Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Tumour-suppressor function in the nervous system

Nature Reviews Cancer volume 4, pages 184–196 (2004)Cite this article

Key Points

  • Tumour-suppressor genes probably evolved to perform specific functions related to development and homeostasis rather than to prevent cancer. Loss of tumour-suppressor function therefore contributes to cancer in some contexts, but leads to pathophysiological states that are distinct from cancer in other contexts.

  • The nervous system provides several examples of the differential effects of loss of tumour-suppressor function. This is related to the fact that it contains several different cell types, which, especially during development, reflect a wide range of proliferation and differentiation statuses.

  • Loss of function of the retinoblastoma protein (RB) in the nervous system causes increased proliferation in some situations and increased apoptosis in others. RB deficiency also influences differentiation in specific cell populations. This context-dependent activity probably contributes to the limited spectrum of tumours that is observed in families with germline RB mutations.

  • The tumour suppressor PTEN is involved in the control of growth, and another, ATM, has a key role in the response to DNA damage. However, mutations of these genes do not necessarily result in tumorigenesis in the nervous system, and can instead lead to distinct neuropathologies.

  • The outcome of disruption of tumour-suppressor signalling pathways is strongly influenced by the developmental stage and cell type in which a mutation occurs. Outcomes can be as varied as changes in cell size versus cell number, for example, due to mutation of PTEN, and cell death versus tumorigenesis, due to mutation of ATM and other components of DNA-damage-response pathways.

  • Loss of tumour-suppressor function might cause defects in surrounding cells that are secondary to the cell-autonomous abnormalities in mutant cells, such as defects in neurofibromatosis type 1 (NF1) function. The interplay between mutant cells and their environment contributes to cancer and to other pathological states in the nervous system.

  • Understanding tumour-suppressor function in different settings is crucial for understanding the complex, multifunctional roles of these key regulatory proteins, how their loss of function contributes to cancer, and how aberrant signals in cancer cells might be modulated to result in outcomes other than cancer.

Abstract

Tumour suppressors prevent cancer by regulating processes such as cell proliferation and survival. However, their functions are diverse, and are often related to the cell type and tissue context. Mutations of tumour-suppressor genes result in unique outcomes in the nervous system that contrast with their roles in other organs. This is closely related to the cell types in which mutations occur and the developmental stage of the tissues that are affected. How can studying the tissue-specific functions of tumour suppressors in the nervous system help us to understand signalling pathways that are relevant to cancer and what are the therapeutic implications of this?

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Development of the nervous system.
Figure 2: The retinoblastoma pathway.
Figure 3: PTEN signalling pathway.
Figure 4: The DNA-damage response.

Similar content being viewed by others

References

  1. Baylin, S. & Bestor, T. H. Altered methylation patterns in cancer cell genomes: cause or consequence? Cancer Cell 1, 299–305 (2002).

    CAS  PubMed  Google Scholar 

  2. Haber, D. & Harlow, E. Tumour-suppressor genes: evolving definitions in the genomic age. Nature Genet. 16, 320–322 (1997).

    CAS  PubMed  Google Scholar 

  3. Jacobsen, M. Developmental Neurobiology (Plenum Press, New York, 1991).

    Google Scholar 

  4. Cameron, H. A. & McKay, R. Stem cells and neurogenesis in the adult brain. Curr. Opin. Neurobiol. 8, 677–680 (1998).

    CAS  PubMed  Google Scholar 

  5. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    CAS  PubMed  Google Scholar 

  6. Gross, C. G. Neurogenesis in the adult brain: death of a dogma. Nature Rev. Neurosci. 1, 67–73 (2000).

    CAS  Google Scholar 

  7. Wechsler-Reya, R. & Scott, M. P. The developmental biology of brain tumors. Annu. Rev. Neurosci. 24, 385–428 (2001).

    CAS  PubMed  Google Scholar 

  8. Zhu, Y. & Parada, L. F. The molecular and genetic basis of neurological tumours. Nature Rev. Cancer 2, 616–626 (2002).

    CAS  Google Scholar 

  9. Kitange, G. J., Templeton, K. L. & Jenkins, R. B. Recent advances in the molecular genetics of primary gliomas. Curr. Opin. Oncol. 15, 197–203 (2003).

    CAS  PubMed  Google Scholar 

  10. Merlo, A. Genes and pathways driving glioblastomas in humans and murine disease models. Neurosurg. Rev. 26, 145–158 (2003).

    PubMed  Google Scholar 

  11. Kleihues, P. & Cavenee, W. K. (eds). Pathology and Genetics of Tumours of the Nervous System (IARC Press, Lyon, 2000). An encyclopedia of brain tumours.

    Google Scholar 

  12. Herrup, K. & Yang, Y. Pictures in molecular medicine: contemplating Alzheimer's disease as cancer: a loss of cell-cycle control. Trends Mol. Med. 7, 527 (2001).

    CAS  PubMed  Google Scholar 

  13. Yang, Y., Mufson, E. J. & Herrup, K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J. Neurosci. 23, 2557–2563 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Heintz, N. Cell death and the cell cycle: a relationship between transformation and neurodegeneration? Trends Biochem. Sci. 18, 157–159 (1993).

    CAS  PubMed  Google Scholar 

  15. Zindy, F. et al. Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. Proc. Natl Acad. Sci. USA 96, 13462–13467 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee, W. H. et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235, 1394–1399 (1987).

    CAS  PubMed  Google Scholar 

  17. Fung, Y. K. et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236, 1657–1661 (1987).

    CAS  PubMed  Google Scholar 

  18. Friend, S. H. et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646 (1986). References 16–18 describe the cloning of RB , the first tumour-suppressor gene to be identified.

    CAS  PubMed  Google Scholar 

  19. Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971). The formulation of the two-hit hypothesis, using retinoblastoma as a model tumour type.

    PubMed  PubMed Central  Google Scholar 

  20. Kern, S. E. Whose hypothesis? Ciphering, sectorials, D lesions, freckles and the operation of Stigler's Law. Cancer Biol. Ther. 1, 571–581 (2002).

    PubMed  Google Scholar 

  21. Classon, M. & Harlow, E. The retinoblastoma tumour suppressor in development and cancer. Nature Rev. Cancer 2, 910–917 (2002).

    CAS  Google Scholar 

  22. Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002).

    CAS  PubMed  Google Scholar 

  23. Lipinski, M. M. & Jacks, T. The retinoblastoma gene family in differentiation and development. Oncogene 18, 7873–7882 (1999).

    CAS  PubMed  Google Scholar 

  24. Chau, B. N. & Wang, J. Y. Coordinated regulation of life and death by RB. Nature Rev. Cancer 3, 130–138 (2003).

    CAS  Google Scholar 

  25. Sage, J., Miller, A. L., Perez-Mancera, P. A., Wysocki, J. M. & Jacks, T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003).

    CAS  PubMed  Google Scholar 

  26. Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 (1996).

    CAS  PubMed  Google Scholar 

  27. Field, S. J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Jiang, Z. & Zacksenhaus, E. Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. J. Cell Biol. 156, 185–198 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).

    CAS  PubMed  Google Scholar 

  30. Robanus-Maandag, E. et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev. 12, 1599–1609 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee, E. Y. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).

    CAS  PubMed  Google Scholar 

  32. Wu, L. et al. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421, 942–947 (2003). Embryonic lethality and many neurological and erythroid abnormalities in Rb−/− embryos can be rescued by a wild-type placenta, providing strong evidence for cell-autonomous and non-cell-autonomous effects of Rb deficiency.

    CAS  PubMed  Google Scholar 

  33. de Bruin, A. et al. Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice. Proc. Natl Acad. Sci. USA 100, 6546–6551 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lipinski, M. M. et al. Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system. EMBO J. 20, 3402–3413 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ferguson, K. L. et al. Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development. EMBO J. 21, 3337–3346 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. MacPherson, D. et al. Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system. Mol. Cell. Biol. 23, 1044–1053 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang, J. et al. Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nature Genet. (in the press).

  38. Marino, S. et al. Rb and p107 are required for normal cerebellar development and granule cell survival but not for Purkinje cell persistence. Development 130, 3359–3368 (2003).

    CAS  PubMed  Google Scholar 

  39. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).

    CAS  Google Scholar 

  41. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    CAS  PubMed  Google Scholar 

  42. Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998). The first demonstration that PIP 3 is a substrate for PTEN, identifying PTEN as a negative regulator of PI3K signalling.

    CAS  PubMed  Google Scholar 

  43. Lee, J. O. et al. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99, 323–334 (1999).

    CAS  PubMed  Google Scholar 

  44. Sun, H. et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc. Natl Acad. Sci. USA 96, 6199–6204 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Potter, C. J. & Xu, T. Mechanisms of size control. Curr. Opin. Genet. Dev. 11, 279–286 (2001).

    CAS  PubMed  Google Scholar 

  46. Gao, X., Neufeld, T. P. & Pan, D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and-independent pathways. Dev. Biol. 221, 404–418 (2000).

    CAS  PubMed  Google Scholar 

  47. Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 13, 3244–3258 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Scanga, S. E. et al. The conserved PI3′K/PTEN/Akt signaling pathway regulates both cell size and survival in Drosophila. Oncogene 19, 3971–3977 (2000).

    CAS  PubMed  Google Scholar 

  49. Huang, H. et al. PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development. Development 126, 5365–5372 (1999). References 46–49 show that PTEN functions in the PI3K pathway to regulate cell size and number in Drosophila.

    CAS  PubMed  Google Scholar 

  50. Funamoto, S., Meili, R., Lee, S., Parry, L. & Firtel, R. A. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611–623 (2002).

    CAS  PubMed  Google Scholar 

  51. Iijima, M. & Devreotes, P. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109, 599–610 (2002).

    CAS  PubMed  Google Scholar 

  52. Manning, B. D. & Cantley, L. C. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 28, 573–576 (2003).

    CAS  PubMed  Google Scholar 

  53. Marsh, D. J. et al. PTEN mutation spectrum and genotype–phenotype correlations in Bannayan–Riley–Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum. Mol. Genet. 8, 1461–1472 (1999).

    CAS  PubMed  Google Scholar 

  54. Robinson, S. & Cohen, A. R. Cowden disease and Lhermitte–Duclos disease: characterization of a new phakomatosis. Neurosurgery 46, 371–383 (2000).

    CAS  PubMed  Google Scholar 

  55. Iida, S. et al. A heterozygous frameshift mutation of the PTEN/MMAC1 gene in a patient with Lhermitte–Duclos disease: only the mutated allele was expressed in the cerebellar tumor. Int. J. Mol. Med. 1, 925–929 (1998).

    CAS  PubMed  Google Scholar 

  56. Ali, I. U., Schriml, L. M. & Dean, M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl Cancer Inst. 91, 1922–1932 (1999).

    CAS  PubMed  Google Scholar 

  57. Duerr, E. M. et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16, 2259–2264 (1998).

    CAS  PubMed  Google Scholar 

  58. Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183–4186 (1997).

    CAS  PubMed  Google Scholar 

  59. Risinger, J. I., Hayes, A. K., Berchuck, A. & Barrett, J. C. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res. 57, 4736–4738 (1997).

    CAS  PubMed  Google Scholar 

  60. Tashiro, H. et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 57, 3935–3940 (1997).

    CAS  PubMed  Google Scholar 

  61. Cairns, P. et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 57, 4997–5000 (1997).

    CAS  PubMed  Google Scholar 

  62. Simpson, L. & Parsons, R. PTEN: life as a tumor suppressor. Exp. Cell Res. 264, 29–41 (2001).

    CAS  PubMed  Google Scholar 

  63. Suzuki, A. et al. T cell-specific loss of pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    CAS  PubMed  Google Scholar 

  64. Crackower, M. A. et al. Regulation of myocardial contractility and cell size by distinct PI3K–PTEN signaling pathways. Cell 110, 737–749 (2002).

    CAS  PubMed  Google Scholar 

  65. Kimura, T. et al. Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development 130, 1691–1700 (2003).

    CAS  PubMed  Google Scholar 

  66. Suzuki, A. et al. Critical roles of Pten in B Cell homeostasis and immunoglobulin class switch recombination. J. Exp. Med. 197, 657–667 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Suzuki, A. et al. Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation. Cancer Res. 63, 674–681 (2003).

    CAS  PubMed  Google Scholar 

  68. Anzelon, A. N., Wu, H. & Rickert, R. C. Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nature Immunol. 4, 287–294 (2003).

    CAS  Google Scholar 

  69. Li, G. et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development 129, 4159–4170 (2002).

    CAS  PubMed  Google Scholar 

  70. Marino, S. et al. PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development 129, 3513–3522 (2002).

    CAS  PubMed  Google Scholar 

  71. Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001). References 70 and 71 use conditional-knockout mice to study Pten function in the developing nervous system.

    CAS  PubMed  Google Scholar 

  72. McMahon, A. P., Ingham, P. W. & Tabin, C. J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1–114 (2003).

    CAS  PubMed  Google Scholar 

  73. Ruiz i Altaba, A., Sanchez, P. & Dahmane, N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer 2, 361–372 (2002).

    CAS  Google Scholar 

  74. Backman, S. A. et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte–Duclos disease. Nature Genet. 29, 396–403 (2001).

    CAS  PubMed  Google Scholar 

  75. Kwon, C. H. et al. Pten regulates neuronal soma size: a mouse model of Lhermitte–Duclos disease. Nature Genet. 29, 404–411 (2001). References 74 and 75 show that the predominant role of Pten in adult post-mitotic neurons is the proper maintenance of cell size.

    CAS  PubMed  Google Scholar 

  76. Kozma, S. C. & Thomas, G. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioessays 24, 65–71 (2002).

    CAS  PubMed  Google Scholar 

  77. Oldham, S. & Hafen, E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 13, 79–85 (2003).

    CAS  PubMed  Google Scholar 

  78. Stocker, H. & Hafen, E. Genetic control of cell size. Curr. Opin. Genet. Dev. 10, 529–535 (2000).

    CAS  PubMed  Google Scholar 

  79. Backman, S., Stambolic, V. & Mak, T. PTEN function in mammalian cell size regulation. Curr. Opin. Neurobiol. 12, 516–522 (2002).

    CAS  PubMed  Google Scholar 

  80. Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999).

    CAS  PubMed  Google Scholar 

  81. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998). The first demonstration of Akt activation as a downstream consequence of Pten deficiency.

    CAS  PubMed  Google Scholar 

  82. Dudek, H. et al. Regulation of neuronal survival by the serine–threonine protein kinase Akt. Science 275, 661–665 (1997).

    CAS  PubMed  Google Scholar 

  83. Brunet, A., Datta, S. R. & Greenberg, M. E. Transcription-dependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297–305 (2001).

    CAS  PubMed  Google Scholar 

  84. Gary, D. S. & Mattson, M. P. PTEN regulates Akt kinase activity in hippocampal neurons and increases their sensitivity to glutamate and apoptosis. Neuromolecular Med. 2, 261–269 (2002).

    CAS  PubMed  Google Scholar 

  85. Wang, Q. et al. Control of synaptic strength, a novel function of Akt. Neuron 38, 915–928 (2003).

    CAS  PubMed  Google Scholar 

  86. Markus, A., Zhong, J. & Snider, W. D. Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35, 65–76 (2002).

    CAS  PubMed  Google Scholar 

  87. Kwon, C. H., Zhu, X., Zhang, J. & Baker, S. J. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc. Natl Acad. Sci. USA 100, 12923–12928 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Tang, S. J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl Acad. Sci. USA 99, 467–472 (2002).

    CAS  PubMed  Google Scholar 

  89. Dasgupta, B. & Gutmann, D. H. Neurofibromatosis 1: closing the GAP between mice and men. Curr. Opin. Genet. Dev. 13, 20–27 (2003).

    CAS  PubMed  Google Scholar 

  90. Zhu, Y. & Parada, L. F. Neurofibromin, a tumor suppressor in the nervous system. Exp. Cell Res. 264, 19–28 (2001).

    CAS  PubMed  Google Scholar 

  91. Bajenaru, M. L. et al. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol. Cell Biol. 22, 5100–5113 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhu, Y. et al. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 15, 859–876 (2001). A conditional-knockout study that showed an important function for Nf1 in neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhu, Y., Ghosh, P., Charnay, P., Burns, D. K. & Parada, L. F. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920–922 (2002). This study was the first to demonstrate that haploinsufficiency for NF1 in the tumour environment strongly contributes to tumour formation of NF1−/− cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bajenaru, M. L. et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res. 63, 8573–8577 (2003).

    CAS  PubMed  Google Scholar 

  95. Reilly, K. M., Loisel, D. A., Bronson, R. T., McLaughlin, M. E. & Jacks, T. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genet. 26, 109–113 (2000). Genetic modifiers strongly influence tumour type and incidence associated with Nf1 and Trp53 mutation.

    CAS  PubMed  Google Scholar 

  96. Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).

    CAS  PubMed  Google Scholar 

  97. Mills, K. D., Ferguson, D. O. & Alt, F. W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol. Rev. 194, 77–95 (2003).

    CAS  PubMed  Google Scholar 

  98. Rajagopalan, H., Nowak, M. A., Vogelstein, B. & Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nature Rev. Cancer 3, 695–701 (2003).

    CAS  Google Scholar 

  99. Lieber, M. R., Ma, Y., Pannicke, U. & Schwarz, K. Mechanism and regulation of human non-homologous DNA end-joining. Nature Rev. Mol. Cell Biol. 4, 712–720 (2003).

    CAS  Google Scholar 

  100. West, S. C. Molecular views of recombination proteins and their control. Nature Rev. Mol. Cell Biol. 4, 435–445 (2003).

    CAS  Google Scholar 

  101. Caldecott, K. W. XRCC1 and DNA strand break repair. DNA Repair 2, 955–969 (2003).

    CAS  PubMed  Google Scholar 

  102. Bartek, J., Falck, J. & Lukas, J. CHK2 kinase: a busy messenger. Nature Rev. Mol. Cell Biol. 2, 877–886 (2001).

    CAS  Google Scholar 

  103. van Gent, D. C., Hoeijmakers, J. H. & Kanaar, R. Chromosomal stability and the DNA double-stranded break connection. Nature Rev. Genet. 2, 196–206 (2001).

    CAS  PubMed  Google Scholar 

  104. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    CAS  Google Scholar 

  105. Kastan, M. B. & Lim, D. S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000). References 104 and 105 provide a comprehensive description of ATM substrates and their biological roles.

    CAS  Google Scholar 

  106. Rotman, G. & Shiloh, Y. ATM: from gene to function. Hum. Mol. Genet. 7, 1555–1563 (1998).

    CAS  PubMed  Google Scholar 

  107. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    CAS  PubMed  Google Scholar 

  108. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).

    CAS  PubMed  Google Scholar 

  109. Westphal, C. H. et al. atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nature Genet. 16, 397–401 (1997).

    CAS  PubMed  Google Scholar 

  110. Shafman, T. D. et al. Prevalence of germline truncating mutations in ATM in women with a second breast cancer after radiation therapy for a contralateral tumor. Genes Chromosom. Cancer 27, 124–129 (2000).

    CAS  PubMed  Google Scholar 

  111. FitzGerald, M. G. et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet. 15, 307–310 (1997).

    CAS  PubMed  Google Scholar 

  112. Gatti, R. A., Tward, A. & Concannon, P. Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol. Genet. Metab. 68, 419–423 (1999).

    CAS  PubMed  Google Scholar 

  113. Xia, F. & Powell, S. N. The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer. Semin. Radiat. Oncol. 12, 296–304 (2002).

    PubMed  Google Scholar 

  114. Spring, K. et al. Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nature Genet. 32, 185–190 (2002). Provides an explanation for cancer predisposition in certain ATM heterozygotes.

    CAS  PubMed  Google Scholar 

  115. Stankovi, T. et al. ATM mutations in sporadic lymphoid tumours. Leuk. Lymphoma 43, 1563–1571 (2002).

    Google Scholar 

  116. Thorstenson, Y. R. et al. Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 63, 3325–3333 (2003).

    CAS  PubMed  Google Scholar 

  117. Boultwood, J. Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J. Clin. Pathol. 54, 512–516 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Herzog, K. H., Chong, M. J., Kapsetaki, M., Morgan, J. I. & McKinnon, P. J. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280, 1089–1091 (1998). The first demonstration that ATM responds to genotoxic stress in the nervous system.

    CAS  PubMed  Google Scholar 

  119. Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902 (1998).

    CAS  PubMed  Google Scholar 

  120. Barnes, D. E., Stamp, G., Rosewell, I., Denzel, A. & Lindahl, T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr. Biol. 8, 1395–1398 (1998). References 119 and 120 provide direct evidence that DNA damage is a key feature of nervous-system development.

    CAS  PubMed  Google Scholar 

  121. Sekiguchi, J. et al. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc. Natl Acad. Sci. USA 98, 3243–3248 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Lee, Y., Barnes, D. E., Lindahl, T. & McKinnon, P. J. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 14, 2576–2580 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Yuan, J. & Yankner, B. A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).

    CAS  PubMed  Google Scholar 

  124. Lee, Y. & McKinnon, P. J. DNA ligase IV suppresses medulloblastoma formation. Cancer Res. 62, 6395–6399 (2002).

    CAS  PubMed  Google Scholar 

  125. Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002).

    CAS  PubMed  Google Scholar 

  126. Offit, K. et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J. Natl Cancer Inst. 95, 1548–1551 (2003). References 124–126 link the non-homologous end joining and homologous recombination repair DNA-repair pathways to medulloblastoma. These data also further underscore the selective susceptibility of different brain regions to genotoxic insult.

    CAS  PubMed  Google Scholar 

  127. Rolig, R. L. & McKinnon, P. J. Linking DNA damage and neurodegeneration. Trends Neurosci. 23, 417–424 (2000).

    CAS  PubMed  Google Scholar 

  128. Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93, 467–476 (1998).

    CAS  PubMed  Google Scholar 

  129. Carney, J. P. et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93, 477–486 (1998). References 128 and 129 establish that mutations in NBS1 are responsible for Nijmegen breakage syndrome and provide an explanation for the similarity to ataxia telangiectasia.

    CAS  PubMed  Google Scholar 

  130. Tauchi, H., Matsuura, S., Kobayashi, J., Sakamoto, S. & Komatsu, K. Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene 21, 8967–8980 (2002).

    CAS  PubMed  Google Scholar 

  131. Shiloh, Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31, 635–662 (1997).

    CAS  PubMed  Google Scholar 

  132. D'Amours, D. & Jackson, S. P. The Mre11 complex: at the crossroads of dna repair and checkpoint signalling. Nature Rev. Mol. Cell Biol. 3, 317–327 (2002).

    CAS  Google Scholar 

  133. Petrini, J. H. & Stracker, T. H. The cellular response to DNA double-strand breaks: defining the sensors and mediators. Trends Cell Biol. 13, 458–462 (2003).

    CAS  PubMed  Google Scholar 

  134. van den Bosch, M., Bree, R. T. & Lowndes, N. F. The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep. 4, 844–849 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Stewart, G. S. et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577–587 (1999). Provides important evidence that defects in the DNA-damage-response pathway can cause neurodegeneration and further establishes the relationship between neurodegeneration, DNA damage and ATM.

    CAS  PubMed  Google Scholar 

  136. Theunissen, J. W. et al. Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11ATLD1/ATLD1 mice. Mol. Cell. 12, 1511–1523 (2003).

    CAS  PubMed  Google Scholar 

  137. Zhu, J., Petersen, S., Tessarollo, L. & Nussenzweig, A. Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr. Biol. 11, 105–109 (2001).

    CAS  PubMed  Google Scholar 

  138. Liao, M. J. & Van Dyke, T. Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma. Genes Dev. 13, 1246–1250 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Perkins, E. J. et al. Sensing of intermediates in V(D)J recombination by ATM. Genes Dev. 16, 159–164 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to colleagues whose primary research papers might not have been cited due to space constraints. We thank T. Curran, C. Fuller and G. Grosveld for helpful discussions and comments on the manuscript. The authors are supported by the National Institutes of Health and the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital.

Author information

Authors and Affiliations

  1. Department of Developmental Neurobiology and Department of Genetics and Tumour Cell Biology, St Jude Children's Research Hospital, Memphis, 38105, TN, USA

    Suzanne J. Baker & Peter J. McKinnon

Authors
  1. Suzanne J. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. McKinnon
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Cancer.gov

breast cancer

endometrial cancer

medulloblastoma

osteosarcoma

prostate tumours

retinoblastoma

thyroid cancer

LocusLink

AKT

ATM

BRCA1

BRCA2

CDK4

CDKN2A

CHK2

cyclin D1

E2f1

EGFR

LIG4

NBS1

NF1

p107

PDGF

PI3K

Ptc1

PTEN

RAS

RB

Shh

TP53

OMIM

ataxia telangiectasia

ATLD

neurofibromatosis type 1

FURTHER INFORMATION

American Brain Tumor Association

Glossary

VENTRICULAR ZONE

The layer of cells surrounding the cerebral ventricles in the developing nervous system that gives rise to neurons and glia.

CEREBELLUM

A large, dorsally projecting part of the brain that is involved in the coordination of muscles and the maintenance of bodily equilibrium. It is situated between the brain stem and the back of the cerebrum and is composed in humans of two lateral lobes and a median lobe.

SUBVENTRICULAR ZONE

The layer of cells that is immediately adjacent to the lateral ventricles.

LATERAL VENTRICLES

Cavities located within the cerebrum that provide a pathway for the circulation of cerebrospinal fluid.

DENTATE GYRUS

An important functional subdomain of the hippocampal formation that comprises granule neurons.

SCHWANN CELLS

Supporting cells of the peripheral nervous system that wrap around nerve axons. A single Schwann cell makes up a single segment of an axon's myelin sheath.

PURKINJE CELL

An output cell of the cerebellum, which has a large body with a characteristic mass of highly branched dendrites and a single axon that sends inhibitory signals to the cerebral cortex. These cells coordinate the development of the cerebellar cortex.

HAMARTOMA

A focal benign growth containing an abnormal proportion of a single-cell population or an abnormal mixture of tissue elements that are normally present at that site. Several hereditary cancer-predisposition syndromes also feature hamartomas in multiple tissues, including tuberous sclerosis and Cowden syndrome.

SYNAPTIC PLASTICITY

A change in the functional properties of a synapse as a result of use.

ASTROCYTE

A star-shaped cell of the central nervous system that provides nutrients, support and insulation for neurons. One of the main classes of neural cells.

REACTIVE ASTROGLIOSIS

A reactive process after insults such as ischaemia, infection or injury in which astrocytes show hypertrophy and increased immunoreactivity against glial fibrillary acidic protein, with or without proliferation.

PERINEURIAL CELLS

The perineurial cells are contained in the perineurium — a sheath of squamous epithelial cells that function as a barrier surrounding the endoneurium within the nerve fibres of the peripheral nervous system.

HAPLOINSUFFICIENCY

A situation in which loss of function of one allele of a gene in a diploid cell causes an abnormal phenotype, even though the other allele is wild type.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baker, S., McKinnon, P. Tumour-suppressor function in the nervous system. Nat Rev Cancer 4, 184–196 (2004). https://doi.org/10.1038/nrc1297

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1297

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing