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.

On the road to cancer: aneuploidy and the mitotic checkpoint

Key Points

  • Aneuploidy, or abnormal chromosome content, is the most common characteristic of human solid tumours. Aneuploidy might contribute to tumour formation and is associated with acquired resistance to some chemotherapeutics.

  • Tumour cells become aneuploid as a result of aberrant mitotic divisions. These aberrant divisions are caused by divisions with a multipolar spindle as a result of previous defects in cytokinesis or centrosome amplification, by defects in chromosome cohesion, by spindle attachment defects, or by impairment of the mitotic checkpoint response.

  • The mitotic checkpoint is a signalling cascade that arrests the cell cycle in mitosis when even a single chromosome is not properly attached to the mitotic spindle. This arrest is achieved by inhibiting the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that is essential for mitotic progression.

  • Many tumour cells have a diminished, but not absent, mitotic checkpoint response. Mouse models in which mitotic checkpoint signalling is decreased show an increase in spontaneous or carcinogen-induced tumour formation.

  • Mutations in mitotic checkpoint genes themselves are not a common mechanism of checkpoint impairment in human tumour cells.

  • Mitotic checkpoint impairment and aneuploidy in human tumour cells are often associated with changes in the protein levels of mitotic checkpoint proteins. In some tumour cells, these changes occur through altered transcriptional regulation by tumour suppressors or oncogene products.

  • Complete inactivation of mitotic checkpoint signalling causes cell-autonomous lethality. Drugs that specifically and efficiently interfere with mitotic checkpoint signalling could therefore be useful as anticancer agents.

Abstract

Abnormal chromosome content — also known as aneuploidy — is the most common characteristic of human solid tumours. It has therefore been proposed that aneuploidy contributes to, or even drives, tumour development. The mitotic checkpoint guards against chromosome mis-segregation by delaying cell-cycle progression through mitosis until all chromosomes have successfully made spindle-microtubule attachments. Defects in the mitotic checkpoint generate aneuploidy and might facilitate tumorigenesis, but more severe disabling of checkpoint signalling is a possible anticancer strategy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The roads to aneuploidy.
Figure 2: The mammalian mitotic checkpoint — signalling and silencing.
Figure 3: Mutations in mitotic checkpoint genes.
Figure 4: Mitotic checkpoint defects in cancer.
Figure 5: Induction of gross chromosome mis-segregations as an anticancer strategy.

References

  1. 1

    Flemming, W. Zellsubstanz, kern und zelltheilung. FCW Vogel, Leipzig, (1882).

    Google Scholar 

  2. 2

    Boveri, T. Über mehrpolige Mitosen als Mittel zur analyse des zellkerns. Verh. d. phys.med. Ges. Würzburg N. F. 35, 67–90 (1902).

    Google Scholar 

  3. 3

    von Hansemann, D. Ueber asymmetrische Zellheilteilung in epithelkrebsen und deren biologische bedeutung. Virschows Arch. Pathol. Anat. 119, 299–326 (1890).

    Article  Google Scholar 

  4. 4

    Boveri, T. Zur Frage der Entstehung maligner tumoren. Jena:Gustav Fischer Verlag (1914).

    Google Scholar 

  5. 5

    Cancer Cytogenetics (eds Heim, S. & Mitelman, F.) (Wiley Liss Inc., New York, 1995).

  6. 6

    Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    Kops, G. J., Foltz, D. R. & Cleveland, D. W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl Acad. Sci. USA 101, 8699–8704 (2004).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Michel, L. et al. Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc. Natl Acad. Sci. USA 101, 4459–4464 (2004). References 7 and 8 show that the complete inhibition of the mitotic checkpoint causes death in human tumour cells.

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Duesberg, P. et al. How aneuploidy may cause cancer and genetic instability. Anticancer Res. 19, 4887–4906 (1999).

    CAS  PubMed  Google Scholar 

  10. 10

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

    CAS  PubMed  Google Scholar 

  11. 11

    Fodde, R. & Smits, R. Cancer biology. A matter of dosage. Science 298, 761–763 (2002).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Wang, T. L. et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc. Natl Acad. Sci. USA 101, 3089–3094 (2004).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Sawyers, C. L. Research on resistance to cancer drug Gleevec. Science 294, 1834 (2001).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Storchova, Z. & Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nature Rev. Mol. Cell Biol. 5, 45–54 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Nigg, E. A. Centrosome aberrations: cause or consequence of cancer progression? Nature Rev. Cancer 2, 815–825 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Zhou, H. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genet. 20, 189–193 (1998).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G. F. Abnormal centrosome amplification in the absence of p53. Science 271, 1744–1747 (1996).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Deng, C. X. Roles of BRCA1 in centrosome duplication. Oncogene 21, 6222–6227 (2002).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Pei, L. & Melmed, S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol. Endocrinol 11, 433–441 (1997).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    McGrew, J. T., Goetsch, L., Byers, B. & Baum, P. Requirement for ESP1 in the nuclear division of Saccharomyces cerevisiae. Mol. Biol. Cell 3, 1443–1454 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Uzawa, S., Samejima, I., Hirano, T., Tanaka, K. & Yanagida, M. The fission yeast cut1+ gene regulates spindle pole body duplication and has homology to the budding yeast ESP1 gene. Cell 62, 913–925 (1990).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Yamamoto, A., Guacci, V. & Koshland, D. Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae. J. Cell Biol. 133, 85–97 (1996).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Jallepalli, P. V. et al. Securin is required for chromosomal stability in human cells. Cell 105, 445–457 (2001).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Zhang, X. et al. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol. Endocrinol. 13, 156–166 (1999).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Zhang, X. et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J. Clin. Endocrinol. Metab. 84, 761–767 (1999).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Cimini, D. et al. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153, 517–527 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Gassmann, R. et al. Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J. Cell Biol. 166, 179–191 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Kaplan, K. B. et al. A role for the adenomatous polyposis coli protein in chromosome segregation. Nature Cell Biol. 3, 429–432 (2001).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Fodde, R. et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nature Cell Biol. 3, 433–438 (2001).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Fodde, R., Smits, R. & Clevers, H. APC, signal transduction and genetic instability in colorectal cancer. Nature Rev. Cancer 1, 55–67 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Green, R. A. & Kaplan, K. B. Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC. J. Cell Biol 163, 949–961 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Shin, H. J. et al. Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability. Cancer Cell 4, 483–497 (2003).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Taylor, S. S. & McKeon, F. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89, 727–735 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Peters, J. M. The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol. Cell 9, 931–943 (2002).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Cleveland, D. W., Mao, Y. & Sullivan, K. F. Centromeres and kinetochores. From epigenetics to mitotic checkpoint signaling. Cell 112, 407–421 (2003).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Rieder, C. L., Schultz, A., Cole, R. & Sluder, G. Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J. Cell Biol. 127, 1301–1310 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Weiss, E. & Winey, M. The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint. J. Cell Biol. 132, 111–123 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Li, R. & Murray, A. W. Feedback control of mitosis in budding yeast. Cell 66, 519–531 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Hoyt, M. A., Totis, L. & Roberts, B. T. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66, 507–517 (1991). References 38 and 39 reported the identification of the molecular components of the mitotic checkpoint in budding yeast.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Abrieu, A. et al. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell 106, 83–93 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Jin, D. Y., Spencer, F. & Jeang, K. T. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 93, 81–91 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Li, Y. & Benezra, R. Identification of a human mitotic checkpoint gene: hsMAD2. Science 274, 246–248 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Taylor, S. S., Ha, E. & McKeon, F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J. Cell Biol. 142, 1–11 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Abrieu, A., Kahana, J. A., Wood, K. W. & Cleveland, D. W. CENP-E as an essential component of the mitotic checkpoint in vitro. Cell 102, 817–826 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Chan, G. K., Jablonski, S. A., Sudakin, V., Hittle, J. C. & Yen, T. J. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J. Cell Biol. 146, 941–954 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Chan, G. K., Jablonski, S. A., Starr, D. A., Goldberg, M. L. & Yen, T. J. Human Zw10 and ROD are mitotic checkpoint proteins that bind to kinetochores. Nature Cell Biol. 2, 944–947 (2000).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Mao, Y., Abrieu, A. & Cleveland, D. W. Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1. Cell 114, 87–98 (2003). This study shows how a lack of attachment at the kinetochore can be converted into a catalytic activity that sustains mitotic checkpoint signalling. The microtubule-binding protein CENPE, when unbound by microtubules, directly activates the checkpoint kinase BUBR1, which is an essential mediator of the mitotic checkpoint response.

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Minshull, J., Sun, H., Tonks, N. K. & Murray, A. W. A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts. Cell 79, 475–486 (1994).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Shah, J. V. et al. Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing. Curr. Biol. 14, 942–952 (2004).

    CAS  PubMed  Google Scholar 

  50. 50

    Howell, B. J. et al. Spindle checkpoint protein dynamics at kinetochores in living cells. Curr. Biol. 14, 953–964 (2004).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Fang, G., Yu, H. & Kirschner, M. W. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev. 12, 1871–1883 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Luo, X. et al. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nature Struct. Mol. Biol. 11, 338–345 (2004).

    CAS  Article  Google Scholar 

  53. 53

    De Antoni, A. et al. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr. Biol. 15, 214–225 (2005).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Fang, G. Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol. Biol. Cell 13, 755–766 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Tang, Z., Bharadwaj, R., Li, B. & Yu, H. Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev. Cell 1, 227–237 (2001).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Sudakin, V., Chan, G. K. & Yen, T. J. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J. Cell Biol. 154, 925–936 (2001). References 55 and 56 challenged the view that MAD2 alone was the APC/C inhibitor. Although reference 55 showed BUBR1 could directly inhibit the APC/C better than MAD2 could, reference 56 showed that in mitotic HeLa cells, both BUBR1 and MAD2, together with BUB3, were found in complex with CDC20, and that this complex was a very potent inhibitor of the APC/C.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Hwang, L. H. et al. Budding yeast Cdc20: a target of the spindle checkpoint. Science 279, 1041–1044 (1998).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Kallio, M., Weinstein, J., Daum, J. R., Burke, D. J. & Gorbsky, G. J. Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events. J. Cell Biol. 141, 1393–1406 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Chen, R. H. Phosphorylation and activation of Bub1 on unattached chromosomes facilitate the spindle checkpoint. EMBO J. 23, 3113–3121 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    Ditchfield, C. et al. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J. Cell Biol. 161, 267–280 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Camasses, A., Bogdanova, A., Shevchenko, A. & Zachariae, W. The CCT chaperonin promotes activation of the anaphase-promoting complex through the generation of functional Cdc20. Mol. Cell 12, 87–100 (2003).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Lens, S. M. et al. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J. 22, 2934–2947 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Sassoon, I. et al. Regulation of Saccharomyces cerevisiae kinetochores by the type 1 phosphatase Glc7p. Genes Dev. 13, 545–555 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Hauf, S. et al. The small molecule hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J. Cell Biol. 161, 281–294 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Tanaka, T. U. et al. Evidence that the Ipl1–Sli15 (aurora kinase–INCENP) complex promotes chromosome bi-orientation by altering kinetochore–spindle pole connections. Cell 108, 317–329 (2002).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Lampson, M. A. & Kapoor, T. M. The human mitotic checkpoint protein BubR1 regulates chromosome–spindle attachments. Nature Cell Biol. 7, 93–98 (2005).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Putkey, F. R. et al. Unstable kinetochore-microtubule capture and chromosomal instability following deletion of CENP-E. Dev. Cell 3, 351–365 (2002).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Weaver, B. A. et al. Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss. J. Cell Biol. 162, 551–563 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Habu, T., Kim, S. H., Weinstein, J. & Matsumoto, T. Identification of a MAD2-binding protein, CMT2, and its role in mitosis. EMBO J. 21, 6419–6428 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Xia, G. et al. Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint. EMBO J. 23, 3133–3143 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Kienitz, A., Vogel, C., Morales, I., Muller, R. & Bastians, H. Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol. Oncogene 24, 4301–4310 (2005).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998). First study to identify mutant alleles of the mitotic checkpoint proteins BUB1 and BUBR1 in human colorectal cancer cell lines.

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Dai, W. et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 64, 440–445 (2004).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Babu, J. R. et al. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J. Cell Biol. 160, 341–353 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Michel, M. L. et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409, 355–359 (2001). References 74 and 75 provided proof-of-principle that reduced levels of a mitotic checkpoint protein can cause checkpoint malfunction and CIN, and thereby contribute to tumour formation.

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36, 744–749 (2004).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Musio, A. et al. Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts. Cancer Res. 63, 2855–2863 (2003).

    CAS  PubMed  Google Scholar 

  78. 78

    Wang, Q. et al. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood 103, 1278–1285 (2004).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Myung, K., Smith, S. & Kolodner, R. D. Mitotic checkpoint function in the formation of gross chromosomal rearrangements in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 101, 15980–15985 (2004).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Iouk, T., Kerscher, O., Scott, R. J., Basrai, M. A. & Wozniak, R. W. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. J. Cell Biol. 159, 807–819 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Campbell, M. S., Chan, G. K. & Yen, T. J. Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase. J. Cell. Sci. 114, 953–963 (2001).

    CAS  PubMed  Google Scholar 

  82. 82

    Rao, C. V. et al. Colonic tumorigenesis in BubR1+/−ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc. Natl Acad. Sci. USA 102, 4365–4370 (2005).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Connor, F. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nature Genet. 17, 423–430 (1997).

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Friedman, L. S. et al. Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res. 58, 1338–1343 (1998).

    CAS  PubMed  Google Scholar 

  85. 85

    Lee, H. et al. Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Mol. Cell 4, 1–10 (1999).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Rieder, C. L. & Maiato, H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev. Cell 7, 637–651 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Ouyang, B., Knauf, J. A., Ain, K., Nacev, B. & Fagin, J. A. Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1. Clin. Endocrinol. (Oxf.) 56, 341–350 (2002).

    CAS  Article  Google Scholar 

  88. 88

    Takahashi, T. et al. Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. Oncogene 18, 4295–4300 (1999).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Wang, X. et al. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res. 62, 1662–1668 (2002).

    CAS  PubMed  Google Scholar 

  90. 90

    Tighe, A., Johnson, V. L., Albertella, M. & Taylor, S. S. Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep. 2, 609–614 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91

    Saeki, A. et al. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer 94, 2047–2054 (2002).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Yoon, D. S. et al. Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am. J. Pathol. 161, 391–397 (2002).

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Grigorova, M., Staines, J. M., Ozdag, H., Caldas, C. & Edwards, P. A. Possible causes of chromosome instability: comparison of chromosomal abnormalities in cancer cell lines with mutations in BRCA1, BRCA2, CHK2 and BUB1. Cytogenet. Genome Res. 104, 333–340 (2004).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Gemma, A. et al. Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer. Genes Chromosomes Cancer 29, 213–218 (2000).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Hempen, P. M., Kurpad, H., Calhoun, E. S., Abraham, S. & Kern, S. E. A double missense variation of the BUB1 gene and a defective mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T. Hum. Mutat. 21, 445 (2003).

    PubMed  Article  CAS  Google Scholar 

  96. 96

    Hernando, E. et al. Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. Int. J. Cancer 95, 223–227 (2001).

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Imai, Y., Shiratori, Y., Kato, N., Inoue, T. & Omata, M. Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Jpn. J. Cancer Res. 90, 837–840 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Ohshima, K. et al. Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma. Cancer Lett. 158, 141–150 (2000).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Nomoto, S. et al. Search for in vivo somatic mutations in the mitotic checkpoint gene, hMAD1, in human lung cancers. Oncogene 18, 7180–7183 (1999).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Percy, M. J. et al. Expression and mutational analyses of the human MAD2L1 gene in breast cancer cells. Genes Chromosomes Cancer 29, 356–362 (2000).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Tsukasaki, K. et al. Mutations in the mitotic check point gene, MAD1L1, in human cancers. Oncogene 20, 3301–3305 (2001).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Shichiri, M., Yoshinaga, K., Hisatomi, H., Sugihara, K. & Hirata, Y. Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer Res. 62, 13–17 (2002).

    CAS  PubMed  Google Scholar 

  103. 103

    Wang, Z. et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res. 64, 2998–3001 (2004).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Haruki, N. et al. Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. Cancer Lett. 162, 201–205 (2001).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Olesen, S. H., Thykjaer, T. & Orntoft, T. F. Mitotic checkpoint genes hBUB1, hBUB1B, hBUB3 and TTK in human bladder cancer, screening for mutations and loss of heterozygosity. Carcinogenesis 22, 813–815 (2001).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58, 181–187 (1999).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Myrie, K. A., Percy, M. J., Azim, J. N., Neeley, C. K. & Petty, E. M. Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Cancer Lett. 152, 193–199 (2000).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Scolnick, D. M. & Halazonetis, T. D. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature 406, 430–435 (2000).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nature Genet. 21, 177–181 (1999).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Song, M. S. et al. The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex. Nature Cell Biol. 6, 129–137 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112

    Grabsch, H. et al. Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer — association with tumour cell proliferation. J. Pathol. 200, 16–22 (2003).

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Hernando, E. et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430, 797–802 (2004). This study shows how a tumour suppressor can manipulate the mitotic checkpoint to create CIN. Aneuploidy occurs in RB-negative tumor cells via increased levels of MAD2. MAD2L1 is a target gene of the RB-controlled transcription factor E2F.

    CAS  Article  PubMed  Google Scholar 

  114. 114

    Cheung, H. W. et al. Mitotic arrest deficient 2 expression induces chemosensitization to a DNA-damaging agent, cisplatin, in nasopharyngeal carcinoma cells. Cancer Res. 65, 1450–1458 (2005).

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Wang, R. H., Yu, H. & Deng, C. X. A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle heckpoint. Proc. Natl Acad. Sci. USA 101, 17108–17113 (2004).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Article  Google Scholar 

  117. 117

    Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 16, 245–256 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118

    Chun, A. C. & Jin, D. Y. Transcriptional regulation of mitotic checkpoint gene MAD1 by p53. J. Biol. Chem. 278, 37439–37450 (2003).

    CAS  PubMed  Article  Google Scholar 

  119. 119

    Iwanaga, Y. & Jeang, K. T. Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant. Cancer Res. 62, 2618–2624 (2002).

    CAS  PubMed  Google Scholar 

  120. 120

    Gupta, A., Inaba, S., Wong, O. K., Fang, G. & Liu, J. Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1. Oncogene 22, 7593–7599 (2003).

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer 4, 253–265 (2004).

    CAS  Article  Google Scholar 

  122. 122

    Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4, 927–936 (2004).

    CAS  Article  Google Scholar 

  123. 123

    Harrington, E. A. et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med. 10, 262–267 (2004).

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Dorer, R. K. et al. A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes. Curr. Biol. 15, 1070–1076 (2005).

    CAS  Article  PubMed  Google Scholar 

  125. 125

    Larsen, N. A. & Harrison, S. C. Crystal structure of the spindle assembly checkpoint protein Bub3. J. Mol. Biol. 344, 885–892 (2004).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Kops, G. J. et al. ZW10 links mitotic checkpoint signaling to the structural kinetochore. J. Cell Biol. 169, 49–60 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

    Luo, X. et al. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nature Struct. Biol. 7, 224–229 (2000).

    CAS  PubMed  Article  Google Scholar 

  128. 128

    Tang, Z., Shu, H., Oncel, D., Chen, S. & Yu, H. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol. Cell 16, 387–397 (2004).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Chen, R. H., Shevchenko, A., Mann, M. & Murray, A. W. Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. J. Cell Biol. 143, 283–295 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Geert J. P. L. Kops or Don W. Cleveland.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

APC

aurora kinase A

aurora kinase B

BRCA1

BRCA2

BUB3

BUBR1

CDC20

CENPE

CMT2

cyclin B1

E2F

MAD1

MAD2

MPS1

PTEN

RASSF1A

RB1

ROD

securin

separase

survivin

TP53

ZW10

zwilch

National Cancer Institute

breast cancer

colorectal cancer

OMIM

mosaic variegated aneuploidy

Glossary

ADENOMATOSIS POLYPOSIS COLI

Tumour-suppressor protein that, in a mutated, defective form, causes familial adenomatous polyposis (FAP), a rare hereditary disease in which patients have thousands of colorectal polyps that develop into tumours. Most sporadic colorectal tumours harbour mutations in both APC alleles.

LOSS OF HETEROZYGOSITY

Following acquisition of a deleterious mutation in one of the two copies of a specific gene, loss of heterozygosity occurs from subsequent loss of, or mutation in, the normal allele.

NUDE MICE

Strains of athymic mice bearing the recessive allele nu/nu, which are largely hairless and lack all, or most, of the T-cell population. Nude mice can accept either allografts or xenografts. nu/nu alleles on some backgrounds have near-normal numbers of T-cells.

KINETOCHORE

A multiprotein structure, positioned at the central constriction of each chromosome (centromere), which is responsible for chromosome attachment to the mitotic spindle, chromosome segregation during anaphase and mitotic checkpoint activity.

ANAPHASE PROMOTING COMPLEX/CYCLOSOME

Multisubunit E3 ubiquitin ligase required for mitotic progression by targeting key mitotic regulators such as cyclin B1 and securin for destruction through direct poly-ubiquitylation. Note that the nomenclature can be confusing here: the APC/C is completely distinct from the APC associated with β-catenin signalling and colorectal cancer.

MICROTUBULE CAPTURE

Process in prometaphase in which unattached kinetochores each interact with one or more microtubules that emanate from one spindle pole. The interaction is mediated by microtubule-binding proteins that stably associate with the kinetochore.

MEGAKARYOPOIESIS

Process that leads to the production of megakaryocytes, the polyploid precursor to platelets. These precursors develop from haematopoietic stem cells by executing several cell-cycles in which cytokinesis is skipped (known as endoreduplication).

DOMINANT-INTERFERING MUTANT

Non-functional mutant protein that inhibits the function of the endogenous wild-type protein. These mutants often work by occupying subcellular binding sites required for the activation or correct subcellular positioning of the wild-type protein.

NOCODAZOLE

Synthetic compound that binds tubulin dimers, thereby causing inibition of microtubule polymerization. Because of the highly dynamic nature of spindle microtubules in mitosis, this results in complete depolymerization of the cellular microtubule network.

CELL-AUTONOMOUS LETHAL

The situation in which a deleterious subcellular environment (such as a genetic lesion that inactivates the mitotic checkpoint) causes cell death from damage solely developed within that cell. Surrounding cells have no influence on this process.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kops, G., Weaver, B. & Cleveland, D. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 5, 773–785 (2005). https://doi.org/10.1038/nrc1714

Download citation

Further reading

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