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.

  • Original Paper
  • Published:

Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents

Oncogene volume 23, pages 6548–6558 (2004)Cite this article

Abstract

Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents that damage DNA. This process is facilitated by defects in the G1 and G2 checkpoints of the cell cycle that are apparent in most cancer cells and which allow the cells to enter mitosis with DNA damage. We have now characterized the dynamics of mitotic catastrophe induced by DNA-damaging agents in p53-deficient cancer cells. Cells that entered mitosis with DNA damage transiently arrested at metaphase for more than 10 h without segregation of chromosomes and subsequently died directly from metaphase. In those metaphase arrested precatastrophic cells, anaphase-promoting complex appeared to be inactivated and BubR1 was persistently localized at kinetochores, suggesting that spindle checkpoint is activated after the DNA damage. Furthermore, suppression of spindle checkpoint function by BubR1 or Mad2 RNA interference in the DNA damaged cells led to escape from catastrophic death and to subsequent abnormal mitosis. Dysfunction of the spindle checkpoint in p53-deficient cancer cells is thus likely a critical factor in resistance to DNA-damaging therapeutic agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 4
Figure 5

Similar content being viewed by others

Abbreviations

APC:

anaphase-promoting complex

GFP:

green fluorescent protein

DIC:

differential interference contrast

CCD:

charge-coupled device

References

  • Anand S, Penrhyn-Lowe S and Venkitaraman AR . (2003). Cancer Cell, 3, 51–62.

  • Borel F, Lacroix FB and Margolis RL . (2002). J. Cell Sci., 115, 2829–2838.

  • Brachman DG, Beckett M, Graves D, Haraf D, Vokes E and Weichselbaum RR . (1993). Cancer Res., 53, 3667–3669.

  • Bradford CR, Zhu S, Ogawa H, Ogawa T, Ubell M, Narayan A, Johnson G, Wolf GT, Fisher SG and Carey TE . (2003). Head Neck, 25, 654–661.

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW and Vogelstein B . (1998). Science, 282, 1497–1501.

  • Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW and Vogelstein B . (1999). J. Clin. Invest., 104, 263–269.

  • Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW and Vogelstein B . (1998). Nature, 392, 300–303.

  • Chan TA, Hermeking H, Lengauer C, Kinzler KW and Vogelstein B . (1999). Nature, 401, 616–620.

  • Chan TA, Hwang PM, Hermeking H, Kinzler KW and Vogelstein B . (2000). Genes Dev., 14, 1584–1588.

  • den Elzen N and Pines J . (2001). J. Cell Biol., 153, 121–136.

  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K and Tuschl T . (2001). Nature, 411, 494–498.

  • Erenpreisa JE, Ivanov A, Dekena G, Vitina A, Krampe R, Freivalds T, Selivanova G and Roach HI . (2000). Cell Biol. Int., 24, 61–70.

  • Fan S, el-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace Jr AJ, Magrath I, Kohn KW and O'Connor PM . (1994). Cancer Res., 54, 5824–5830.

  • Fan S, Smith ML, Rivet DJ, Duba II D, Zhan Q, Kohn KW, Fornace Jr AJ and O'Connor PM . (1995). Cancer Res., 55, 1649–1654.

  • Fingert HJ, Chang JD and Pardee AB . (1986). Cancer Res., 46, 2463–2467.

  • Garber PM and Rine J . (2002). Genetics, 161, 521–534.

  • Goto H, Tomono Y, Ajiro K, Kosako H, Fujita M, Sakurai M, Okawa K, Iwamatsu A, Okigaki T, Takahashi T and Inagaki M . (1999). J. Biol. Chem., 274, 25543–25549.

  • Haber JE . (1999). Trends Biochem. Sci., 24, 271–275.

  • Kapoor TM, Mayer TU, Coughlin ML and Mitchison TJ . (2000). J. Cell Biol., 150, 975–988.

  • Lens SM, Wolthuis RM, Klompmaker R, Kauw J, Agami R, Brummelkamp T, Kops G and Medema RH . (2003). EMBO J., 22, 2934–2947.

  • Li Y and Benezra R . (1996). Science, 274, 246–248.

  • Maringele L and Lydall D . (2002). Genes Dev., 16, 1919–1933.

  • Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E and Saya H . (2003). J. Biol. Chem., 278, 51786–51795.

  • Masuda A, Maeno K, Nakagawa T, Saito H and Takahashi T . (2003). Am. J. Pathol., 163, 1109–1116.

  • Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, Dobles M, Sorger PK, Murty VV and Benezra R . (2001). Nature, 409, 355–359.

  • Mikhailov A, Cole RW and Rieder CL . (2002). Curr. Biol., 12, 1797–1806.

  • O'Connor DS, Wall NR, Porter AC and Altieri DC . (2002). Cancer Cell, 2, 43–54.

  • Rogakou EP, Boon C, Redon C and Bonner WM . (1999). J. Cell Biol., 146, 905–916.

  • Rogakou EP, Pilch DR, Orr AH, Ivanova VS and Bonner WM . (1998). J. Biol. Chem., 273, 5858–5868.

  • Roninson IB, Broude EV and Chang BD . (2001). Drug Resist. Update, 4, 303–313.

  • Ru HY, Chen RL, Lu WC and Chen JH . (2002). Oncogene, 21, 4673–4679.

  • Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I, Kawata S and Matsuzawa Y . (2002). Cancer, 94, 2047–2054.

  • Sausville EA, Arbuck SG, Messmann R, Headlee D, Bauer KS, Lush RM, Murgo A, Figg WD, Lahusen T, Jaken S, Jing X, Roberge M, Fuse E, Kuwabara T and Senderowicz AM . (2001). J. Clin. Oncol., 19, 2319–2333.

  • Servomaa K, Kiuru A, Grenman R, Pekkola-Heino K, Pulkkinen JO and Rytomaa T . (1996). Cell Prolif., 29, 219–230.

  • Shannon KB, Canman JC and Salmon ED . (2002). Mol. Cell. Biol., 13, 3706–3719.

  • Sudo T, Nitta M, Saya H and Ueno NT . (2004). Cancer Res., 64, 2502–2508.

  • Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S and Osada H . (1999). Oncogene, 18, 4295–4300.

  • Toledo F, Coquelle A, Svetlova E and Debatisse M . (2000). Nucleic Acids Res., 28, 4805–4813.

  • Vogt U, Zaczek A, Klinke F, Granetzny A, Bielawski K and Falkiewicz B . (2002). J. Cancer Res. Clin. Oncol., 128, 141–147.

  • Wang H, Liu D, Wang Y, Qin J and Elledge SJ . (2001). Genes Dev., 15, 1361–1372.

  • Wang X, Jin DY, Ng RW, Feng H, Wong YC, Cheung AL and Tsao SW . (2002). Cancer Res., 62, 1662–1668.

Download references

Acknowledgements

We thank Dr AB Pardee for helpful discussions and critical reading; Dr B Vogelstein (Johns Hopkins University) for providing p53+/+ and p53−/− HCT116 cells; Dr T Yen (Fox Chase Cancer Center) for the anti-BubR1 monoclonal antibodies; Dr WM Bonner for the anti-γ-H2AX antibodies; Drs GM Wahl and T Kanda for the GFP-tagged histone H2B expression plasmid; Dr K Brocklehurst for editorial assistance; Y Fukushima for help in preparing the manuscript; members of the Saya lab for valuable suggestions; and members of the Gene Technology Center at Kumamoto University for their contributions to the technical assistance. This work was supported by the Research for the Future program of the Japan Society for the promotion of Science and by a grant for Cancer Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to HS).

Author information

Author notes

  1. Masayuki Nitta and Osamu Kobayashi: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, University of Kumamoto, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Masayuki Nitta, Osamu Kobayashi, Shinobu Honda, Toru Hirota, Shinji Kuninaka, Tomotoshi Marumoto & Hideyuki Saya

  2. Department of Neurosurgery, Graduate School of Medical Sciences, University of Kumamoto, Kumamoto, Japan

    Masayuki Nitta, Osamu Kobayashi & Yukitaka Ushio

Authors
  1. Masayuki Nitta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Osamu Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shinobu Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toru Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinji Kuninaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomotoshi Marumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yukitaka Ushio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideyuki Saya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideyuki Saya.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nitta, M., Kobayashi, O., Honda, S. et al. Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene 23, 6548–6558 (2004). https://doi.org/10.1038/sj.onc.1207873

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207873

Keywords

This article is cited by

Search

Advanced search

Quick links