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Review article: Biomedical intelligence

Vol. 141 No. 0910 (2011)

Mechanisms of aneuploidy and its suppression by tumour suppressor proteins

  • C Thoma
  • A Toso
  • P Meraldi
  • W Krek
DOI
https://doi.org/10.4414/smw.2011.13170
Cite this as:
Swiss Med Wkly. 2011;141:w13170
Published
28.02.2011

Summary

Aneuploidy, as a result of numerical changes in chromosome number, was observed in tumours almost a century ago. The molecular mechanisms underlying this phenomenon and their impact on tumour development are still poorly understood. A series of recent observations provide direct linkages between the normal function of tumour suppressor proteins and the suppression of aneuploidy. The prospects that these findings offer for understanding the role of aneuploidy in cancer are discussed in this review.

References

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
  2. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13:472–82.
  3. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009;136:823–37.
  4. Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002;2:331–41.
  5. COSMIC. (2009) Catalog of somatic mutations in cancer. http://www.sanger.ac.uk/genetics/CGP/cosmic/.
  6. Boveri T. Zur Frage der Entstehung maligner Tumoren. Gustav Fischer, Jena, 1914.
  7. Mitelman F, Johansson B, Mertens F. (2010) Mitelman Database of Chromosome Aberrations in Cancer. http://cgap.nci.nih.gov/Chromosomes/Mitelman.
  8. Duesberg P, Li R. Multistep carcinogenesis: a chain reaction of aneuploidizations. Cell Cycle. 2003;2:202–10.
  9. Zimonjic D, Brooks MW, Popescu N, Weinberg RA, Hahn WC. Derivation of human tumor cells in vitro without widespread genomic instability. Cancer Res. 2001;61:8838–44.
  10. Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell. 2007;11:25–36.
  11. Gasparini P, Sozzi G, Pierotti MA. The role of chromosomal alterations in human cancer development. J Cell Biochem. 2007;102:320–31.
  12. Rowley JD. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet. 1973;16:109–12.
  13. Sandberg AA, Meloni-Ehrig AM. Cytogenetics and genetics of human cancer: methods and accomplishments. Cancer Genet Cytogenet. 2010;203:102–26.
  14. Lingle WL, Lukasiewicz K, Salisbury JL. Deregulation of the centrosome cycle and the origin of chromosomal instability in cancer. Adv Exp Med Biol. 2005;570:393–421.
  15. Cimini D, Wan X, Hirel CB, Salmon ED. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol. 2006;16:1711–8.
  16. Knowlton AL, Lan W, Stukenberg PT. Aurora B is enriched at merotelic attachment sites, where it regulates MCAK. Curr Biol. 2006;16:1705–10.
  17. Cimini D. Detection and correction of merotelic kinetochore orientation by Aurora B and its partners. Cell Cycle. 2007;6:1558–64.
  18. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–93.
  19. Cheeseman IM, Desai A. Molecular architecture of the kinetochore-microtubule interface. Nat Rev Mol Cell Biol. 2008;9:33–46.
  20. Rieder CL, Cole RW, Khodjakov A, Sluder G. The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J Cell Biol. 1995;130:941–8.
  21. Sironi L, Mapelli M, Knapp S, De Antoni A, Jeang KT, Musacchio A. Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a “safety belt” binding mechanism for the spindle checkpoint. Embo J. 2002;21:2496–506.
  22. Chan GK, Jablonski SA, Sudakin V, Hittle JC, Yen TJ. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J Cell Biol. 1999;146:941–54.
  23. Yao X, Abrieu A, Zheng Y, Sullivan KF, Cleveland DW. CENP-E forms a link between attachment of spindle microtubules to kinetochores and the mitotic checkpoint. Nat Cell Biol. 2000;2:484–91.
  24. Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 2004;117:1577–89.
  25. Meraldi P, Sorger PK. A dual role for Bub1 in the spindle checkpoint and chromosome congression. Embo J. 2005;24:1621–33.
  26. De Antoni A, Pearson CG, Cimini D, Canman JC, Sala V, Nezi L, et al. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol. 2005;15:214–25.
  27. Mapelli M, Massimiliano L, Santaguida S, Musacchio A. The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint. Cell. 2007;131:730–43.
  28. Luo X, Fang G, Coldiron M, Lin Y, Yu H, Kirschner MW, Wagner G. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct Biol. 2000;7:224–9.
  29. Kim Y, Heuser JE, Waterman CM, Cleveland DW. CENP-E combines a slow, processive motor and a flexible coiled coil to produce an essential motile kinetochore tether. J Cell Biol. 2008;181:411–9.
  30. Mao Y, Abrieu A, Cleveland DW. Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1. Cell. 2003;114:87–98.
  31. Howell BJ, McEwen BF, Canman JC, Hoffman DB, Farrar EM, Rieder CL, Salmon ED. Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J Cell Biol. 2001;155:1159–72.
  32. Wojcik E, Basto R, Serr M, Scaerou F, Karess R, Hays T. Kinetochore dynein: its dynamics and role in the transport of the Rough deal checkpoint protein. Nat Cell Biol. 2001;3;1001–7.
  33. Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001;409:355–9.
  34. Sotillo R, Hernando E, Diaz-Rodriguez E, Teruya-Feldstein J, Cordon-Cardo C, Lowe SW, Benezra R. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell. 2007;11:9–23.
  35. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, et al. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998;392:300–3.
  36. Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006;18:658–67.
  37. Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell. 2000;101:635–45.
  38. Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM Jr, et al. Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res. 2007;67:160–6.
  39. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM. Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol. 2007;179:255–67.
  40. Kalitsis P, Earle E, Fowler KJ, Choo KH. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev. 2000;1:2277–82.
  41. Wang Q, Liu T, Fang Y, Xie S, Huang X, Mahmood R, et al. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood. 2004;103:1278–85.
  42. Weaver BA, Bonday ZQ, Putkey FR, Kops GJ, Silk AD, Cleveland DW. Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss. J Cell Biol. 2003;162:551–63.
  43. Perez de Castro I, de Carcer G, Malumbres M. A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis. 2007;28:899–912.
  44. Kalitsis P, Fowler KJ, Griffiths B, Earle E, Chow CW, Jamsen K, Choo KH. Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice. Genes Chromosomes Cancer. 2005;44:29–36.
  45. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet. 2004;36:744–9.
  46. Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, Mahmood R, et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 2004;64:440–5.
  47. Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van Deursen JM. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol. 2003;160:341–53.
  48. Foijer F, Draviam VM, Sorger PK. Studying chromosome instability in the mouse. Biochim Biophys Acta. 2008;1786:73–82.
  49. Schvartzman JM, Sotillo R, Benezra R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer. 10:102–15.
  50. Segal DJ, McCoy EE. Studies on Down’s syndrome in tissue culture. I. Growth rates and protein contents of fibroblast cultures. J Cell Physiol. 1974;83:85–90.
  51. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, Amon A. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007;317:916–24.
  52. Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA, Housman DE, Amon A. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008;322:703–9.
  53. Williams BR, Amon A. Aneuploidy: cancer’s fatal flaw? Cancer Res. 2009;69:5289–91.
  54. Nicholson JM, Duesberg P. On the karyotypic origin and evolution of cancer cells. Cancer Genet Cytogenet. 2009;194:96–110.
  55. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP, et al. Identification of aneuploidy-tolerating mutations. Cell. 2010;143:71–83.
  56. Sotillo R, Schvartzman JM, Socci ND, Benezra R. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature.
  57. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–70.
  58. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.
  59. Nathke IS. The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. Annu Rev Cell Dev Biol. 2004;20:337–66.
  60. Mimori-Kiyosue Y, Shiina N, Tsukita S. Adenomatous polyposis coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells. J Cell Biol. 2000;148:505–18.
  61. Nathke IS, Adams CL, Polakis P, Sellin JH, Nelson WJ. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol. 1996;134:165–79.
  62. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol. 2001;3:433–8.
  63. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS. A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol. 2001;3:429–32.
  64. Dikovskaya D, Schiffmann D, Newton IP, Oakley A, Kroboth K, Sansom O, et al. Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. J Cell Biol. 2007;176:183–95.
  65. Zhang J, Ahmad S, Mao Y. BubR1 and APC/EB1 cooperate to maintain metaphase chromosome alignment. J Cell Biol. 2007;178:773–84.
  66. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability – an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–8.
  67. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science. 1996;271:1744–7.
  68. Oikawa T, Okuda M, Ma Z, Goorha R, Tsujimoto H, Inokuma H, Fukasawa K. Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1. Mol Cell Biol. 2005;25:4046–61.
  69. Sabado Alvarez C. Molecular biology of retinoblastoma. Clin Transl Oncol. 2008;10:389–94.
  70. Chen HZ, Tsai SY, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9:785–97.
  71. Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol. 1999;1:88–93.
  72. Lentini L, Pipitone L, Di Leonardo A. Functional inactivation of pRB results in aneuploid mammalian cells after release from a mitotic block. Neoplasia. 2002;4:380–7.
  73. Zheng L, Flesken-Nikitin A, Chen PL, Lee WH. Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability. Cancer Res. 2002;62:2498–502.
  74. Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M, et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature. 2004;430:797–802.
  75. Coschi CH, Martens AL, Ritchie K, Francis SM, Chakrabarti S, Berube NG, Dick FA. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev. 2010;24:1351–63.
  76. Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 2010;24:1364–76.
  77. van Harn T, Foijer F, van Vugt M, Banerjee R, Yang F, Oostra A, et al. Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev. 2010;24:1377–88.
  78. Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, et al. A genetic screen for candidate tumor suppressors identifies REST. Cell. 2005;121:837–48.
  79. Coulson JM, Edgson JL, Woll PJ, Quinn JP. A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker. Cancer Res. 2000;60:1840–4.
  80. Palm K, Metsis M, Timmusk T. Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. Brain Res Mol Brain Res. 1999;72:30–9.
  81. Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, et al. Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature. 2008;452:365–9.
  82. Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, et al. SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature. 2008;452:370–4.
  83. Frew IJ, Krek W. pVHL: a multipurpose adaptor protein. Sci Signal, 1, pe30. (2008).
  84. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–5.
  85. Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol. 2003;5:64–70.
  86. Thoma CR, Matov A, Gutbrodt KL, Hoerner CR, Smole Z, Krek W, Danuser G. Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability. J Cell Biol. 2010;190:991–1003.
  87. Schermer B, Ghenoiu C, Bartram M, Muller RU, Kotsis F, Hohne M, et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol. 2006;175:547–54.
  88. Thoma CR, Frew IJ, Hoerner CR, Montani M, Moch H, Krek W. pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol. 2007;9:588–95.
  89. Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell. 1998;1:959–68.
  90. Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ, Schraml P, et al. VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol. 2009;11:994–1001.
  91. Draviam VM, Shapiro I, Aldridge B, Sorger PK. Misorientation and reduced stretching of aligned sister kinetochores promote chromosome missegregation in EB1- or APC-depleted cells. Embo J. 2006;25:2814–27.
  92. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387-98.
  93. Nathke I. Relationship between the role of the adenomatous polyposis coli protein in colon cancer and its contribution to cytoskeletal regulation. Biochem Soc Trans. 2005;33:694-7.
  94. Meek DW. Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer. 2009;9:714-23.
  95. Zuckerman V. Wolyniec K, Sionov RV, Haupt S, Haupt Y. Tumour suppression by p53: the importance of apoptosis and cellular senescence. J Pathol. 2009;219:3-15.
  96. Thompson SL, Compton DA. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol. 2010;188;369-81.
  97. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer. 2008;8:671-82.
  98. Kaelin WG, Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008;8:865-73.