Skip to main content
SpringerLink
Log in

Tumor suppressor gene regulation of cell growth

Recent insights into neurofibromatosis 1 and 2 gene function

  • Original Article
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

The development of cancer involves a myriad of genetic changes that impact on multiple processes important for the orderly regulation of cell growth and differentiation. Genes whose protein products are disrupted during neoplastic transformation are termed “tumor suppressor genes” (TSGs). Many of these TSGs are associated with familial cancer predisposition syndromes, in which affected individuals have an increased risk of certain malignancies. Studies on the mechanism of action for known TSGs have revealed three intracellular loci of critical importance: environmental sensing and signal initiation, signal propagation and transduction, and cell cycle control. The neurofibromatosis 1 and neurofibromatosis 2 genes are discussed as illustrative examples of tumor suppressors that function at the levels of signal transduction and environmental sensing, respectively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Paggi, M. G., Baldi, A., Bonetto, F., and Giordano, A. (1996) Retinoblastoma protein family in cell cycle and cancer: a review. J. Cell. Biochem. 62, 418–430.

    Article  PubMed  CAS  Google Scholar 

  2. Bischoff, F. Z., Strong, L. C., Yim, S. O., Pratt, D. R., Siciliano, M. J., Giovanella, B. C., Tainsky, M. A. (1991) Tumorigenic transformation of spontaneously immortalized fibroblasts from patients with a familial cancer syndrome. Oncogene 5, 101–106.

    Google Scholar 

  3. Clarke, A. R., Maandag, E. R., van Roon, M., van der Lugt, N. M. T., van der Valk, M., Hooper, M. L., Berns, A., and te Riele, H. (1992) Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330.

    Article  PubMed  CAS  Google Scholar 

  4. Jacks, T., Fazeli, A., Schmitt, E. M., Bronson, R. T., Goodell, M. A., and Weinberg, R. A. (1992) Effects of an Rb mutation in the mouse. Nature 359, 295–300.

    Article  PubMed  CAS  Google Scholar 

  5. Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A., and Jacks, T. (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362, 847–849.

    Article  PubMed  CAS  Google Scholar 

  6. Knudson, A. G. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USA 68, 820–823.

    Article  PubMed  Google Scholar 

  7. Shin, S. I., Freedman, V. H., Risser, R., and Pollack, R. (1975) Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro. Proc. Natl. Acad. Sci. USA 72, 4435–4439.

    Article  PubMed  CAS  Google Scholar 

  8. Kinzler, K. W. and Vogelstein, B. (1997) Cancersusceptibility genes: gatekeepers and caretakers. Nature 386, 761–763.

    Article  PubMed  CAS  Google Scholar 

  9. Evans, D. G. R., Huson, S. M., Donnai, D., Neary, W., Blair, V., Newton, V., and Harris, R. (1992) A clinical study of type 2 neurofibromatosis. Q. J. Med. 304, 603–618.

    Google Scholar 

  10. Trofatter, J. A., MacCollin, M. M., Rutter, J. L., Murrell, J. R., Duyao, M. P., Parry, D. M., Eldridge, R., Klay, N., Menon, A. G., Pulaski, K., et al. (1993) A novel moesin-, ezrin-, radixinlike gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72, 1–20.

    Article  Google Scholar 

  11. Rouleau, G. A., Merel, P., Lutchman, M., Sanson, M., Zucman, J., Marineau, C., Hoang-Xuan, K., Demczuk, M., Desmaze, C., Plougastel, B., et al. (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 363, 515–521.

    Article  PubMed  CAS  Google Scholar 

  12. Bianchi, A. B., Hara, T., Ramesh, V., Gao, J., Klein-Szanto, A. J. P., Morin, F., Menon, A. G., Trofatter, J. A., Gusella, J. F., Seizinger, B. R., and Kley, N. (1994) Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumor types. Nature Genet. 6, 185–192.

    Article  PubMed  CAS  Google Scholar 

  13. Gutmann, D. H., Geist, R. T., Wright, D. E., and Snider, W. D. (1995) Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues. Cell Growth Differ. 6, 315–322.

    PubMed  CAS  Google Scholar 

  14. Pykett, M. J., Murphy, M., Harnish, P. R., and George, D. L. (1994) The neurofibromatosis 2 (NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts. Hum. Mol. Genet. 3, 559–564.

    Article  PubMed  CAS  Google Scholar 

  15. Hara, T., Bianchi, A. B., Seizinger, B. R., and Kley, N. (1994) Molecular cloning and characterization of alternatively spliced transcripts of the mouse neurofibromatosis 2 gene. Cancer Res. 54, 330–335.

    PubMed  CAS  Google Scholar 

  16. Haase, V. K., Trofatter, J. A., MacCollin, M., Tarttelin, E., Gusella J. F., and Ramesh, V. (1994) The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms. Hum. Mol. Genet. 3, 407–411.

    Article  PubMed  CAS  Google Scholar 

  17. Tsukita, S., Yonemura, S., and Tsukita, S. (1997) ERM family: from cytoskeleton to signal transduction. Curr. Opin. Cell Biol. 9, 70–75.

    Article  PubMed  CAS  Google Scholar 

  18. McCartney, B. M. and Fehon, R. G. (1996) Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J. Cell. Biol. 133, 843–852.

    Article  PubMed  CAS  Google Scholar 

  19. Chishti, A. H., Kim, A. C., Marfatia, S. M., Lutchman, M., Hanspal, M., Jindal, H., Liu, S.-C., Low, P. S., Rouleau, G. A., Mohandas, N., et al. (1998) The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem. Sci. 23, 281–282.

    Article  PubMed  CAS  Google Scholar 

  20. Hirao, M., Sato, N., Kondo, T., Yonemura, S., Monden, M., Sasaki, T., Takai, Y., Tsukita, S., and Tsukita, S. (1996) Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. J. Cell. Biol. 135, 37–51.

    Article  PubMed  CAS  Google Scholar 

  21. Amano, M., Chihara, K., Nakamura, N., Kaneko, T., Matsuura, Y., and Kaibuchi, K. (1999) The COOH terminus of Rho-kinase negatively regulates rho-kinase activity. J. Biol. Chem. 274, 32,418–32,424.

    CAS  Google Scholar 

  22. Mangeat, P., Roy, C., and Martin, M. (1999) ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol. 9, 187–192.

    Article  PubMed  CAS  Google Scholar 

  23. Takeuchi, K., Sato, N., Kasahara, H., Funayama, N., Nagafuchi, A., Yonemura, S., Tsukita, S., and Tsukita, S. (1994) Perturbation of cell adhesion and microvilli formation by antisense oligonucleotides to ERM family members. J. Cell. Biol. 125, 1371–1384.

    Article  PubMed  CAS  Google Scholar 

  24. Hiscox, S. and Jiang, W. G. (1999) Ezrin regulates cell-cell and cell-matrix adhesion, a possible role with E-cadherin-catenin. J. Cell Sci. 112, 3081–3090.

    PubMed  CAS  Google Scholar 

  25. Sherman, L., Xu, H-M., Geist, R. T., Saporito-Irwin, S., Howells, N., Ponta, H., Herrlich, P., and Gutmann, D. H. (1997) Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 15, 2505–2509.

    Article  PubMed  CAS  Google Scholar 

  26. Gutmann, D. H., Haipek, C. A., and Lu, K. H. (1999) Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations. J. Neurosci. Res. 58, 706–716.

    Article  PubMed  CAS  Google Scholar 

  27. Gary, R. and Bretscher, A. (1995) Ezrin self-association involves binding of an N-terminal domain to a normally masked C-terminal domain that includes the F-actin binding site. Mol. Biol. Cell. 6, 1061–1075.

    PubMed  CAS  Google Scholar 

  28. Tsukita, S., Yonemura, S., and Tsukita, S. (1997) ERM proteins: head-to-tail regulation of actin-plasma membrane interaction. TIBS 22, 53–58.

    PubMed  CAS  Google Scholar 

  29. Martin, M., Roy, C., Montcourrier, P., Sahuquet, A., and Mangeat, P. (1997) Three determinants in ezrin are responsible for cell extension activity. Mol. Biol. Cell. 8, 1543–1557.

    PubMed  CAS  Google Scholar 

  30. Matsui, T., Maeda, M., Doi, Y., Yonemura, S., Amano, M., Kaibuchi, K., Tsukita, S., and Tsukita, S. (1998) Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J. Cell. Biol. 104, 647–657.

    Article  Google Scholar 

  31. Shaw, R. J., Henry, M., Solomon, F., and Jacks, T. (1998) RhoA-dependent phosphorylation and relocalization of ERM proteins into apical membrane/actin protrusions in fibroblasts. Mol. Biol. Cell. 9, 403–419.

    PubMed  CAS  Google Scholar 

  32. Gutmann, D. H., Wright, D. E., Geist, R. T., and Snider, W. D. (1995) Expression of the neurofibromatosis 2 (NF2) gene isoforms during rat embryonic development. Hum. Mol. Genet. 4, 471–478.

    Article  PubMed  CAS  Google Scholar 

  33. Claudio, J. O., Lutchman, M., and Rouleau, G. A. (1995) Widespread but cell type-specific expression of the mouse neurofibromatosis type 2 gene. NeuroReport 6, 1942–1946.

    Article  PubMed  CAS  Google Scholar 

  34. Xu, L., Agosti-Gonzalez, C., Beauchamp, R., Pinney, D., Sterner, C., and Ramesh, V. (1998) Analysis of molecular domains of epitopetagged merlin isoforms in COS-7 cells and primary rat Schwann cells. Exp. Cell Res. 238, 231–240.

    Article  PubMed  CAS  Google Scholar 

  35. Scherer, S. S. and Gutmann, D. H. (1996) Expression of the neurofibromatosis 2 tumor suppressor gene product, merlin, in Schwann cells. J. Neurosci. Res. 46, 595–605.

    Article  PubMed  CAS  Google Scholar 

  36. Huynh, D. P., Tran, T. M. D., Nechiporuk, T., and Pulst, S. M. (1996) Expression of neurofibromatosis 2 transcript and gene product during mouse fetal development. Cell Growth Differ. 7, 1551–1561.

    PubMed  CAS  Google Scholar 

  37. Dransfield, D. T., Bradford, A. J., Smith, J., Martin, M., Roy, C., Mangeat, P., and Goldenring, J. R. (1997) Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. EMBO J. 16, 35–43.

    Article  PubMed  CAS  Google Scholar 

  38. Hanzel, D., Reggio, H., Bretscher, A., Forte, J. G., and Mangeat, P. (1991) The secretion-stimulated 80 K phosphoprotein of parietal cells is ezrin, and has properties of a membrane cytoskeletal linker in the induced apical microvilli. EMBO J. 10, 2363–2373.

    PubMed  CAS  Google Scholar 

  39. Tsukita, S., Heida, Y., and Tsukita, S. (1989) A new 82 kD barbed end-capping protein (radixin) localized in the cell-to-cell adherens junction: purification and characterization. J. Cell. Biol. 108, 2369–2382.

    Article  PubMed  CAS  Google Scholar 

  40. Lankes, W. T. and Furthmayr, H. (1991) Moesin: a member of the protein 4.1-talin-ezrin family of proteins. Proc. Natl. Acad. Sci. USA 88, 8297–8301.

    Article  PubMed  CAS  Google Scholar 

  41. Lutchman, M. and Rouleau, G. A. (1995) The neurofibromatosis type 2 gene product, schwannomin, suppresses growth of NIH 3T3 cells. Cancer Res. 55, 2270–2274.

    PubMed  CAS  Google Scholar 

  42. Crepaldi, T., Gautreau, A., Comoglio, P. M., Louvard, D., and Arpin, M. (1997) Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells. J. Cell Biol. 138, 423–434.

    Article  PubMed  CAS  Google Scholar 

  43. Gutmann, D. H., Sherman, L., Seftor, L., Haipek, C., Lu, K. H., and Hendrix, M. (1999) Increased expression of the NF2 tumor suppressor gene product, merlin, impairs cell motility, adhesion and spreading. Hum. Mol. Genet. 8, 267–275.

    Article  PubMed  CAS  Google Scholar 

  44. McClatchey, A. I., Saotome, I., Mercer, K., Crowley, D., Gusella, J. F., Bronson, R. T., and Jacks, T. (1998) Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 12, 1121–1133.

    PubMed  CAS  Google Scholar 

  45. Pelton, P. D., Sherman, L. S., Rizvi, T. A., Marchionni, M. A., Wood, P., Friedman, R. A., and Ratner, N. (1998) Ruffling membrane, stress fiber, cell spreading, and proliferation abnormalities in human schwannoma cells. Oncogene 17, 2195–2209.

    Article  PubMed  CAS  Google Scholar 

  46. Sainio, M., Zhao, F., Heiska, L., Turunen, O., den Bakker, M., Zwarthoff, E., Lutchman, M., Rouleau, G. A., Jaaskelainen, J., Vaheri, A., and Carpen, O. (1997) Neurofibromatosis 2 tumor suppressor protein co-localizes with ezrin and CD44 and associates with actin-containing cytoskeleton. J. Cell Sci. 110, 2249–2260.

    PubMed  CAS  Google Scholar 

  47. Tsukita, S., Oishi, K., Sato, N., Sagara, J., Kawai, A., and Tsukita, S. (1994) ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J. Cell. Biol. 126, 391–401.

    Article  PubMed  CAS  Google Scholar 

  48. Gary, R. and Bretscher, A. (1993) Heterotypic and homotypic associations between ezrin and moesin, two putative membrane-cytoskeletal linking proteins. Proc. Natl. Acad. Sci. USA 90, 10,846–10,850.

    Article  CAS  Google Scholar 

  49. Gonzalez-Agosti, C., Wiederhold, T., Herndon, M. E., Gusella, J., and Ramesh, V. (1999) Interdomain interaction of merlin isoforms and its influence on intermolecular binding to NHE-RF. J. Biol. Chem. 274, 34,438–34,442.

    CAS  Google Scholar 

  50. Gronholm, M., Sainio, M., Zhao, F., Heiska, L., Vaheri, A., and Carpen, O. (1999) Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin. J. Cell. Sci. 112, 895–904.

    PubMed  CAS  Google Scholar 

  51. Huang, L., Ichimaru, E., Pestonjamasp, K., Cui, X., Nakamura, H., Lo, G. Y. H., Lin, F. I. K., Luna, E. J., and Furthmayr, H. (1998) Merlin differs from moesin in binding to F-actin and in its intra- and intermolecular interactions. Biochem. Biophys. Res. Commun. 248, 548–553.

    Article  PubMed  CAS  Google Scholar 

  52. Scoles, D. R., Huynh, D. P., Morcos, P. A., Coulsell, E. R., Robinson, N. G. G., Tamanoi, F., and Pulst, SM. (1998) Neurofibromatosis 2 tumour suppressor schwannomin interacts with netaII-spectrin. Nature Genet. 18, 354–359.

    Article  PubMed  CAS  Google Scholar 

  53. Murthy, A., Gonzalez-Agosti, C., Cordero, E., Pinney, D., Candia, C., Solomon, F., Gusella, J., and Ramesh, V. (1998) NHE-RF, a regulatory cofactor for Na+-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins. J. Biol. Chem. 273, 1273–1276.

    Article  PubMed  CAS  Google Scholar 

  54. Kamleiter, M., Hanemann, C. O., Kluwe, L., Rosenbaum, C., Wosch, S., Mautner, V. F., Muller, H. W., and Grafe, P. (1998) Voltage-dependent membrane currents of cultured human neurofibromatosis type 2 Schwann cells. Glia 24, 313–322.

    Article  PubMed  CAS  Google Scholar 

  55. Mayer, C., Kamleiter, M., Sanchez-Brandelik, R., Rosenbaum, C., Kluwe, L., Hanemann, C. O., and Grafe, P. (1999) Neuroligand-mediated calcium signaling in cultured human schwannoma cells. J. Peripheral Nervous System 4, 99–105.

    CAS  Google Scholar 

  56. Ruttledge, M. H., Sarrazin, J., Rangaratnam, S., Phelan, C. M., Twist, E., Merel, P., Delattre, O., Thomas, G., Nordenskjold, M., Collins, V. P., et al. (1994) Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nature Genet. 6, 180–184.

    Article  PubMed  CAS  Google Scholar 

  57. McClatchey, A. I., Saotome, I., Ramesh, V., Gusella, J. F., and Jacks, T. (1997) The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes Dev. 11, 1253–1265.

    Article  PubMed  CAS  Google Scholar 

  58. Giovannini, M., Robanus-Maandag, E., Niwa-Kawakita, M., van der Valk, M., Woodruff, J. M., Goutebroze, L., Merel, P., Berns, A., and Thomas, G. (1999) Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein. Genes Dev. 13, 978–986.

    PubMed  CAS  Google Scholar 

  59. LaJeunesse, D. R., McCartney, B. M., and Fehon, R. G. (1998) Structural analysis of Drosophila merlin reveals functional domains important for growth control and subcellular localization. J. Cell Biol. 141, 1589–1599.

    Article  PubMed  CAS  Google Scholar 

  60. Obremski, V. J., Hall, A. M., and Fernandez-Valle, C. (1998) Merlin, the neurofibromatosis type 2 gene product, and beta-1 integrin associate in isolated and differentiating Schwann cells. J. Neurobiol. 37, 487–501.

    Article  PubMed  CAS  Google Scholar 

  61. Tikoo, A., Varga, M., Ramesh, V., Gusella, J., and Maruta, H. (1994) An anti-Ras function of neurofibromatosis type 2 gene product (NF2/Merlin). J. Biol. Chem. 269, 23,387–23,390.

    CAS  Google Scholar 

  62. McCormick, F. (1999) Signalling networks that cause cancer. Trends Cell Biol. 12, M53–56.

    Article  Google Scholar 

  63. Friedman, J. M., Gutmann, D. H., MacCollin, M., and Riccardi, V. M. (1999) Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 3rd ed., Baltimore, Johns Hopkins Press.

    Google Scholar 

  64. Listernick, R., Louis, D. N., Packer, P. J., and Gutmann, D. H. (1997) Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 optic pathway glioma task force. Ann. Neurol. 41, 143–149.

    Article  PubMed  CAS  Google Scholar 

  65. Marchuk, D. A., Saulino, A. M., Tavakkol, R., Swaroop, M., Wallace, M. R., Andersen, L. B., Mitchell, A. L., Gutmann, D. H., Boguski, M., and Collins, F. S. (1991) cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11, 931–940.

    Article  PubMed  CAS  Google Scholar 

  66. Wallace, M. R., Marchuk, D. A., Andersen, L. B., Letcher, R., Odeh, H. M., Saulino, A. M., Fountain, J. W., Brereton, A., Nicholson, J., Mitchell, A. L., et al. (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186.

    Article  PubMed  CAS  Google Scholar 

  67. Viskochil, D., Buchberg, A. M., Xu, G., Cawthom, R. M., Stevens, J., Wolff, R. K., Culver, M., Carey, J. C., Copeland, N. G. Jenkins, N. A., et al. (1990) Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187–192.

    Article  PubMed  CAS  Google Scholar 

  68. Cawthon, R. M., Oconnell, P., Buchberg, A. M., Viskochil, D., Weiss, M., Culver, M, Stevens, J., Jenkins, N. A., Copeland, N. G., and White, R. (1990) Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EV12 and mapping of other transcripts. Genomics 7, 555–565.

    Article  PubMed  CAS  Google Scholar 

  69. Habib, A. A., Gulcher, J. R., Hognason, T., Zheng, L., and Stefansson, K. (1998) The OMgp gene, a second growth suppressor within the NF1 gene. Oncogene 16, 1525–1531.

    Article  PubMed  CAS  Google Scholar 

  70. Andersen, L. B., Ballester, R., Marchuk, D. A., Chang, E., Gutmann, D. H., Saulino, A. M., Camonis, J., Wigler, M., and Collins, F. S. (1993) A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase activating protein activity. Mol. Cell. Biol. 13, 487–495.

    PubMed  CAS  Google Scholar 

  71. Gutmann, D. H., Geist, R. T., Rose, K., and Wright, D. E. (1995) Expression of two new protein isoforms of the neurofibromatosis type 1 gene product, neurofibromin, in muscle tissues. Dev. Dynamics 202, 302–311.

    CAS  Google Scholar 

  72. Gutmann, D. H., Andersen, L. B., Cole, J. L., Swaroop, M., and Collins, F. S. (1993) An alternatively spliced mRNA in the carboxy terminus of the neurofibromatosis type 1 (NF1) gene is expressed in muscle. Hum. Mol. Genet. 2, 989–992.

    Article  CAS  Google Scholar 

  73. Danglot, G., Teinturier, C., Duverger, A., and Bernheim, A. (1994) Tissue-specific alternative splicing of neurofibromatosis 1 (NF1) mRNA. Biomed. Pharmacother. 48, 365–372.

    Article  PubMed  CAS  Google Scholar 

  74. Geist, R. T. and Gutmann, D. H. (1996) Expression of a developmentally-regulated neuron-specific isoform of the neurofibromatosis 1 (NF1) gene. Neurosci. Lett. 211, 85–88.

    Article  PubMed  CAS  Google Scholar 

  75. Gutmann, D. H., Zhang, Y., and Hirbe, A. (1999) Developmental regulation of a neuron-specific neurofibromatosis 1 isoform. Ann. Neurol. 46, 777–782.

    Article  PubMed  CAS  Google Scholar 

  76. DeClue, J. E., Cohen, B. D., and Lowy, D. R. (1991) Identification and characterization of the neurofibromatosis type 1 gene product. Proc. Natl. Acad. Sci. USA 88, 9914–9918.

    Article  PubMed  CAS  Google Scholar 

  77. Daston, M. M., Scrable, H., Norlund, M., Sturbaum, A. K., Nissen, L. M., and Ratner, N. (1992) The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells and oligodendrocytes. Neuron 8, 415–428.

    Article  PubMed  CAS  Google Scholar 

  78. Gutmann, D. H., Wood, D. L., and Collins, F. S. (1991) Identification of the neurofibromatosis type 1 gene product. Proc. Natl. Acad. Sci. USA 88, 9658–9662.

    Article  PubMed  CAS  Google Scholar 

  79. Xu, G., O’Connell, P., Viskochil, D., Cawthon, R., Robertson, R., Culver, M., Dunn, D., Stevens, J., Gesteland, R., White, R., and Weiss, R. (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608.

    Article  PubMed  CAS  Google Scholar 

  80. Daston, M. M. and Ratner, N. (1993) Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development. Dev. Dynamics 195, 216–226.

    Google Scholar 

  81. Huynh, D. P., Lin, C. T., and Pulst, S. M. (1992) Expression of neurofibromin, the neurofibromatosis type 1 gene product: studies in human neuroblastoma cells and rat brain. Neurosci. Lett. 143, 233–236.

    Article  PubMed  CAS  Google Scholar 

  82. Bollag, G., McCormick, F., and Clark, R. (1993) Characterization of full-length neurofibromin: tubulin inhibits Ras GAP activity. EMBO J. 12, 1923–1927.

    PubMed  CAS  Google Scholar 

  83. Ballester, R., Marchuk, D. A., Boguski, M., Saulino, A. M., Letcher, R., Wigler, M., and Collins, F. S. (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859.

    Article  PubMed  CAS  Google Scholar 

  84. Martin, G. A., Viskochil, D., Bollag, G., McCabe, P. C., Crosier, W. J., Haubruck, H., Conroy, L., Clark, R., O’Connell, P., Cawthon, R. M, et al. (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843–849.

    Article  PubMed  CAS  Google Scholar 

  85. Xu, G., Lin, B., Tanaka, K., Dunn, D., Wood, D., Gesteland, R., White, R., Weiss, R., and Tamanoi, F. (1990) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835–841.

    Article  PubMed  CAS  Google Scholar 

  86. Gutmann, D. H., Boguski, M., Marchuk, D., Wigler, M., Collins, F. S., and Ballester, R. (1993) Analysis of the neurofibromatosis type 1 (NF1) GAP-related domain by site-directed mutagenesis. Oncogene 8, 761–769.

    PubMed  CAS  Google Scholar 

  87. DeClue, J. E., Papageorge, A. G., Fletcher, J. A., Diehl, S. R., Ratner, N., Vass, W. C., and Lowy, D. R. (1992) Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265–273.

    Article  PubMed  CAS  Google Scholar 

  88. Basu, T. N., Gutmann, D. H., Fletcher, J. A., Glover, T. W., Collins, F. S., and Downward, J. (1992) Aberrant regulation of ras proteins in tumour cells from type 1 neurofibromatosis patients. Nature 356, 713–715.

    Article  PubMed  CAS  Google Scholar 

  89. Guha, A., Lau, N., Huvar, I., Gutmann, D. H., Provias, J., Pawson, T., and Boss, G. (1996) Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene 12, 507–513.

    PubMed  CAS  Google Scholar 

  90. Kim, H. A., Rosenbaum, T., Marchionni, M. A., Ratner, N., and DeClue, J. E. (1995) Schwann cells from neurofibromin-deficient mice exhibit activation of p21-ras, inhibition of cell proliferation and morphological changes. Oncogene 11, 325–335.

    PubMed  CAS  Google Scholar 

  91. Largaespada, D. A., Brannan, C. I., Jenkins, N. A., and Copeland, N. G. (1996) Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. Nature Genet. 12, 137–143.

    Article  PubMed  CAS  Google Scholar 

  92. Gregory, P. E., Gutmann, D. H., Boguski, M., Mitchell, A. M., Parks, S., Jacks, T., Wood, D. L., Jove, R., and Collins, F. S. (1993) The neurofibromatosis type 1 gene product, neurofibromin, associates with microtubules. Somatic Cell Mol. Genet. 19, 265–274.

    Article  CAS  Google Scholar 

  93. Xu, H.- M. and Gutmann, D. H. (1997) Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules. Brain Res. 759, 149–152.

    Article  PubMed  CAS  Google Scholar 

  94. Boyer, M., Gutmann, D. H., Collins, F. S., and Bar-Sagi, D. (1994) Co-capping of neurofibromin, but not of GAP, with surface immunoglobulin in B lymphocytes. Oncogene 9, 349–357.

    PubMed  CAS  Google Scholar 

  95. Nordlund, M., Gu, X., Shipley, M. T., and Ratner, N. (1993) Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons. J. Neurosci. 13, 1588–1600.

    PubMed  CAS  Google Scholar 

  96. Golubic, M., Roudebush, M., Dobrowolski, S., Wolfman, A., and Stacey, D. W. (1992) Catalytic properties, tissue, and intracellular distribution of the native neurofibromatosis type 1 protein. Oncogene 7, 2151–2159.

    PubMed  CAS  Google Scholar 

  97. Brannan, C. I., Perkins, A. S., Vogel, K. S., Ratner, N., Nordlund, M. L., Reid, S. W., Buchberg, A. M., Jenkins, N. A., Parada, L. F., and Copeland, N. G. (1994) Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029.

    Article  PubMed  CAS  Google Scholar 

  98. Jacks, T., Shih, T. S., Schmitt, E. M., Bronson, R. T., Bernards A., and Weinberg, R. A. (1994) Tumor predisposition in mice heterozygous for a targeted mutation in NF1. Nature Genet. 7, 353–361.

    Article  PubMed  CAS  Google Scholar 

  99. Lakkis, M. M. and Epstein, J. A. (1998) Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development 125, 4359–4367.

    PubMed  CAS  Google Scholar 

  100. Vogel, K. S., Brannan, C. I., Jenkins, N. A., Copeland, N. G., and Parada, L. F. (1995) Loss of neurofibromin results is neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell 82, 733–742.

    Article  PubMed  CAS  Google Scholar 

  101. Snider, W. D. (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638.

    Article  PubMed  Google Scholar 

  102. Vogel, K. S., Kleese, L. J., Velasco-Miguel, S., Meyers, K., Rushing, E. J., and Parada, L. F. (1999) Mouse tumor model for neurofibromatosis type 1. Science 286, 2176–2179.

    Article  PubMed  CAS  Google Scholar 

  103. Bollag, G., Clapp, D. W., Shih, S., Adler, F., Zhang, Y. Y., Thompson, P., Lange, B. J., Freedman, M. H., McCormick, f., Jacks, T., and Shannon, K. (1996) Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nature Genet. 12, 144–148.

    Article  PubMed  CAS  Google Scholar 

  104. Rosenbaum, T., Boissy, Y. L., Kombrinck, K., Brannan, C. I., Jenkins, N. A., Copeland, N. G., and Ratner, N. A. (1995) Neurofibromin-deficient fibroblasts fail to form perineurium in vitro. Development 121, 3583–3592.

    PubMed  CAS  Google Scholar 

  105. Kim, H. A., Ling, B., and Ratner, N. (1997) Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farsenyl protein transferase. Mol. Cell. Biol. 17, 862–872.

    PubMed  CAS  Google Scholar 

  106. Atit, R. P., Crowe, M. J., Greenhalgh, D. G., Wenstrup, R. J., and Ratner, N. (1999) The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts. J. Invest. Dermatol. 112, 835–842.

    Article  PubMed  CAS  Google Scholar 

  107. Tischler, A. S., Shih, T. S., Williams, B. O., and Jacks, T. (1995) Characterization of pheochromocytomas in a mouse strain with a targeted disruptive mutation of the neurofibromatosis gene, Nf1. Endocr. Pathol. 6, 323–335.

    PubMed  Google Scholar 

  108. Cichowski, K., Shih, T. S., Schmitt, E., Santiago, S., Reilly, K., McLaughlin, M. E., Bronson, R. T., and Jacks, T. (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286, 2172–2176.

    Article  PubMed  CAS  Google Scholar 

  109. Ridley, A. J., Paterson, H. F., Noble. M., and Land, H. (1988) ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J. 7, 1635–1645.

    PubMed  CAS  Google Scholar 

  110. Gutmann, D. H., Loehr, A., Zhang, Y., Kim, J., Henkemeyer, M., and Cashen, A. (1999) Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene 18, 4450–4459.

    Article  PubMed  CAS  Google Scholar 

  111. Guo, H-F., The, I., Hannan, F., Bernards, A., and Zhong, Y. (1997) Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276, 795–798.

    Article  PubMed  CAS  Google Scholar 

  112. The, I., Hannigan, G. E., Cowley, G. S., Reginald, S., Zhong, Y., Gusella, J. F., Hariharan, I. K., and Bernards, A. (1997) Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276, 791–794.

    Article  PubMed  CAS  Google Scholar 

  113. Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M., and Lowe, S. W. (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019.

    PubMed  CAS  Google Scholar 

  114. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., and Lowe, S. W. (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16-ink4a. Cell 88, 593–602.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, 63110, St. Louis, MO

    Erik J. Uhlmann & David H. Gutmann

Authors
  1. Erik J. Uhlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David H. Gutmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David H. Gutmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Uhlmann, E.J., Gutmann, D.H. Tumor suppressor gene regulation of cell growth. Cell Biochem Biophys 34, 61–78 (2001). https://doi.org/10.1385/CBB:34:1:61

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/CBB:34:1:61

Index Entries

Search

Navigation