Polyploidy: Mechanisms and Cancer Promotion in Hematopoietic and Other Cells

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 676)


Polyploidy, the state of having greater than a diploid content of DNA (e.g., tetraploid, octaploid, etc) has been recognized in a large variety of both, plant and animal cells. Human and murine megakaryocytes, hepatocytes, arterial smooth muscle cells and cardiac myocytes, all develop a certain degree of polyploidy during their normal lifespan. In addition, polyploid cells may be found in some tissues under conditions of stress, including uterine smooth muscle during pregnancy, aortic vascular smooth muscle cells during aging and hypertension, beta-cells in diabetic human or mouse thyroid cells in hyperthyroidism and cells in seminal vesicles with aging. Polyploid cells are also found in malignant tissues in which they are believed to contribute to the development of cells with intermediate DNA content values (e.g., 3n, 4.5n, etc.) (reviewed in refs. 1,2). With the use of micro-array, researchers have demonstrated that genetically identical yeast strains (Saccharomyces cerevisiae) with differences only in ploidy status (from haploid to tetraploid) display a substantial difference in gene expression, including of the G1 cyclins.3 This finding has suggested that DNA content per se might affect cellular functions.


Mitotic Spindle Chromosome Segregation Aurora Kinase Spindle Assembly Spindle Assembly Checkpoint 
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  1. 1.
    Zimmet J, Ravid K. Polyploidy: occurrence in nature, mechanisms and significance for the megakaryocyte-platelet system. Exp Hematol 2000; 28:3–16.PubMedCrossRefGoogle Scholar
  2. 2.
    Ravid K, Lu J, Zimmet JM et al. Roads to polyploidy: the megakaryocyte example. J Cell Physiol 2002; 190:7–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Galitski T, Saldanha AJ, Styles CA et al. Ploidy regulation of gene expression. Science 1999; 285:251–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Storchova Z, Pellman D. From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 2004; 5:45–54.PubMedCrossRefGoogle Scholar
  5. 5.
    Jones MR, Ravid K. Vascular smooth muscle polyploidization as a biomarker for aging and its impact on differential gene expression. J Biol Chem 2004; 279:5306–13.PubMedCrossRefGoogle Scholar
  6. 6.
    Wagner M, Hampel B, Bernhard D et al. Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis. Exp Gerontol 2001; 36:1327–47.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang Z, Zhang Y, Kamen D et al. Cyclin D3 is essential for megakaryocytopoiesis. Blood 1995; 86:3783–8.PubMedGoogle Scholar
  8. 8.
    Zimmet JM, Ladd D, Jackson CW et al. A role for cyclin D3 in the endomitotic cell cycle. Mol Cell Biol 1997; 17:7248–59.PubMedGoogle Scholar
  9. 9.
    Wang Z, Zhang Y, Lu J et al. Mpl ligand enhances the transcription of the cyclin D3 gene: a potential role for Sp1 transcription factor. Blood 1999; 93:4208–21.PubMedGoogle Scholar
  10. 10.
    Malkin D, Brown EJ, Zipursky A. The role of p53 in megakaryocyte differentiation and the megakaryocytic leukemias of Down syndrome. Cancer Genet Cytogenet 2000; 116:1–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Stewart ZA, Leach SD, Pietenpol JA. p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption. Mol Cell Biol 1999; 19:205–15.PubMedGoogle Scholar
  12. 12.
    Mantel C, Braun SE, Reid S et al. p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy and relaxed microtubule damage checkpoints in human hematopoietic cells. Blood 1999; 93:1390–8.PubMedGoogle Scholar
  13. 13.
    Dethloff LA, de la Iglesia FA. Chemical-induced hepatocyte ploidy. Toxicol Appl Pharmacol 1998; 150:443.PubMedCrossRefGoogle Scholar
  14. 14.
    Gupta S. Hepatic polyploidy and liver growth control. Semin Cancer Biol 2000; 10:161–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Gandillet A, Alexandre E, Royer C et al. Hepatocyte ploidy in regenerating livers after partial hepatectomy, drug-induced necrosis and cirrhosis. Eur Surg Res 2003; 35:148–60.PubMedCrossRefGoogle Scholar
  16. 16.
    Oberringer M, Lothschutz D, Jennewein M et al. Centrosome multiplication accompanies a transient clustering of polyploid cells during tissue repair. Mol Cell Biol Res Commun 1999; 2:190–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Chobanian AV, Prescott MF, Haudenschild CC. Recent advances in molecular pathology. The effects of hypertension on the arterial wall. Exp Mol Pathol 1984; 41:153–69.PubMedCrossRefGoogle Scholar
  18. 18.
    Hixon ML, Obejero-Paz C, Muro-Cacho C et al. Cks1 mediates vascular smooth muscle cell polyploidization. J Biol Chem 2000; 275:40434–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Edgar BA, Orr-Weaver TL. Endoreplication cell cycles: more for less. Cell 2001; 105:297–306.PubMedCrossRefGoogle Scholar
  20. 20.
    Galipeau PC, Cowan DS, Sanchez CA et al. 17p (p53) allelic losses, 4N (G2/tetraploid) populations and progression to aneuploidy in Barrett’s esophagus. Proc Natl Acad Sci USA 1996; 93:7081–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Hauf S, Cole RW, LaTerra 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 2003; 161:281–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Shin HJ, Baek KH, Jeon AH et al. Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability. Cancer Cell 2003; 4:483–97.PubMedCrossRefGoogle Scholar
  23. 23.
    Meraldi P, Honda R, Nigg EA. Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev 2004; 14:29–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 2004; 5:429–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Kusuzaki K, Takeshita H, Murata H et al. Polyploidization induced by acridine orange in mouse osteosarcoma cells. Anticancer Res 2000; 20:965–70.PubMedGoogle Scholar
  26. 26.
    Verdoodt B, Decordier I, Geleyns K et al. Induction of polyploidy and apoptosis after exposure to high concentrations of the spindle poison nocodazole. Mutagenesis 1999; 14:513–20.PubMedCrossRefGoogle Scholar
  27. 27.
    Ivanov A, Cragg MS, Erenpreisa J et al. Endopolyploid cells produced after severe genotoxic damage have the potential to repair DNA double strand breaks. J Cell Sci 2003; 116:4095–106.PubMedCrossRefGoogle Scholar
  28. 28.
    Dai W, Wang Q, Liu T et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res 2004; 64:440–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Margolis RL, Lohez OD, Andreassen PR. G1 tetraploidy checkpoint and the suppression of tumorigenesis. J Cell Biochem 2003; 88:673–83.PubMedCrossRefGoogle Scholar
  30. 30.
    Meraldi P, Honda R, Nigg EA. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J 2002; 21:483–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Brinkley BR. Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol 2001; 11:18–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Cahill DP, Lengauer C, Yu J et al. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 392:300–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Nowak MA, Komarova NL, Sengupta A et al. The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA 2002; 99:16226–31.PubMedCrossRefGoogle Scholar
  34. 34.
    Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature 2004; 432:338–41.PubMedCrossRefGoogle Scholar
  35. 35.
    Duesberg P, Stindl R, Hehlmann R. Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proc Natl Acad Sci USA 2000; 97:14295–300.PubMedCrossRefGoogle Scholar
  36. 36.
    Roh M, Gary B, Song C et al. Overexpression of the oncogenic kinase Pim-1 leads to genomic instability. Cancer Res 2003; 63:8079–84.PubMedGoogle Scholar
  37. 37.
    Doherty SC, McKeown SR, McKelvey-Martin V et al. Cell cycle checkpoint function in bladder cancer. J Natl Cancer Inst 2003; 95:1859–68.PubMedCrossRefGoogle Scholar
  38. 38.
    Lothschutz D, Jennewein M, Pahl S et al. Polyploidization and centrosome hyperamplification in inflammatory bronchi. Inflamm Res 2002; 51:416–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Gunawan B, Bergmann F, Braun S et al. Polyploidization and losses of chromosomes 1, 2, 6, 10, 13 and 17 in three cases of chromophobe renal cell carcinomas. Cancer Genet Cytogenet 1999; 110:57–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Kaplan SS, Rybka WB, Blom J et al. Tetraploidy in acute myeloid leukemia secondary to large cell lymphoma. Leuk Lymphoma 1998; 31:617–23.PubMedGoogle Scholar
  41. 41.
    Parry EM, Ulucan H, Wyllie FS et al. Segregational fidelity of chromosomes in human thyroid tumour cells. Chromosoma 1998; 107:491–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Borre M, Hoyer M, Nerstrom B et al. DNA ploidy and survival of patients with clinically localized prostate cancer treated without intent to cure. Prostate 1998; 36:244–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Lemez P, Michalova K, Zemanova Z et al. Three cases of near-tetraploid acute myeloid leukemias originating in pluripotent myeloid progenitors. Leuk Res 1998; 22:581–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Takanishi DM Jr, Hart J, Covarelli P et al. Ploidy as a prognostic feature in colonic adenocarcinoma. Arch Surg 1996; 131:587–92.PubMedCrossRefGoogle Scholar
  45. 45.
    Park SH, Maeda T, Mohapatra G et al. Heterogeneity, polyploidy, aneusomy and 9p deletion in human glioblastoma multiforme. Cancer Genet Cytogenet 1995; 83:127–35.PubMedCrossRefGoogle Scholar
  46. 46.
    Li YS, Fan YS, Armstrong RF. Endoreduplication and telomeric association in a choroid plexus carcinoma. Cancer Genet Cytogenet 1996; 87:7–10.PubMedCrossRefGoogle Scholar
  47. 47.
    Patel D, Incassati A, Wang N et al. Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res 2004; 64:1299–306.PubMedCrossRefGoogle Scholar
  48. 48.
    Teixeira MR, Heim S. Multiple numerical chromosome aberrations in cancer: what are their causes and what are their consequences? Semin Cancer Biol 2005; 15:3–12.PubMedCrossRefGoogle Scholar
  49. 49.
    Fabarius A, Hehlmann R, Duesberg PH. Instability of chromosome structure in cancer cells increases exponentially with degrees of aneuploidy. Cancer Genet Cytogenet 2003; 143:59–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Nigg EA. Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002; 2:815–25.PubMedCrossRefGoogle Scholar
  51. 51.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759–67.PubMedCrossRefGoogle Scholar
  53. 53.
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396:643–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Duesberg P, Rausch C, Rasnick D. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci USA 1998; 95:13692–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001; 1:157–62.PubMedCrossRefGoogle Scholar
  56. 56.
    Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002; 347:1593–603.PubMedCrossRefGoogle Scholar
  57. 57.
    Soto AM, Sonnenschein C. The somatic mutation theory of cancer: growing problems with the paradigm? Bioessays 2004; 26:1097–107.PubMedCrossRefGoogle Scholar
  58. 58.
    Loeb LA. A mutator phenotype in cancer. Cancer Res 2001; 61:3230–9.PubMedGoogle Scholar
  59. 59.
    Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991; 51:3075–9.PubMedGoogle Scholar
  60. 60.
    Loeb LA, Loeb KR, Anderson JP. Multiple mutations and cancer. Proc Natl Acad Sci USA 2003; 100:776–81.PubMedCrossRefGoogle Scholar
  61. 61.
    Bielas JH, Loeb LA. Mutator phenotype in cancer: Timing and perspectives. Environ Mol Mutagen 2005.Google Scholar
  62. 62.
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature 1997; 386:623–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Cahill DP, Kinzler KW, Vogelstein B. Genetic instability and darwinian selection in tumours. Trends Cell Biol 1999; 9:M57–60.PubMedCrossRefGoogle Scholar
  64. 64.
    Lengauer C. Aneuploidy and genetic instability in cancer. Semin Cancer Biol 2005; 15:1.PubMedCrossRefGoogle Scholar
  65. 65.
    Hanks S, Coleman K, Reid S et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 2004; 36:1159–61.PubMedCrossRefGoogle Scholar
  66. 66.
    Duesberg P, Li R. Multistep carcinogenesis: a chain reaction of aneuploidizations. Cell Cycle 2003; 2:202–10.PubMedCrossRefGoogle Scholar
  67. 67.
    Sharpless NE, DePinho RA. Telomeres, stem cells, senescence and cancer. J Clin Invest 2004; 113:160–8.PubMedGoogle Scholar
  68. 68.
    Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001; 2:21–32.PubMedCrossRefGoogle Scholar
  69. 69.
    Nasmyth K. Segregating sister genomes: the molecular biology of chromosome separation. Science 2002; 297:559–65.PubMedCrossRefGoogle Scholar
  70. 70.
    Gisselsson D, Pettersson L, Hoglund M et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci USA 2000; 97:5357–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Fishman GI. Timing is everything in life: conditional transgene expression in the cardiovascular system. Circ Res 1998; 82:837–44.PubMedGoogle Scholar
  72. 72.
    Katayama H, Brinkley WR, Sen S. The Aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev 2003; 22:451–64.PubMedCrossRefGoogle Scholar
  73. 73.
    Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004; 51:1–28.PubMedCrossRefGoogle Scholar
  74. 74.
    Al-Hajj M, Wicha MS, Benito-Hernandez A et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100:3983–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Bissell MJ, Labarge MA. Context, tissue plasticity and cancer; Are tumor stem cells also regulated by the microenvironment? Cancer Cell 2005; 7:17–23.PubMedGoogle Scholar
  76. 76.
    Deng G, Lu Y, Zlotnikov G et al. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 1996; 274:2057–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Smith GH, Boulanger CA. Mammary stem cell repertoire: new insights in aging epithelial populations. Mech Ageing Dev 2002; 123:1505–19.PubMedCrossRefGoogle Scholar
  78. 78.
    Wang X, Willenbring H, Akkari Y et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003; 422:897–901.PubMedCrossRefGoogle Scholar
  79. 79.
    Vagnarelli P, Earnshaw WC. Chromosomal passengers: the four-dimensional regulation of mitotic events. Chromosoma 2004; 113:211–22.PubMedCrossRefGoogle Scholar
  80. 80.
    Ota T, Suto S, Katayama H et al. Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res 2002; 62:5168–77.PubMedGoogle Scholar
  81. 81.
    Adams RR, Eckley DM, Vagnarelli P et al. Human INCENP colocalizes with the Aurora-B/AIRK2 kinase on chromosomes and is overexpressed in tumour cells. Chromosoma 2001; 110:65–74.PubMedCrossRefGoogle Scholar
  82. 82.
    Ainsztein AM, Kandels-Lewis SE, Mackay AM et al. INCENP centromere and spindle targeting: identification of essential conserved motifs and involvement of heterochromatin protein HP1. J Cell Biol 1998; 143:1763–74.PubMedCrossRefGoogle Scholar
  83. 83.
    Cutts SM, Fowler KJ, Kile BT et al. Defective chromosome segregation, microtubule bundling and nuclear bridging in inner centromere protein gene (Incenp)-disrupted mice. Hum Mol Genet 1999; 8:1145–55.PubMedCrossRefGoogle Scholar
  84. 84.
    Bishop JD, Schumacher JM. Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the Aurora B Kinase stimulates Aurora B kinase activity. J Biol Chem 2002; 277:27577–80.PubMedCrossRefGoogle Scholar
  85. 85.
    Adams RR, Maiato H, Earnshaw WC. Essential roles of Drosophila inner centromere protein (INCENP) and aurora B in histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction and chromosome segregation. J Cell Biol 2001; 153:865–80.PubMedCrossRefGoogle Scholar
  86. 86.
    Greaves S. A roar for INCENP. Nat Cell Biol 2001; 3:E14.PubMedCrossRefGoogle Scholar
  87. 87.
    Cooke CA, Heck MM, Earnshaw WC. The inner centromere protein (INCENP) antigens: movement from inner centromere to midbody during mitosis. J Cell Biol 1987; 105:2053–67.PubMedCrossRefGoogle Scholar
  88. 88.
    Wheatley SP, Carvalho A, Vagnarelli P. INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis. Curr Biol 2001; 11:886–90.PubMedCrossRefGoogle Scholar
  89. 89.
    Vagnarelli PB, Earnshaw WC. INCENP loss from an inactive centromere correlates with the loss of sister chromatid cohesion. Chromosoma 2001; 110:393–401.PubMedCrossRefGoogle Scholar
  90. 90.
    Pereira G, Schiebel E. Separase regulates INCENP-Aurora B anaphase spindle function through Cdc14. Science 2003; 302:2120–4.PubMedCrossRefGoogle Scholar
  91. 91.
    Adam P, Regan C, Hautmann M. Positive-and negative-acting Kruppel-like transcription factors bind a transforming growth factor β?control element required for expression of the smooth muscle cell differentiation marker SM22α?in vivo. J Biol Chem 2000; 275:37798–37806.PubMedCrossRefGoogle Scholar
  92. 92.
    Gassmann R, Carvalho A, Henzing AJ et al. Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J Cell Biol 2004; 166:179–91.PubMedCrossRefGoogle Scholar
  93. 93.
    Sampath SC, Ohi R, Leismann O et al. The chromosomal passenger complex is required for chromatininduced microtubule stabilization and spindle assembly. Cell 2004; 118:187–202.PubMedCrossRefGoogle Scholar
  94. 94.
    Chantalat L, Skoufias DA, Kleman JP et al. Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Mol Cell 2000; 6:183–9.PubMedGoogle Scholar
  95. 95.
    Muchmore SW, Chen J, Jakob C et al. Crystal structure and mutagenic analysis of the inhibitor-of-apoptosis protein survivin. Mol Cell 2000; 6:173–82.PubMedGoogle Scholar
  96. 96.
    Verdecia MA, Huang H, Dutil E et al. Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement. Nat Struct Biol 2000; 7:602–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Zhao J, Tenev T, Martins LM et al. The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner. J Cell Sci 2000; 113(Pt23):4363–71.PubMedGoogle Scholar
  98. 98.
    Fukuda S, Pelus LM. Elevation of Survivin levels by hematopoietic growth factors occurs in quiescent CD34+ hematopoietic stem and progenitor cells before cell cycle entry. Cell Cycle 2002; 1:322–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Tran J, Rak J, Sheehan C et al. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem Biophys Res Commun 1999; 264:781–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Blanc-Brude OP, Yu J, Simosa H et al. Inhibitor of apoptosis protein survivin regulates vascular injury. Nat Med 2002; 8:987–94.PubMedCrossRefGoogle Scholar
  101. 101.
    Kobayashi K, Hatano M, Otaki M. Expression of a murine homologue of the inhibitor of apoptosis protein is related to cell proliferation. Proc Natl Acad Sci USA 1999; 96:1457–62.PubMedCrossRefGoogle Scholar
  102. 102.
    Li F. Role of survivin and its splice variants in tumorigenesis. Br J Cancer 2005; 92:212–6.PubMedGoogle Scholar
  103. 103.
    Conway EM, Pollefeyt S, Cornelissen J et al. Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions. Blood 2000; 95:1435–42.PubMedGoogle Scholar
  104. 104.
    Song Z, Liu S, He H et al. A single amino acid change (Asp 53 →Ala53) converts Survivin from anti-apoptotic to pro-apoptotic. Mol Biol Cell 2004; 15:1287–96.PubMedCrossRefGoogle Scholar
  105. 105.
    Krieg A, Mahotka C, Krieg T et al. Expression of different survivin variants in gastric carcinomas: first clues to a role of survivin-2B in tumour progression. Br J Cancer 2002; 86:737–43.PubMedCrossRefGoogle Scholar
  106. 106.
    Fortugno P, Wall NR, Giodini A et al. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J Cell Sci 2002; 115:575–85.PubMedGoogle Scholar
  107. 107.
    Wheatley SP, Henzing AJ, Dodson H et al. Aurora-B phosphorylation in vitro identifies a residue of survivin that is essential for its localization and binding to inner centromere protein (INCENP) in vivo. J Biol Chem 2004; 279:5655–60.PubMedCrossRefGoogle Scholar
  108. 108.
    Uren AG, Wong L, Pakusch M et al. Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol 2000; 10:1319–28.PubMedCrossRefGoogle Scholar
  109. 109.
    Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3:917–21.PubMedCrossRefGoogle Scholar
  110. 110.
    Grossman D, Kim PJ, Blanc-Brude OP et al. Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clin Invest 2001; 108:991–9.PubMedGoogle Scholar
  111. 111.
    Suzuki A, Ito T, Kawano H et al. Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene 2000; 19:1346–53.PubMedCrossRefGoogle Scholar
  112. 112.
    Suzuki A, Hayashida M, Ito T et al. Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16(INK4a) and Cdk2/cyclin E complex activation. Oncogene 2000; 19:3225–34.PubMedCrossRefGoogle Scholar
  113. 113.
    Nagata Y, Jones MR, Nguyen HG et al. Vascular smooth muscle cell polyploidization involves changes in chromosome passenger proteins and an endomitotic cell cycle. Exp Cell Res 2005; 305:277–91.PubMedCrossRefGoogle Scholar
  114. 114.
    Geddis AE, Kaushansky K. Megakaryocytes express functional Aurora-B kinase in endomitosis. Blood 2004; 104:1017–24.PubMedCrossRefGoogle Scholar
  115. 115.
    Baccini V, Roy L, Vitrat N et al. Role of p21(Cip1/Waf1) in cell-cycle exit of endomitotic megakaryocytes. Blood 2001; 98:3274–82.PubMedCrossRefGoogle Scholar
  116. 116.
    Roy L, Coullin P, Vitrat N et al. Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes. Blood 2001; 97:2238–47.PubMedCrossRefGoogle Scholar
  117. 117.
    Song Z, Yao X, Wu M. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem 2003; 278:23130–40.PubMedCrossRefGoogle Scholar
  118. 118.
    Marusawa H, Matsuzawa S, Welsh K et al. HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J 2003; 22:2729–40.PubMedCrossRefGoogle Scholar
  119. 119.
    Castedo M, Perfettini JL, Roumier T et al. Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004; 23:2825–37.PubMedCrossRefGoogle Scholar
  120. 120.
    Carter BZ, Wang RY, Schober WD et al. Targeting Survivin expression induces cell proliferation defect and subsequent cell death involving mitochondrial pathway in myeloid leukemic cells. Cell Cycle 2003; 2:488–93.PubMedCrossRefGoogle Scholar
  121. 121.
    Li F, Ackermann EJ, Bennett CF et al. Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1999; 1:461–6.PubMedCrossRefGoogle Scholar
  122. 122.
    Adams RR, Carmena M, Earnshaw WC. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 2001; 11:49–54.PubMedCrossRefGoogle Scholar
  123. 123.
    Castro A, Arlot-Bonnemains Y, Vigneron S et al. APC/Fizzy-Related targets Aurora-A kinase for proteolysis. EMBO Rep 2002; 3:457–62.PubMedCrossRefGoogle Scholar
  124. 124.
    Andrews PD, Knatko E, Moore WJ et al. Mitotic mechanics: the auroras come into view. Curr Opin Cell Biol 2003; 15:672–83.PubMedCrossRefGoogle Scholar
  125. 125.
    Ducat D, Zheng Y. Aurora kinases in spindle assembly and chromosome segregation. Exp Cell Res 2004; 301:60–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, INCENP and survivin in mitosis. Mol Biol Cell 2003; 14:3325–41.PubMedCrossRefGoogle Scholar
  127. 127.
    Kang J, Cheeseman IM, Kallstrom G et al. Functional cooperation of Dam1, Ipl1 and the inner centromere protein (INCENP)-related protein Sli15 during chromosome segregation. J Cell Biol 2001; 155:763–74.PubMedCrossRefGoogle Scholar
  128. 128.
    Chen J, Jin S, Tahir SK et al. Survivin enhances Aurora-B kinase activity and localizes Aurora-B in human cells. J Biol Chem 2003; 278:486–90.PubMedCrossRefGoogle Scholar
  129. 129.
    Nguyen HG, Chinnappan D, Urano T. Mechanism of Aurora-B Degradation and Its Dependency on Intact KEN and A-Boxes: Identification of an Aneuploidy-Promoting Property. Mol Cell Biol 2005; 25:4977–92.PubMedCrossRefGoogle Scholar
  130. 130.
    Scrittori L, Skoufias DA, Hans F et al. A small C-terminal sequence of Aurora B is responsible for localization and function. Mol Biol Cell 2005; 16:292–305.PubMedCrossRefGoogle Scholar
  131. 131.
    Kallio MJ, McCleland ML, Stukenberg PT. Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint and perturbs microtubule dynamics in mitosis. Curr Biol, 2002; 12:900–5.PubMedCrossRefGoogle Scholar
  132. 132.
    Lan W, Zhang X, Kline-Smith SL et al. Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity. Curr Biol 2004; 14:273–86.PubMedGoogle Scholar
  133. 133.
    Andrews PD, Ovechkina Y, Morrice N et al. Aurora B regulates MCAK at the mitotic centromere. Dev Cell 2004; 6:253–68.PubMedCrossRefGoogle Scholar
  134. 134.
    Sugiyama K, Sugiura K, Hara T et al. Aurora-B associated protein phosphatases as negative regulators of kinase activation. Oncogene 2002; 21:3103–11.PubMedCrossRefGoogle Scholar
  135. 135.
    Murnion ME, Adams RR, Callister DM et al. Chromatin-associated protein phosphatase 1 regulates aurora-B and histone H3 phosphorylation. J Biol Chem 2001; 276:26656–65.PubMedCrossRefGoogle Scholar
  136. 136.
    Biggins S, Severin FF, Bhalla N et al. The conserved protein kinase Ipl1 regulates microtubule binding to kinetochores in budding yeast. Genes Dev 1999; 13:532–44.PubMedCrossRefGoogle Scholar
  137. 137.
    Tanaka TU, Rachidi N, Janke C et al. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 2002; 108:317–29.PubMedCrossRefGoogle Scholar
  138. 138.
    Pinsky BA, Tatsutani SY, Collins KA et al. An Mtw1 complex promotes kinetochore biorientation that is monitored by the Ipl1/Aurora protein kinase. Dev Cell 2003; 5:735–45.PubMedCrossRefGoogle Scholar
  139. 139.
    Dewar H, Tanaka K, Nasmyth K. Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle. Nature 2004; 428:93–7.PubMedCrossRefGoogle Scholar
  140. 140.
    Cheeseman IM, Anderson S, Jwa M et al. Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p. Cell 2002; 111:163–72.PubMedCrossRefGoogle Scholar
  141. 141.
    Carvalho A, Carmena M, Sambade C et al. Survivin is required for stable checkpoint activation in taxol-treated HeLa cells. J Cell Sci 2003; 116:2987–98.PubMedCrossRefGoogle Scholar
  142. 142.
    Ditchfield C, Johnson VL, Tighe A et al. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2 and Cenp-E to kinetochores. J Cell Biol 2003; 161:267–80.PubMedCrossRefGoogle Scholar
  143. 143.
    Lampson MA, Renduchitala K, Khodjakov A et al. Correcting improper chromosome-spindle attachments during cell division. Nat Cell Biol 2004; 6:232–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Murata-Hori M, Wang YL. The kinase activity of aurora B is required for kinetochore-microtubule interactions during mitosis. Curr Biol 2002; 12:894–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Vigneron S, Prieto S, Bernis C et al. Kinetochore localization of spindle checkpoint proteins: who controls whom? Mol Biol Cell 2004; 15:4584–96.PubMedCrossRefGoogle Scholar
  146. 146.
    Goto H, Yasui Y, Kawajiri A et al. Aurora-B regulates the cleavage furrow-specific vimentin phosphorylation in the cytokinetic process. J Biol Chem 2003; 278:8526–8530.PubMedCrossRefGoogle Scholar
  147. 147.
    Terada Y. Role of chromosomal passenger complex in chromosome segregation and cytokinesis. Cell Struct Funct 2001; 26:653–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Kimura M, Kotani S, Hattori T et al. Cell cycle-dependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1. J Biol Chem, 1997; 272:13766–71.PubMedCrossRefGoogle Scholar
  149. 149.
    Terada Y, Tatsuka M, Suzuki F et al. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J 1998; 17:667–76.PubMedCrossRefGoogle Scholar
  150. 150.
    Giet R, Glover DM. 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 2001; 152:669–82.PubMedCrossRefGoogle Scholar
  151. 151.
    Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4:927–36.PubMedCrossRefGoogle Scholar
  152. 152.
    Zhang Y, Nagata Y, Yu G et al. Aberrant quantity and localization of Aurora-B/AIM-1 and survivin during megakaryocyte polyploidization and the consequences of Aurora-B/AIM-1-deregulated expression. Blood 2004; 103:3717–26.PubMedCrossRefGoogle Scholar
  153. 153.
    Terada Y, Tatsuka M, Suzuki F et al. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J 1998; 17:667–676.PubMedCrossRefGoogle Scholar
  154. 154.
    Goepfert TM, Brinkley BR. The centrosome-associated Aurora/Ipl-like kinase family. Curr Top Dev Biol 2000; 49:331–42.PubMedCrossRefGoogle Scholar
  155. 155.
    Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003; 4:842–54.PubMedCrossRefGoogle Scholar
  156. 156.
    Bischoff JR, Anderson L, Zhu Y et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998; 17:3052–65.PubMedCrossRefGoogle Scholar
  157. 157.
    Tatsuka M, Katayama H, Ota T et al. Multinuclearity and increased ploidy caused by overexpression of the aurora-and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 1998; 58:4811–6.PubMedGoogle Scholar
  158. 158.
    Giet R, Prigent C. Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci 1999; 112(Pt 21):3591–601.PubMedGoogle Scholar
  159. 159.
    Altieri DC. Survivin in apoptosis control and cell cycle regulation in cancer. Prog Cell Cycle Res 2003; 5:447–52.PubMedGoogle Scholar
  160. 160.
    Sen S, Zhou H, Zhang RD et al. Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 2002; 94:1320–9.PubMedCrossRefGoogle Scholar
  161. 161.
    Fujita M, Mizuno M, Nagasaka T et al. Aurora-B dysfunction of multinucleated giant cells in glioma detected by site-specific phosphorylated antibodies. J Neurosurg 2004; 101:1012–7.PubMedCrossRefGoogle Scholar
  162. 162.
    Tatsuka M, Sato S, Kitajima S et al. Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene 2005; 24:1122–7.PubMedCrossRefGoogle Scholar
  163. 163.
    Sorrentino R, Libertini S, Pallante PL et al. Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 2005; 90:928–35.PubMedCrossRefGoogle Scholar
  164. 164.
    Mayer F, Stoop H, Sen S et al. Aneuploidy of human testicular germ cell tumors is associated with amplification of centrosomes. Oncogene 2003; 22:3859–66.PubMedCrossRefGoogle Scholar
  165. 165.
    Araki K, Nozaki K, Ueba T et al. High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol 2004; 67:53–64.PubMedCrossRefGoogle Scholar
  166. 166.
    Doggrell SA. Dawn of Aurora kinase inhibitors as anticancer drugs. Expert Opin Investig Drugs 2004; 13:1199–201.PubMedCrossRefGoogle Scholar
  167. 167.
    Harrington EA, Bebbington D, Moore J et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004; 10:262–7.PubMedCrossRefGoogle Scholar
  168. 168.
    Gadea BB, Ruderman JV. Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Mol Biol Cell 2005; 16:1305–18.PubMedCrossRefGoogle Scholar
  169. 169.
    Bischoff JR. Plowman GD. The Aurora/Ipl1p kinase family: regulators of chromosome segregation and cytokinesis. Trends Cell Biol 1999; 9:454–9.PubMedCrossRefGoogle Scholar
  170. 170.
    Descamps S, Prigent C. Two mammalian mitotic aurora kinases: who’s who? Sci STKE 2001; PE1.Google Scholar
  171. 171.
    Cong XL, Han ZC. Survivin and leukemia. Int J Hematol 2004; 80:232–8.PubMedCrossRefGoogle Scholar
  172. 172.
    Choi N, Baumann M, Flentjie M et al. Predictive factors in radiotherapy for nonsmall cell lung cancer: present status. Lung Cancer 2001; 31:43–56.PubMedCrossRefGoogle Scholar
  173. 173.
    Sasaki T, Lopes MB, Hankins GR et al. Expression of survivin, an inhibitor of apoptosis protein, in tumors of the nervous system. Acta Neuropathol (Berl) 2002; 104:105–9.CrossRefGoogle Scholar
  174. 174.
    Sui L, Dong Y, Ohno M et al. Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors. Int J Oncol 2002; 21:315–20.PubMedGoogle Scholar
  175. 175.
    Kajiwara Y, Yamasaki F, Hama S et al. Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 2003; 97:1077–83.PubMedCrossRefGoogle Scholar
  176. 176.
    Nakayama K, Kamihira S. Survivin an important determinant for prognosis in adult T-cell leukemia: a novel biomarker in practical hemato-oncology. Leuk Lymphoma 2002; 43:2249–55.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Department of Biochemistry and Whitaker Cardiovascular InstituteBoston University School of MedicineBostonUSA

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