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  • Review Article
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Chromosome segregation and cancer: cutting through the mystery

Nature Reviews Cancer volume 1, pages 109–117 (2001)Cite this article

Key Points

  • Cyclin-dependent kinases (CDKs) are the master regulators of mitosis.They delegate portions of the mitotic programme to other downstream transducers that act directly on various components of mitotic chromosomes, the spindle apparatus and the cytoskeleton.

  • The anaphase-promoting complex/cyclosome (APC/C) normally becomes active at the metaphase–anaphase transition. It triggers the degradation of an anaphase-inhibiting protein, called securin, and cyclin B. Inhibition of the APC/C is one of the principal consequences of spindle-checkpoint activation.

  • In human cells, the formation of a securin–separin complex primes the separin protease for eventual activation in anaphase. Otherwise, securin functions primarily as an inhibitor of the separin protease, which cleaves cohesin bridges, allowing the sister chromatids to move poleward along the mitotic spindle.

  • Genetic instability is a hallmark of virtually all solid tumours. Most cancers are aneuploid and often exhibit cytological abnormalities during mitosis, including abnormal centrosomes, multipolar spindles and lagging chromosomes.

  • More than 100 genes can cause chromosomal instability (CIN) when mutated in yeast cells, many of which have several homologues in humans. These include genes that are involved in chromosome metabolism, spindle assembly and dynamics, cell-cycle regulation and mitotic checkpoint control.

  • Genetic alterations in the mitotic-spindle checkpoint of human cells lead directly to CIN. However, the underlying chromosomal segregration defects can be quite distinct.

  • Cancer cells have numerous defects in their genetic stability mechanisms. The effect of such defects might render most cancers vulnerable to genotoxic challenges that threaten genomic integrity, indicating a possible route to drug discovery.

Abstract

Mitosis is the most dramatic — and potentially dangerous — event in the cell cycle, as sister chromatids are irreversibly segregated to daughter cells. Defects in the checkpoints that normally maintain the fidelity of this process can lead to chromosomal instability (CIN) and cancer. However, CIN — a driving force of tumorigenesis — could be the cancer cell's ultimate vulnerability. An important goal is to identify novel anticancer compounds that directly target the mitotic errors at the heart of CIN.

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Figure 1: Regulation of mitosis.
Figure 2: Examples of mitotic abnormalities in cancer cells.
Figure 3: Regulation of sister chromatid separation.
Figure 4: Chromosomal instability in cells with defective spindle checkpoints or sister-chromatid separation.
Figure 5: One approach for identifying CIN-selective anticancer compounds through in vivo drug screening116.

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References

  1. Paweletz, N. Walther Flemming: pioneer of mitosis research. Nature Rev. Mol. Cell Biol. 2, 72–75 (2001).

    Article  CAS  Google Scholar 

  2. Jackman, M. R. & Pines, J. N. Cyclins and the G2/M transition. Cancer Surv. 29, 47–73 (1997).

    CAS  PubMed  Google Scholar 

  3. Hsu, J. Y. et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102, 279–291 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Giet, R. & Glover, D. M. Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J. Cell Biol. 152, 669–682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Adams, R. R., Carmena, M. & Earnshaw, W. C. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol. 11, 49–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Nigg, E. A. Polo-like kinases: positive regulators of cell division from start to finish. Curr. Opin. Cell Biol. 10, 776–783 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Sato, N. et al. Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells. Cancer Genet. Cytogenet. 126, 13–19 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Saunders, W. S. et al. Chromosomal instability and cytoskeletal defects in oral cancer cells. Proc. Natl Acad. Sci. USA 97, 303–308 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li–Fraumeni syndrome. Science 286, 2528–2531 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).First reported evidence for a defect in the mitotic spindle checkpoint pathway in CIN colorectal cancers.

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Velculescu, V. E. et al. Analysis of human transcriptomes. Nature Genet. 23, 387–388 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Heaney, A. P. et al. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet 355, 716–719 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Bischoff, J. R. et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 17, 3052–3065 (1998).Provides evidence for a causal relationship between aurora-A overexpression and tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Boveri, T. Zur Frage der Enstehung Maligner Tumoren (Gustav Fischer Verlag, Jena, 1914).Landmark paper that first postulated a link between chromosome missegregation and the origins of cancer.

    Google Scholar 

  19. Nowell, P. & Hungerford, D. Chromosomes of normal and leukemic human leukocytes. J. Natl Cancer Inst. 25, 85 (1960).

    CAS  PubMed  Google Scholar 

  20. Rowley, J. D. Nonrandom chromosomal abnormalities in hematologic disorders of man. Proc. Natl Acad. Sci. USA 72, 152–156 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ben-Neriah, Y., Daley, G. Q., Mes-Masson, A. M., Witte, O. N. & Baltimore, D. The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene. Science 233, 212–214 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Druker, B. J. et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Kallioniemi, A. et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818–821 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Speicher, M. R., Gwyn Ballard, S. & Ward, D. C. Karyotyping human chromosomes by combinatorial multi-fluor FISH. Nature Genet. 12, 368–375 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Schrock, E. et al. Multicolor spectral karyotyping of human chromosomes. Science 273, 494–497 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Press, M. F. et al. HER2/NEU gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J. Clin. Oncol. 15, 2894–2904 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Watanabe, T. et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 344, 1196–1206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Loeb, L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).The author argues that a sustained increase in the rate of genetic alterations per cell division is a prerequisite for the development of cancer within the lifetime of an individual.

    CAS  PubMed  Google Scholar 

  31. Leach, F. S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Umar, A. et al. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J. Biol. Chem. 269, 14367–14370 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Shibata, D., Peinado, M. A., Ionov, Y., Malkhosyan, S. & Perucho, M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nature Genet. 6, 273–281 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Marra, G. & Boland, C. R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Natl Cancer Inst. 87, 1114–1125 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Thibodeau, S. N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Eshleman, J. R. et al. Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene 17, 719–725 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Miyoshi, Y., Iwao, K., Takahashi, Y., Egawa, C. & Noguchi, S. Acceleration of chromosomal instability by loss of BRCA1 expression and p53 abnormality in sporadic breast cancers. Cancer Lett. 159, 211–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Beheshti, B. et al. Evidence of chromosomal instability in prostate cancer determined by spectral karyotyping (SKY) and interphase fish analysis. Neoplasia 3, 62–69 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Eshleman, J. R. et al. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10, 33–37 (1995).

    CAS  PubMed  Google Scholar 

  45. Shih, I. M. et al. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 61, 818–822 (2001).Provides an important clue that CIN might arise very soon after colorectal tumour initiation, leading to profound allelic losses even in very small adenomatous polyps.

    CAS  PubMed  Google Scholar 

  46. Duesberg, P., Rausch, C., Rasnick, D. & Hehlmann, R. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc. Natl Acad. Sci. USA 95, 13692–13697 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Strand, M., Prolla, T. A., Liskay, R. M. & Petes, T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365, 274–276 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Peltomaki, P. & de la Chapelle, A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv. Cancer Res. 71, 93–119 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Spencer, F., Gerring, S. L., Connelly, C. & Hieter, P. Mitotic chromosome transmission fidelity mutants in Saccharomyces cerevisiae. Genetics 124, 237–249 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kinzler, K. W. & Vogelstein, B. The Genetic Basis of Human Cancer (McGraw–Hill, Toronto, 1998).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Abdel-Rahman, W. M. et al. Spectral karyotyping suggests additional subsets of colorectal cancers characterized by pattern of chromosome rearrangement. Proc. Natl Acad. Sci. USA 98, 2538–2543 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Amon, A. The spindle checkpoint. Curr. Opin. Genet. Dev. 9, 69–75 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. Michel, L. S. et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409, 355–359 (2001).Demonstrates that inactivation of a single copy of the MAD2 gene in either human colon cancer cells or in the intact mouse leads to elevated rates of chromosome loss and to late-onset tumours of the mouse lung.

    Article  CAS  PubMed  Google Scholar 

  60. Hartwell, L. H. & Weinert, T. A. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629–634 (1989).

    Article  CAS  PubMed  Google Scholar 

  61. Canman, C. E. Replication checkpoint: preventing mitotic catastrophe. Curr. Biol. 11, R121–R124 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Bunz, F. et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest. 104, 263–269 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. Shah, J. V. & Cleveland, D. W. Waiting for anaphase: Mad2 and the spindle assembly checkpoint. Cell 103, 997–1000 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Page, A. M. & Hieter, P. The anaphase-promoting complex: new subunits and regulators. Annu. Rev. Biochem. 68, 583–609 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. King, R. W., Deshaies, R. J., Peters, J. M. & Kirschner, M. W. How proteolysis drives the cell cycle. Science 274, 1652–1659 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Yanagida, M. Cell cycle mechanisms of sister chromatid separation; roles of Cut1/separin and Cut2/securin. Genes Cells 5, 1–8 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Nasmyth, K., Peters, J. M. & Uhlmann, F. Splitting the chromosome: cutting the ties that bind sister chromatids. Science 288, 1379–1385 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tang, Z., Bharadwaj, R., Li, B. & Yu, H. MAD2-independent inhibition of APC CDC20 by the mitotic checkpoint protein BUBR1. Dev. Cell 1, 227–237 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Sudakin, V., Chen, G. K. T. & 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hoyt, M. A. A new view of the spindle checkpoint. J. Cell Biol. 154, 909–912 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Yamamoto, A., Guacci, V. & Koshland, D. Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s). J. Cell Biol. 133, 99–110 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Funabiki, H., Kumada, K. & Yanagida, M. Fission yeast Cut1 and Cut2 are essential for sister chromatid separation, concentrate along the metaphase spindle and form large complexes. EMBO J. 15, 6617–6628 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ciosk, R. et al. An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 93, 1067–1076 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Kumada, K. et al. Cut1 is loaded onto the spindle by binding to Cut2 and promotes anaphase spindle movement upon Cut2 proteolysis. Curr. Biol. 8, 633–641 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Zou, H., McGarry, T. J., Bernal, T. & Kirschner, M. W. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285, 418–422 (1999).Demonstration that human securin is identical to the pituitary tumour-transforming gene ( PTTG ), a candidate oncogene that is overexpressed in several cancer types.

    Article  CAS  PubMed  Google Scholar 

  84. Uhlmann, F., Wernic, D., Poupart, M.-A., Koonin, E. V. & Nasmyth, K. Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 103, 375–386 (2000).By combining the power of yeast genetics with biochemistry, the authors show that separin is a cohesin-specific protease that is distantly related to the caspase family of cysteine endopeptidases.

    Article  CAS  PubMed  Google Scholar 

  85. Waizenegger, I. C., Hauf, S., Meinke, A. & Peters, J. M. Two distinct pathways remove mammalian cohesin complexes from chromosome arms in prophase and from centromeres in anaphase. Cell 103, 399–410 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Michaelis, C., Ciosk, R. & Nasmyth, K. Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35–45 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Guacci, V., Koshland, D. & Strunnikov, A. A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae. Cell 91, 47–57 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Uhlmann, F. & Nasmyth, K. Cohesion between sister chromatids must be established during DNA replication. Curr. Biol. 8, 1095–1101 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Nasmyth, K. Separating sister chromatids. Trends Biochem. Sci. 24, 98–104 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Stratmann, R. & Lehner, C. F. Separation of sister chromatids in mitosis requires the Drosophila pimples product, a protein degraded after the metaphase/anaphase transition. Cell 84, 25–35 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Leismann, O., Herzig, A., Heidmann, S. & Lehner, C. F. Degradation of Drosophila PIM regulates sister chromatid separation during mitosis. Genes Dev. 14, 2192–2205 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  93. Jensen, S., Segal, M., Clarke, D. J. & Reed, S. I. A novel role of the budding yeast separin Esp1 in anaphase spindle elongation: evidence that proper spindle association of Esp1 is regulated by Pds1. J. Cell Biol. 152, 27–40 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Alexandru, G., Uhlmann, F., Mechtler, K., Poupart, M. A. & Nasmyth, K. Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast. Cell 105, 459–472 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Arnaud, L., Pines, J. & Nigg, E. A. GFP tagging reveals human Polo-like kinase 1 at the kinetochore/centromere region of mitotic chromosomes. Chromosoma 107, 424–429 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).Shows that the mouse Bub1 kinase is involved in the timing of anaphase onset during normal mitosis.

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  100. Wang, X. et al. Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells. Carcinogenesis 21, 2293–2297 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Lee, H. et al. Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, BRCA2. Mol. Cell 4, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. McKeon, F. Killing the umpire: cooperative defects in mitotic checkpoint and BRCA2 genes on the road to transformation. Breast Cancer Res. 1, 8–10 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dominguez, A. et al. hPTTG, a human homologue of rat Pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG. Oncogene 17, 2187–2193 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Saez, C. et al. hPTTG is over-expressed in pituitary adenomas and other primary epithelial neoplasias. Oncogene 18, 5473–5476 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  106. Zur, A. & Brandeis, M. Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis. EMBO J. 20, 792–801 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dobles, M., Liberal, V., Scott, M. L., Benezra, R. & Sorger, P. K. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101, 635–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Kalitsis, P., Earle, E., Fowler, K. J. & Choo, K. H. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev. 14, 2277–2282 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mei, J., Huang, X. & Zhang, P. Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts. Curr. Biol. 11, 1197–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Gibbs, J. B. Mechanism-based target identification and drug discovery in cancer research. Science 287, 1969–1973 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Cahill, D. P., Kinzler, K. W., Vogelstein, B. & Lengauer, C. Genetic instability and Darwinian selection in tumours. Trends Cell Biol. 9, M57–M60 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Bootsma, D., Kraemer, K. H., Cleaver, J. E. & Hoeijmakers, J. H. J. in The Genetic Basis of Human Cancer (eds Kinzler, K. W. & Vogelstein, B.) 245–274 (McGraw–Hill, New York, 1998).

    Google Scholar 

  113. Gowen, L. C., Avrutskaya, A. V., Latour, A. M., Koller, B. H. & Leadon, S. A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281, 1009–1012 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Sharan, S. K. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Boyd, M. R. & Paull, K. D. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev. Res. 34, 91–109 (1995).

    Article  CAS  Google Scholar 

  116. Torrance, C., Agrawal, V., Kinzler, K. W. & Vogelstein, B. Use of isogenic human cancer cells for highthroughput screening and drug discovery. Nature Biotechnol. 19, 940–945 (2001).Description of a novel strategy for drug screening based on isogenic human cancer cell lines.

    Article  CAS  Google Scholar 

  117. Bardelli, A. et al. Carcinogen-specific induction of genetic instability. Proc. Natl Acad. Sci. USA 98, 5770–5775 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank G. Lederer and M. Speicher (University of Munich), W. Saunders and S. M. Gollin (University of Pittsburgh), and K. Mizumoto (Kyushu University) for kindly providing images displayed in figure 2. C.L. is supported by the V Foundation. P.V.J. is a Fellow of the Damon Runyon–Walter Winchell Foundation Cancer Research Fund.

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Authors and Affiliations

  1. The Johns Hopkins Oncology Center, 1650 Orleans Street, Baltimore, 21231, Maryland, USA

    Prasad V. Jallepalli & Christoph Lengauer

Authors
  1. Prasad V. Jallepalli
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  2. Christoph Lengauer
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Correspondence to Prasad V. Jallepalli or Christoph Lengauer.

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DATABASES

CancerNet:

breast cancer

chronic myelogenous leukaemia

colon cancer

oropharyngeal cancer

prostate cancer

 LocusLink:

ABL

Apc

APC

APC/C

ATM

aurora-a

BCR

Brca2

Bub1

BUB1

BUB3

BUBR1

CDC20

CENPE

CHK2

cohesin

MAD1

MAD2

Mad3l

MPS1

p53

securin

separin

survivin

 Medscape DrugInfo:

Gleevec

taxol

 OMIM:

Hereditary nonpolyposis colon cancer

FURTHER INFORMATION

NCI in vitro cell line screening project

Comparative genomic hybridization

DTP Human Tumor Cell Line Screen

Mitelman database of chromosomal aberrations in cancer

Glossary

CYCLIN-DEPENDENT KINASES

Heterodimeric cell-cycle kinases that consist of a catalytic subunit and a larger activating subunit (a cyclin) that is synthesized and degraded in a periodic manner.

AURORA KINASES

A large family of mitotic kinases involved in phosphorylation of histones (and probably other substrates as well); they are overexpressed in some human cancers.

CHROMOSOMAL PASSENGER PROTEINS

These transiently bind to mitotic chromosomes, before being transported to cytoskeletal components of the spindle late in mitosis.

POLO-LIKE KINASES

(PLKs). Mitotic serine–threonine kinases that are involved in many aspects of mitotic regulation.

ANAPHASE-PROMOTING COMPLEX/CYCLOSOME

(APC/C). A large (20S) multiprotein assembly that promotes the degradation of key mitotic regulatory proteins.

ANEUPLOIDY

A chromosome complement that is not a simple multiple of the haploid set.

CENTROSOMES

Paired structures that nucleate the microtubule arrays of the mitotic spindle. They are often abnormal in cancer cells.

SECURIN

An evolutionarily divergent class of anaphase inhibitors; called Pds1 in budding yeast, Cut2 in fission yeast, and PTTG/securin in vertebrates.

KARYOTYPE

A complete description of the chromosomes present in a cell; characterized by numerical and structural abnormalities in most cancers.

COMPARATIVE GENOMIC HYBRIDIZATION

(CGH). A molecular cytogenetic method of screening cells for DNA gains and losses on a chromosomal level. Differentially labelled test and reference DNA are hybridized simultaneously to generate a map of DNA copy number changes.

MULTIPLEX IN SITU HYBRIDIZATION

(M-FISH). Painting of the entire chromosome complement by combinations of five different fluorophores. A combinatorial labelling algorithm allows separation and identification of all chromosomes that are displayed in characteristic pseudocolours. Facilitates the identification of chromosomal aberrations.

SPECTRAL KARYOTYPING

(SKY). Simultaneous visualization of an organism's chromosomes, each labelled with a different colour. This technique is useful for identifying chromosome abnormalities.

MISMATCH REPAIR

A genomic system that detects and repairs incorrectly paired nucleotides that are introduced during DNA replication.

MICROSATELLITE REPEATS

A class of repetitive DNA that is made up of repeats that are 2–8 nucleotides in length. Their mutation is used as a marker of defective mismatch repair.

DYSPLASTIC LESION

The earliest stage in cancer progression, characterized by increased cell proliferation and architectural disarray at the tissue level.

ADENOMATOUS POLYP

A premalignant stage in colorectal cancer that is associated with initial genetic alterations in the tumour-suppressor gene adenomatous polyposis coli (APC) and often the RAS oncogene.

CARCINOMA

The final, invasive stage of evolution of an epithelial cancer.

KINETOCHORE

Specialized assembly of proteins that binds to a region of the chromosome called the centromere.

SISTER CHROMATIDS

The two genetically identical copies of a chromosome synthesized during S phase; they remain closely attached until they undergo segregation to the twin daughter cells at anaphase.

UBIQUITIN-PROTEIN LIGASES

Also called E3 enzymes; they facilitate covalent addition of a polyubiquitin chain to a protein substrate that is being targeted for destruction.

SEPARINS

Large cysteine proteases, also called separases, that catalyse cleavage of cohesin bridges at anaphase.

COHESINS

Multiprotein complexes that link sister chromatids; their proteolytic cleavage is required for sister-chromatid separation.

HAPLOINSUFFICIENCY

A situation in which a loss-of-function phenotype is produced by mutating one allele of a gene in a diploid cell, even though the other allele is wild type.

NUCLEOTIDE EXCISION REPAIR

A system for correcting DNA damage (often inflicted by chemical carcinogens or UV irradiation) by excising and resynthesizing the damaged region.

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Jallepalli, P., Lengauer, C. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 1, 109–117 (2001). https://doi.org/10.1038/35101065

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