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Caspase-Independent Mitotic Death

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Essentials of Apoptosis

Abstract

The spindle checkpoint ensures proper chromosomal segregation by monitoring kinetochore–microtubule attachment. A failure of this checkpoint causes aneuploidy, which leads to tumorigenesis. The cell death that prevents the aneuploidy caused by failure of the spindle checkpoint is yet unknown. We have identified a novel type of mitotic cell death, which we term caspase-independent mitotic death (CIMD). When BUB1 but not MAD2 is depleted, CIMD is induced by conditions that activate the spindle checkpoint [e.g., cold shock or treatment with microtubule inhibitors or 17-AAG (17-allylaminogeldanamycin)]. CIMD depends on the apoptosis-inducing factor (AIF) and endonuclease G (Endo G), which are effectors of caspase-independent cell death. CIMD also depends on p73, a homologue of p53, but not on p53. When BUB1 is completely depleted, aneuploidy occurs instead of CIMD. Therefore, CIMD may be the programmed cell death that protects cells from aneuploidy by inducing the death of cells prone to substantial chromosome missegregation.

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References

  1. Wang X, Cheung HW, Chun AC, Jin DY, Wong YC. Mitotic checkpoint defects in human cancers and their implications to chemotherapy. Front Biosci 2008;13:2103–14.

    Article  PubMed  CAS  Google Scholar 

  2. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525–32.

    Article  PubMed  CAS  Google Scholar 

  3. Amon A. The spindle checkpoint. Curr Opin Genet Dev 1999;9:69–75.

    Article  PubMed  CAS  Google Scholar 

  4. Li R, Murray AW. Feedback control of mitosis in budding yeast. Cell 1991;66:519–31.

    Article  PubMed  CAS  Google Scholar 

  5. Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 1991;66:507–17.

    Article  PubMed  CAS  Google Scholar 

  6. Wells WA, Murray AW. Aberrantly segregating centromeres activate the spindle assembly checkpoint in budding yeast. J Cell Biol 1996;133:75–84.

    Article  PubMed  CAS  Google Scholar 

  7. Kitagawa K, Hieter P. Evolutionary conservation between budding yeast and human kinetochores. Nat Rev Mol Cell Biol 2001;2:678–87.

    Article  PubMed  CAS  Google Scholar 

  8. Cahill DP, Lengauer C, Yu J, et al. Mutations of mitotic checkpoint genes in human cancers. Nature 1998;392:300–3.

    Article  PubMed  CAS  Google Scholar 

  9. Ohshima K, Haraoka S, Yoshioka S, et al. Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma. Cancer Lett 2000;158:141–50.

    Article  PubMed  CAS  Google Scholar 

  10. Ru HY, Chen RL, Lu WC, Chen JH. hBUB1 defects in leukemia and lymphoma cells. Oncogene 2002;21:4673–9.

    Article  PubMed  CAS  Google Scholar 

  11. Tsukasaki K, Miller CW, Greenspun E, et al. Mutations in the mitotic check point gene, MAD1L1, in human cancers. Oncogene 2001;20:3301–5.

    Article  PubMed  CAS  Google Scholar 

  12. Shigeishi H, Oue N, Kuniyasu H, et al. Expression of Bub1 gene correlates with tumor proliferating activity in human gastric carcinomas. Pathobiology 2001;69:24–9.

    Article  PubMed  CAS  Google Scholar 

  13. Saeki A, Tamura S, Ito N, et al. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer 2002;94:2047–54.

    Article  PubMed  CAS  Google Scholar 

  14. Wang X, Jin DY, Ng RW, et al. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res 2002;62:1662–8.

    PubMed  CAS  Google Scholar 

  15. Yoon DS, Wersto RP, Zhou W, et al. Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am J Pathol 2002;161:391–7.

    Article  PubMed  Google Scholar 

  16. Michel LS, Liberal V, Chatterjee A, et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 2001;409:355–9.

    Article  PubMed  CAS  Google Scholar 

  17. Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van Deursen JM. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol 2003;160:341–53.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. Perez de Castro I, de Carcer G, Malumbres M. A census of mitotic cancer genes: New insights into tumor cell biology and cancer therapy. Carcinogenesis 2007;28:899–912.

    Article  PubMed  CAS  Google Scholar 

  20. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 2006;38:1043–8.

    Article  PubMed  CAS  Google Scholar 

  21. Basu J, Bousbaa H, Logarinho E, et al. Mutations in the essential spindle checkpoint gene bub1 cause chromosome missegregation and fail to block apoptosis in Drosophila. J Cell Biol 1999;146:13–28.

    PubMed  CAS  Google Scholar 

  22. Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 2000;101:635–45.

    Article  PubMed  CAS  Google Scholar 

  23. Burds AA, Lutum AS, Sorger PK. Generating chromosome instability through the simultaneous deletion of Mad2 and p53. Proc Natl Acad Sci USA 2005;102:11296–301.

    Article  PubMed  CAS  Google Scholar 

  24. Niikura Y, Dixit A, Scott R, Perkins G, Kitagawa K. BUB1 mediation of caspase-independent mitotic death determines cell fate. J Cell Biol 2007;178:283–96.

    Article  PubMed  CAS  Google Scholar 

  25. Rieder CL, Maiato H. Stuck in division or passing through: What happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 2004;7:637–51.

    Article  PubMed  CAS  Google Scholar 

  26. Mollinedo F, Gajate C. Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 2003;8:413–50.

    Article  PubMed  CAS  Google Scholar 

  27. Blank M, Lerenthal Y, Mittelman L, Shiloh Y. Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage. J Cell Biol 2006;174:195–206.

    Article  PubMed  CAS  Google Scholar 

  28. Burns TF, Fei P, Scata KA, Dicker DT, El-Deiry WS. Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells. Mol Cell Biol 2003;23:5556–71.

    Article  PubMed  CAS  Google Scholar 

  29. DeLuca JG, Moree B, Hickey JM, Kilmartin JV, Salmon ED. hNuf2 inhibition blocks stable kinetochore-microtubule attachment and induces mitotic cell death in HeLa cells. J Cell Biol 2002;159:549–55.

    Article  PubMed  CAS  Google Scholar 

  30. Woods CM, Zhu J, McQueney PA, Bollag D, Lazarides E. Taxol-induced mitotic block triggers rapid onset of a p53-independent apoptotic pathway. Mol Med 1995;1:506–26.

    PubMed  CAS  Google Scholar 

  31. Yang Z, Guo J, Chen Q, Ding C, Du J, Zhu X. Silencing mitosin induces misaligned chromosomes, premature chromosome decondensation before anaphase onset, and mitotic cell death. Mol Cell Biol 2005;25:4062–74.

    Article  PubMed  CAS  Google Scholar 

  32. Niikura Y, Ohta S, Vandenbeldt KJ, Abdulle R, McEwen BF, Kitagawa K. 17-AAG, an Hsp90 inhibitor, causes kinetochore defects: A novel mechanism by which 17-AAG inhibits cell proliferation. Oncogene 2006;25:4133–46.

    Article  PubMed  CAS  Google Scholar 

  33. Marabese M, Vikhanskaya F, Broggini M. p73: A chiaroscuro gene in cancer. Eur J Cancer 2007;43:1361–72.

    Article  PubMed  CAS  Google Scholar 

  34. Fulco M, Costanzo A, Merlo P, et al. p73 is regulated by phosphorylation at the G2/M transition. J Biol Chem 2003;278:49196–202.

    Article  PubMed  CAS  Google Scholar 

  35. Merlo P, Fulco M, Costanzo A, et al. A role of p73 in mitotic exit. J Biol Chem 2005;280:30354–60.

    Article  PubMed  CAS  Google Scholar 

  36. Meraldi P, Sorger PK. A dual role for Bub1 in the spindle checkpoint and chromosome congression. EMBO J 2005;24:1621–33.

    Article  PubMed  CAS  Google Scholar 

  37. Chan GK, Jablonski SA, Sudakin V, Hittle JC, Yen TJ. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J Cell Biol 1999;146:941–54.

    Article  PubMed  CAS  Google Scholar 

  38. Roberts BT, Farr KA, Hoyt MA. The Saccharomyces cerevisiae checkpoint gene BUB1 encodes a novel protein kinase. Mol Cell Biol 1994;14:8282–91.

    PubMed  CAS  Google Scholar 

  39. Taylor SS, 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 1998;142:1–11.

    Article  PubMed  CAS  Google Scholar 

  40. Wang X, Babu JR, Harden JM, et al. The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. J Biol Chem 2001;276:26559–67.

    Article  PubMed  CAS  Google Scholar 

  41. Kiyomitsu T, Obuse C, Yanagida M. Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev Cell 2007;13:663–76.

    Article  PubMed  CAS  Google Scholar 

  42. Pyo JO, Jang MH, Kwon YK, et al. Essential roles of Atg5 and FADD in autophagic cell death: Dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 2005;280:20722–9.

    Article  PubMed  CAS  Google Scholar 

  43. Shimizu S, Kanaseki T, Mizushima N, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 2004;6:1221–8.

    Article  PubMed  CAS  Google Scholar 

  44. Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004;304:1500–2.

    Article  PubMed  CAS  Google Scholar 

  45. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G. Cell death by mitotic catastrophe: A molecular definition. Oncogene 2004;23:2825–37.

    Article  PubMed  CAS  Google Scholar 

  46. Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 2004;4:592–603.

    Article  PubMed  CAS  Google Scholar 

  47. Nitta M, Kobayashi O, Honda S, et al. Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene 2004;23:6548–58.

    Google Scholar 

  48. Asnaghi L, Calastretti A, Bevilacqua A, et al. Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene 2004;23:5781–91.

    Article  PubMed  CAS  Google Scholar 

  49. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM. Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol 2007;179:255–67.

    Article  PubMed  CAS  Google Scholar 

  50. Drysdale MJ, Brough PA, Massey A, Jensen MR, Schoepfer J. Targeting Hsp90 for the treatment of cancer. Curr Opin Drug Discov Devel 2006;9:483–95.

    PubMed  CAS  Google Scholar 

  51. Solit DB, Rosen N. Hsp90: A novel target for cancer therapy. Curr Top Med Chem 2006;6:1205–14.

    Article  PubMed  CAS  Google Scholar 

  52. Doak SH, Jenkins GJ, Parry EM, Griffiths AP, Baxter JN, Parry JM. Differential expression of the MAD2, BUB1 and HSP27 genes in Barrett's oesophagus—Their association with aneuploidy and neoplastic progression. Mutat Res 2004;547:133–44.

    Article  PubMed  CAS  Google Scholar 

  53. 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 2002;62:13–7.

    PubMed  CAS  Google Scholar 

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  1. Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA

    Katsumi Kitagawa

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    Kitagawa, K. (2009). Caspase-Independent Mitotic Death. In: Dong, Z., Yin, XM. (eds) Essentials of Apoptosis. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-381-7_28

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