ras en tant que thérapie dans cette tumeur est aussi à l'étude présentement.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 25 , Issue 4 , November 1998 , pp. 267 - 281
Copyright
Copyright © Canadian Neurological Sciences Federation 1998

References

REFERENCES

1. Mahaley, M, Mettlin, C, Natarajan, N, Laws, E, Peace, B. National survey of patterns of care for brain tumor patients. J Neurosurgery 1989; 71: 826–836.CrossRefGoogle ScholarPubMed
2. Kleihues, P, Burger, P, Scheithauer, B,. Histological Typing of Tumors of the Nervous System, 2nd Edition. Berlin: Springer-Verlag, 1993.CrossRefGoogle Scholar
3. Daumas-Duport, C, Scheithauer, B, O’Fallon, J, Kelly, P. Grading of astrocytomas; a simple and reproducible method. Cancer 1988; 62: 2152–2165.3.0.CO;2-T>CrossRefGoogle ScholarPubMed
4. von Recklinghausen, FD. Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. Berlin: Hirschwald, 1882.Google Scholar
5. Lott, IT, Richardson, EP Jr. Neuropathological findings and the biology of neurofibromatosis. Adv Neurol 1981; 29: 23–32.Google Scholar
6. Riccardi, V. Neurofibromatosis: phenotype, natural history, and pathogenesis. Baltimore: John Hopkins Univ. Press, 1992.Google Scholar
7. Grifa, A, Piemontese, MR, Melchionda, S, et al. Screening of neurofibromatosis type 1 gene: identification of a large deletion and of an intronic variant. Clin Genet 1995; 47: 281–284.Google Scholar
8. Zoller, M, Rembeck, B, Akesson, HO, Angervall, L. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Goteborg, Sweden. Acta Derm Venereol 1995; 75: 136–140.CrossRefGoogle ScholarPubMed
9. Sorensen, S, Mulvhill, J, Nielsen, A. Longterm followup of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. 1986; 314: 1010–1015.CrossRefGoogle Scholar
10. Guha, A, Lau, N, Gutmann, D, et al. Ras-GTP Levels are elevated in human NF1 peripheral nerve tumors. Oncogene 1996; 12: 507–513.Google ScholarPubMed
11. Guha, A., Bilbao, J, Kline, DG, Hudson, AR. Tumors of the peripheral nervous system. In: Youmans, JR, ed., Tumors of the Peripheral Nervous System, pp. Philadelphia: W.B. Saunders, 1996.Google Scholar
12. Bigner, SH, Mark, J, Burger, PC, et al. Specific chromosomal abnormalities in malignant human gliomas. Cancer Research 1988; 48: 405–411.Google ScholarPubMed
13. von Deimling, A, Eibl, R, Ohgaki, H, et al. p53 Mutations are associated with 17p allelic loss in gradell and gradelll astrocytoma. Cancer Res 1992; 52: 2987–2990.Google Scholar
14. Sidransky, D, Mikkelsen, T, Schwechheimer, K, et al. Clonal expansion of p53 mutant cells is associated with brain tumor progression. Nature 1992; 355: 846–847.Google Scholar
15. Pershouse, MA, Stubblefield, E, Hadi, A, et al. Analysis of the functional role of chromosome 10 loss in human glioblastomas. Cancer Res, 1993. 53: 5043–5050.Google Scholar
16. James, C, Collins, V. Molecular genetic characterization of CNS tumor oncogenesis. Adv Can Res 1992; 58: 121–142.Google Scholar
17. James, CD, Carlbom, E, Dumanski, JP, et al. Clonal genomic alterations in glioma malignancy stages. Cancer Res 1988; 48: 5546–5551.Google ScholarPubMed
18. Li, D-M, Sun, H. TEP1, Encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor-b. Cancer Res 1997; 57: 2124–2129.Google Scholar
19. Li, J, Yen, C, Liaw, D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science 1997; 275: 1943–1947.Google Scholar
20. Steck, P, Pershouse, MA, Jasser, SA, et al. Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genetics 1997; 15: 356–362.Google Scholar
21. Kamb, A, Gruis, NA, Weaver-Feldhaus, , et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994; 264: 436–440.CrossRefGoogle ScholarPubMed
22. Noborl, T, Miura, K, Wu, DJ, et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994; 368: 753–756.Google Scholar
23. Rubio, M-P, Correa, KM, Ueki, K, et al. Putative glioma tumor suppressor gene on chromosome 19q maps between APOC2 and HRC. Cancer Res 1994; 54: 4760–4763.Google Scholar
24. Libermann, T, Razon, N. Expression of EGF receptors in human brain tumors. Cancer Res 1984; 44: 753–760.Google ScholarPubMed
25. Libermann, T, Nusbaum, H, Razon, N, et al. Amplification, enhanced expression and possible rearrangement of EGF-receptor gene in primary human tumors of glial origin. Nature 1985; 313: 144–147.Google Scholar
26. Steck, P, Lee, P, Hung, M-C, Yung, W. Expression of an altered epidermal growth factor receptor by human glioblastoma cells. Cancer Res 1988; 48: 5433–5439.Google Scholar
27. Ekstrand, A, Sugawa, N, James, C, Collins, V. Amplified and rearranged epiderma growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad Sci USA 1992; 89: 4309–4313.CrossRefGoogle ScholarPubMed
28. Ekstrand, AJ, Longo, N, Hamid, ML, et al. Functional characterization of a EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGF-R gene amplification. Oncogene 1994; 9: 2313–2320.Google Scholar
29. Nishikawa, R, JiX, Harmon, RC, et al. A mutant epidermal growth factor receptor common in human gliomas confers enhanced tumorigenicity. Proc Nat Acad Sci USA 1994; 91: 7727–7731.CrossRefGoogle ScholarPubMed
30. Nistér, M, Claesson-Welsh, L, Eriksson, A, Heldin, C-H, Westermark, B. Differential expression of platelet derived growth factor receptors in human malignant glioma cell lines. J Biol Chem, 1991; 266: 16755–16763.CrossRefGoogle ScholarPubMed
31. Fleming, T, Saxena, A, Clark, W, et al. Amplification and/or overexpression of platelet derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 1992; 52: 4550–4553.Google Scholar
32. Fleming, TP, Matsui, T, Heidran, MA, et al. Demonstration of an activated platelet-derived growth factor autocrine pathway and its role in human tumor cell proliferation in vitro 1992; 7: 1355–1359,Google Scholar
33. Guha, A,. Platelet derived growth factor: a general review with emphasis on astrocytomas. Pediatr Neurosurg 1992; 92: 14–20.Google Scholar
34. Guha, A, Dashner, K, McL Black, P, Wagner, J, Stiles, C. Expression of PDGF and PDGF-receptors in human astrocytoma operative specimens. Int J Cancer 1995: 60: 168–173.CrossRefGoogle Scholar
35. Guha, A, Gowacka, D, Carrol, R, et al. Expression of platelet derived growth factor and platelet derived growth factor receptor mRNA in a glioblastoma from a patient with Li-Fraumeni syndrome. J Neurol Neurosurg Psychiatry 1995; 58: 711–714.Google Scholar
36. Mercola, M, Deininger, P, Shamah, S, et al. Dominant-negative mutants of a PDGF gene. Genes Development 1990; 4: 2333–2341.Google Scholar
37. Shamah, S, Stiles, C, Guha, A. Dominant-negative mutants of platelet-derived growth factor (PDGF) revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol 1993; 13: 7203–7212.Google ScholarPubMed
38. Folkman, J, Shing, Y. Angiogenesis. J Biol Chem 1992; 267: 10931–10934.CrossRefGoogle ScholarPubMed
39. Folkman, J. What is the evidence that tumors are angiogenesisdependent? J. Natl Cancer Inst 1990; 82: 4–6.Google Scholar
40. Folkman, J, Klagsburn, M. Angiogenic factors. Science 1987; 235: 442–447.Google Scholar
41. Klein, G, Weinhouse, S. Tumor. Angiogenesis. In: Folkman, J., ed.Advances in Cancer Research, New York, Academic Press 1974; 43–52.Google Scholar
42. Folkma, J. How is blood vessel growth regulated in normal and neoplastic tissue? Cancer Res, 1986. 46: 467–473.Google Scholar
43. Fidler, IJ, Ellis, LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994; 79: 185–188.CrossRefGoogle ScholarPubMed
44. Bouck, N. Tumor angiogenesis: the role of oncogenes and tumor suppressor genes. Cancer Cells 1990; 2: 179–185.Google ScholarPubMed
45. O’Reilly, MS, Holmgre, L, Shing, Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 70: 315–328.Google Scholar
46. Senger, DR, Galli, SJ, Dvorak, AM, et al. Tumor cells secret a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–985.Google Scholar
47. Senger, DR, Peruzzi, CA, Feder, J, Dvorak, HF. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res 1986; 46: 5629–5632.Google ScholarPubMed
48. Senger, DR, Connelly, DT, Van De Water, L, Feder, J, Dvorak, H.F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 1990; 50: 1774–1778.Google ScholarPubMed
49. Leung, DW, Cachianes, G, Kuang, W-K, Goeddel, DV, Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–1312.CrossRefGoogle ScholarPubMed
50. Ferrara, N, Houck, K, Jakeman, L, Leung, D. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocrine Rev 1992; 13: 18–32.Google Scholar
51. Houck, KA, Ferrara, N, Winer, J, et al. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 1991; 5.Google Scholar
52. Tischer, E, Mitchell, R, Hartman, T, et al. The human gene for vascular endothelial growth factor. J Biol Chem 1991; 266: 11947–11954.Google Scholar
53. Tsai, J-C, Goldman, CK, Gillespie, GY. Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg 1995; 82: 864–873.Google Scholar
54. Shweiki, D, Itin, A, Soffer, D, Keshe, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359: 843–845.Google Scholar
55. Goldman, CK, Kim, J, Wong, W-L, et al. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 1993; 4: 121–133.CrossRefGoogle Scholar
56. Mukhopadhyay, D, Tsiokas, L, Zhou, X-M, et al. Hypoxic induction of human vascular endothelial growth factor expression through c-src activation. Nature 1995; 375: 577–581.CrossRefGoogle ScholarPubMed
57. Finkenzeller, G, Technau, A, Marme, D. Hypoxia induced transcription of the vascular endothelial growth factor gene is independent of functional API transcription gactor. Biochem Biophys Res Comm 1995; 208: 432–439.Google Scholar
58. Rak, J, Mitsuhashi, Y, Bayko, L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995; 55: 4575–4580.Google Scholar
59. Grugel, S, Finkenzeller, G, Weindel, K, Barleon, B, Marme, D. Both v-Ha-ras and v-raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem 1995; 270: 25915–25919.Google Scholar
60. Barelon, B, Hauser, S, Schollmann, C, et al. Differential expression of the two VEGF receptors fit and KDR in placenta and vascular endothelial cells. J Cell Biochem 1994; 54: 56–66.Google Scholar
61. De Vries, C, Escobedo, JA, Ueno, H, et al. The FMS-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989–991.CrossRefGoogle ScholarPubMed
62. Terman, BI, Dougher-Vermazen, D, Carrion, ME, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Comm 1992; 87: 1579–1586.Google Scholar
63. Brown, LF, Berse, B, Jackman, RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 1993; 53: 4727–4735.Google Scholar
64. Breier, G, Albrecht, U, Sterrer, S, Risau, W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 1992; 114: 521–532.CrossRefGoogle ScholarPubMed
65. Millauer, B, Wizigmann-Voos, S, SchnGrch, H, et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of fasculogenesis and angiogenesis. Cell 1993; 72: 835–846.CrossRefGoogle Scholar
66. Connelly, DT, Heuvelman, DM, Nelson, R, et al. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 1989; 84: 1470–1478.Google Scholar
67. Pepper, MS, Ferrara, N, Orci, L, Montesano, R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 1991; 181: 902–906.Google Scholar
68. Unemori, EN, Ferrara, N, Bauer, EA, Amenoto, EP. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 1992; 153: 557–562.CrossRefGoogle ScholarPubMed
69. Burger, PC, Scheithauer, B, Vogel, FS. Surgical pathology of the nervous system and its coverings. Churchill-Livingstone, London. 1991.Google Scholar
70. Feldkamp, M, Lau, N, Provias, J, Guha, A. Acute presentation of a neurogenic sarcoma in a patient with neurofibromatosis type 1: a pathologic and molecular explanation. J Neurosurgery, accepted: 1996.Google Scholar
71. Sheela, S, Riccardi, V, Ratner, N. Angiogenic and invasive properties of neurofibroma Schwann cells. J. Cell Biol 1990; 111: 645–653.CrossRefGoogle ScholarPubMed
72. Windel, K, Moringlane, JR, Marme, D, Weich, HA. Detection and quantification of vascular endothelial growth factor/vascular permeability factor in brain tumor tissue and cyst fluid: the key to angiogenesis? Neurosurgery 1994; 35: 439–449.Google Scholar
73. Plate, KH, Breier, G, Millauer, B, Ullrich, A, Risau, W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 1993; 53: 5822–5827.Google Scholar
74. Kim, KJ, Li, B, Armanini, M, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 1993; 362: 841–844.Google Scholar
75. Beckmann, M, Betsholtz, C, Heldin, C, et al. Comparison of the biological properties and transforming potential of human PDGF-A and PDGF-B Chains. Science 1988; 241: 1346–1349.Google Scholar
76. Provias, JP, Claffey, K, delAguila, L, et al. Meningiomas: the role of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) in angiogenesis and peri-tumoral edema. Neurosurgery 1997; 40: 1016–1026.Google Scholar
77. Sioussat, TM, Dvorak, HF, Brock, TA, Senger, DR. Inhibition of vascular permeability factor (vascular endothelial growth factor) with antipeptide antibodies. Arch Biochem Biophys 1993; 301: 15–20.CrossRefGoogle ScholarPubMed
78. Melnyk, O, Shuman, MA, Kim, KJ. Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth. Cancer Res, 1996. 56: 921–924.Google Scholar
79. Asano, M, Yukita, A, Matsumoto, T, Kondo, S, Suzuki, H. Inhibition of tumor growth and metastasis by an immuno-neutralizing monoclonal antibody to human vascular endothelial growth gactor/vascular permeability factor121 . Cancer Res 1995; 55: 5296–5301.Google Scholar
80. Saleh, M, Stacker, SA, Wilks, AF. Inhibition of growth of C6 glioma cells in-vitro by expression of antisense vascular endothelial growth factor sequence. Cancer Res 1996; 56: 393–401.Google Scholar
81. Millauer, B, Shawver, LK, Plate, KH, Risau, W, Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative F1K-1 mutant. Nature 1994; 367: 576–578.Google Scholar
82. Strawn, L, McMahon, G, App, H, et al. Flk-1 as a target for tumor growth inhibition. Cancer Res 1996; 56: 3540–3545,.Google Scholar
83. Marchuk, DA, Saulino, AM, Tavakkol, R, et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 1991; 11: 931–940.Google Scholar
84. Upadhyaya, M, Shen, M, Cherryson, A, et al. Analysis of mutations at the neurofibromatosis 1 (NF1) locus. Hum Mol Genet 1992; 1: 735–740.Google Scholar
85. Li, Y, O’Connell, P, Breidenbach, HH, et al. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 1995; 25: 9–18.Google Scholar
86. Stumpf, S, Alksne, JF, Annegers, JF, et al. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988; 45: 575–578.Google Scholar
87. Buchberg, AM, Cleveland, LS, Jenkins, NA, Copeland, NG. Sequence homology shared by neurofibromatosis type-1 gene and IRA-l and IRA-2 negative regulators of the RAS cyclic AMP pathway. Nature 1990; 347: 291–294.CrossRefGoogle Scholar
88. Xu, G, O’Conell, P, Viskochil, D, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 1990; 62: 599–608.Google Scholar
89. Bollag, G, McCormick, F. Differential regulation of rasGAP and neurofibromatosis gene product activities. Nature 1991; 351: 576–579.Google Scholar
90. Downward, J. Regulation of p21 ras by GTPase activating proteins and guanine nucleotide exchange proteins. Curr Opin Gen Dev 1992; 2: 13–18.Google Scholar
91. Downward, JL. Regulatory mechanisms for ras proteins. BioEssays 1992; 14: 177–184.Google Scholar
92. McCormick, F. How receptors turn ras on. Nature 1993; 363: 15–16.Google Scholar
93. McCormick, F. Ras signaling and NF-1. Curr Opin Gen Dev 1995; 5: 51–55.Google Scholar
94. McCormick, F. ras GTPase activating protein: signal transmitter and signal terminator. Cell 1989; 56: 5–8.Google Scholar
95. DeClue, J, Papageorge, A, Fletcher, , et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (typel) neurofibromatosis. Cell 1992; 69: 265–273.Google Scholar
96. Basu, T, Gutman, D, Fletcher, J, et al. Aberrant regulation of ras proteins in malignant tumour cells from typel neurofibromatosis patients. Nature 1992; 356: 713–715.Google Scholar
97. Yan, N, Ricca, C, Fletcher, J, et al. Farnesyltransferase inhibitors block the neurofibromatosis type 1 (NF-1) malignant phenotype. Cancer Res, 1995. 55: 3569–3575.Google Scholar
98. Scheele, JS, Rhee, JM, Boss, GR. Determination of absolute amounts of ras GDP and GTP bound to ras in mammalian cells: comparison of parental and ras-overproducing NIH 3T3 fibroblasts. Proc Natl Acad Sci USA 1994; 92: 1097–1100.Google Scholar
99. Bos, JL. Ras oncogenes in human cancers: a review. Cancer Res 1989; 49: 4682–4689.Google Scholar
100. Cantley, LC. Auger, KR, Carpenter, C, et al. Oncogenes and signal transduction. Cell 1991; 64: 281–302.CrossRefGoogle ScholarPubMed
101. Satoh, T, Endo, M, Nakafuku, M, et al. Accumulation of p21 ras-GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity. Proc Natl Acad Sci USA 1990; 87: 7926–7929.Google Scholar
102. Satoh, T, Kaziro, Y. Ras in signal transduction. Cancer Biology 1992; 3: 169–177.Google Scholar
103. Satoh, T, Endo, M, Nakafuku, M, Nakamura, S, Kaziro, Y. Plateletderived growth factor stimulates formation of active p21ras.GTP complex in Swiss mouse 3T3 cells. Proc Natl Acad Sci 1990; 87: 5993–5997.Google Scholar
104. Muroya’, K, Hattori, S, Nakamura, S. Nerve growth factor induces accumulation of the GTP-bound form of p21ras in rat pheochromocytoma PC12 cells. Oncogene 1992; 7: 277–281.Google Scholar
105. Qui, M-S, Green, SH. NGF and EGF rapidly activate p21ras in PC12 cells by distinct, convergent pathways involving tyrosine phosphorylation. Neuron 1991; 7: 937–946.Google Scholar
106. Mulcahy, LS, Smith, MR, Stacey, DW. Requirement for ras protooncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 1985; 313: 241–243.Google Scholar
107. Kung, H-F, Smith, MR, Bekesi, E, Manne, V, Stacey, DW. Reversal of transformed phenotype by monoclonal antibodies against Ha-ras p21 proteins. Exp Cell Res 1986; 162: 363–371.Google Scholar
108. Farnsworth, C, Feig, L. Dominant inhibitory mutations in the Mg‣2 binding site of RasH prevent its activation by GTP. Mol Cell Biol 1991; 11: 4822–4829.Google Scholar
109. Farnsworth, C, Marshall, M, Gibbs, J, Stacey, D, Feig, L. Preferential inhibition of the oncogenic form of RasH by mutations in the gap binding/“effector” domain. Cell 1991; 64: 625–633.Google Scholar
110. Medema, RH, de Vries-Smits, AM, van der Zon, GCM, Maasen, JA, Bos, JL. Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21 ras. Mol and Cell Biol 1993; 13: 155–162.Google Scholar
111. Cai, H, Szeberenyi, J, Cooper, G. Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells. Mol Cell Biol 1990; 10: 5314–5323.Google ScholarPubMed
112. Szeberenyi, J, Cai, H, Cooper, G. Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells. Mol Cell Biol 1990; 10: 5324–5332.Google Scholar
113. Moran, MF, Koch, CA, Anderson, D, et al. Src homology region 2 domains direct protein-protein interactions in signal transduction. Proc Natl Acad Sci USA 1990; 87: 8622–8626.Google Scholar
114. Pawson, T, Gish, G. SH2 and SH3 domains: from structure to function. Cell 1992; 71: 359–362.Google Scholar
115. Songyang, Z, Shoelson, S, Chaudhuri, et al. SH2 domains recognize specific phosphopeptide sequences. Cell 1993; 72: 767–778.Google Scholar
116. Koch, CA, Anderson, D, Moran, MF, Ellis, C, Pawson, T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 1991; 252: 668–674.Google Scholar
117. Kavanaugh, WM, Turck, C, Williams, L. PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine. Science 1995; 268: 1177–1179.Google Scholar
118. Pawson, T. Protein modules and signalling networks. Nature 1995; 373: 573–580.CrossRefGoogle ScholarPubMed
119. James, GL, Goldstein, JL, Brown, MS, et al. Benzodiazepine peptidomimetics: potent inhibitors of ras farnesylation in animal cells. Science 1993; 260: 1937–1942.Google Scholar
120. Kohl, NE, Mosser, SD, deSolms, J, et al. Selective inhibition of rasdependent transformation by a farnesyltransferase inhibitor. Science 1993; 260: 1934–1937.Google Scholar
121. Kohl, NE, Wilson, FR, Mosser, SD, et al. Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA 1994; 91: 9141–9145.Google Scholar
122. Bonfini, L, Karlovich, CA, Dasgupta, C, Bannerjee, U. The son of sevenless gene product: a putative activator of ras. Science 1992; 255: 603–606.Google Scholar
123. Rozakis-Adcock, M, McGlade, J, Mbamalu, G, et al. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the ras pathway by tyrosine kinases. Nature 1992; 360: 689–692.Google Scholar
124. Pelicci, G, Lanfrancone, L, Grignani, F, et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal. Cell 1992; 70: 93–104.Google Scholar
125. Lowenstein, E, Daly, R, Batzer, A, et al. The SH2 and SH3 domaincontaining protein GRB2 links receptor tyrosine kinases to Ras signaling. Cell 1992; 70: 431–442.Google Scholar
126. Pronk, GJ, de Vries-Smits, AMM, Buday, L, et al. Involvement of Shc in insulin and epidermal growth factor induced activation of p21 Ras Mol Cell Biol 1994; 14: 1575–1581.Google Scholar
127. Basu, T, Warne, PH, Downward, J. Role of Shc in the activation of Ras in response to epidermal growth factor and nerve growth factor. Oncogene 1994; 9: 3483–3491.Google Scholar
128. Gibbs, J, Marshall, M, Scolnick, E, Dixon, R, Vogel, U. Modulation of guanine nucleotides bound to Ras in N1H3T3 cells by oncogenes, growth factors, and the GTPase activating protein (GAP). J Biol Chem 1990; 265: 20437–20442.Google Scholar
129. Bollag, G, McCormick, F. GTPase activating proteins. Cancer Biol 1992; 3.Google Scholar
130. Daston, M, Scrable, H, Nordlund, M, et al. The protein product of the neurofibromatosis typel gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron 1992; 8: 415–428.Google Scholar
131. DeClue, J, Cohen, B, Lowy, D. Identification and characterization of the neurofibromatosis typel protein product. Proc Natl Acad Sci 1991; 88: 9914–9918.Google Scholar
132. Gutmann, D, Wood, D, Collins, F. Identification of the neurofibromatosis typel gene product. Proc Natl Acad Sci 1991; 88: 9658–9662.Google Scholar
133. Gutmann, D, Collins, F. The neurofibromatosis typel gene and its protein product, neurofibromin. Neuron 1993; 10: 335–343.CrossRefGoogle Scholar
134. Li, Y, Bollag, G, Clark, R, et al. Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 1992; 69: 275–281.Google Scholar
135. Gutmann, DH, Mahadeo, D, Giordano, M, Silbergeld, D, Guha, A. Increased neurofibromatosis 1 gene expression in astrocytic tumors: positive regulation by p21-Ras. Oncogene 1996; 12: 2121–2127.Google Scholar
136. Guha, A, Feldkamp, M, Lau, N. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 1997; 15: 2755–2766.Google Scholar
137. Feldkamp, MM, Lau, N, Guha, A. Astrocytomas are growth inhibited by farnesyl transferase inhibitors through a combination of anti-proliferative and anti-angiogenic activities. Cancer Res, submitted: 1998.Google Scholar
138. Pollack, IF, Randall, MS, Kristofik, M, et al. Response of malignant glioma cell lines to activation and inhibition of protein kinase-C pathways. J Neurosurg 1990; 73: 98–105.Google Scholar
139. Pollac, IF, Randall, MS, Kristofik, MP, et al. Effect of tomoxifen on DNA synthesis and proliferation of human malignant glioma lines in vitro. Cancer Res 1990; 50: 7134–7138.Google Scholar
140. Benzil, DL, Finkelstein, SD, Epstein, MH, Finch, PW. Expression pattern of a-protein kinase C in human astrocytomas indicates a role in malignant progression. Cancer Res 1992; 52: 2951–2956.Google Scholar
141. Ahmad, S, Mineta, T, Martuza, R, Glazer, R. Antisense expression of protein kinase Ca inhibits the growth and tumorgenecity of human glioblastoma cells. Neurosurgery 1994; 35: 904–909.Google Scholar
142. Misra-Press, A, Fields, A, Samols, D, Goldthwait, D. Protein kinase C isoforms in human glioblastoma cells. Glia 1992; 6: 188–197.Google Scholar
143. Gibbs, J. Ras C-terminal processing enzymes - new drug targets? Cell 1991; 65: 1–4.Google Scholar
144. Gibbs, JB, Pompliano, DL, Mosser, SD, et al. Selective inhibition of farnesyl-protein transferase blocks Ras processing in vivo. J Biol Chem 1993; 268: 7617–7620.Google Scholar
145. Gibbs, JB, Oliff, A, Kohl, NE. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 1994; 77: 175–178.Google Scholar
146. Manne, V, Yan, N, Carboni, JM, et al. Bisubstrate inhibitors of farnesyltransferase: a novel class of specific inhibitors of ras transformed cells. Oncogene 1995; 10: 1763–1779.Google Scholar
147. Olson, JJ, James, CD, Krisht, A, Barnett, D, Hunter, S. Analysis of epidermal growth factor receptor gene amplification and alteration in stereotactic biopsies of brain tumors. Neurosurgery, 1994; 36: 740–748.Google Scholar
148. Wong, A, Bigner, S, Bigner, D, et al. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc. Natl Acad Sci USA 1987; 84: 6899–6903.Google Scholar
149. Hermanson, M, Funa, K, Hartman, M, et al. Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 1992; 52: 3213–3219.Google Scholar
150. Rozakis-Adcock, M, Fernley, R, Wade, J, Pawson, T, Bowtell, D. The SH2 and SH3 domains of mammalian GRB2 couple the EGF receptor to the ras activator mSosl. Nature 1993; 363: 83–85.Google Scholar
151. Egan, SE, Giddings, BW, Brooks, M., et al. Association of sos exchange protein with GRB2 is implicated in tyrosine kinase signal transduction and transformation. Nature 1993; 363: 45–51.Google Scholar
152. Egan, S, Weinberg, R. The pathway to signal achievment. Science 1993; 365: 781–783.Google Scholar
153. Arvidsson, A-K, Rupp, E, Nanberg, E, et al. Tyr-716 in the platelet derived growth factor b-Receptor kinase insert is involved in Grb-2 binding and Ras activation. Mol Cell Biol 1994; 14: 6715–6726.Google Scholar
154. Batzer, A, Rotin, D, Urena, J, Skolnik, E, Schlessinger, J. Hierarchy of binding sites for Grb-2 and Shc on the epidermal growth factor receptor. Mol Cell Bio 1994; 14: 5192–5201.Google Scholar
155. Aronheim, A, Engelberg, D, Nanxin, L, et al. Membrane targetting of the nucleotide exchange factor Sos is sufficient for activating the Ras signalling pathway. Cell 1994; 78: 949–961.Google Scholar
156. van der Geer, P, Pawson, T. The PTB domain: a new protein module implicated in signal transduction. Trends Biochem Sci 1995; 20: 277–280.Google Scholar
157. van der Geer, P, Wiley, S, Gish, G, et al. Identification of residues that control specific binding of the Shc phosphotyrosine-binding domain to phosphotyrosine sites. Proc Natl Acad Sci USA 1996; 93: 963–968.Google Scholar
158. Yokote, K, Mori, S, Hansen, K, et al. Direct interaction between Shc and the platelet derived growth factor b-receptor. J Biol Chem 1994; 269: 15337–15343.Google Scholar
159. Li, B, Subleski, M, Fusaki, N, et al. Catalytic activity of the mouse guanine nucleotide exchanger mSos is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells. Proc Natl Acad Sci USA 1996; 93: 1001–1005.Google Scholar
160. Hancock, J, Magee, A, Childs, J, Marshall, C. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989; 57: 1167–1177.Google Scholar
161. Kato, K, Cox, A, Hisaka, M, et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A 1992; 89: 6403–6407.Google Scholar
162. Sepp-Lorenzino, L, Zhenting, M, Rands, E, et al. A petidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage dependent and independent growth of human tumor cell lines. Cancer Res 1995; 55: 5302–5309.Google Scholar
163. Nagasu, T, Yoshimatsu, K, Rowell, C, Lewis, M, Garcia, A. Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 1995; 55: 5310–5314.Google Scholar
164. Knudson, AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Sci 1971; 68: 820–823.Google Scholar
165. Knudson, AG. Hereditary cancer, oncogenes and anti-oncogenes. Cancer Res 1985; 45: 1437–1443.Google Scholar