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Unraveling cell division mechanisms with small-molecule inhibitors

Abstract

Cell division is the process by which a cell creates two genetically identical daughter cells. To maintain genomic integrity, a complex and highly regulated sequence of events ensures that the replicated chromosomes are equally partitioned between the daughter cells. For more than 50 years, strategies designed around small-molecule inhibitors have been critical in advancing our understanding of this essential process. Here we introduce a series of questions on the biology of cell division and illustrate how small molecules have been used to design experiments to address these questions. Because of the highly dynamic nature of cell division, the temporal control over protein function that is possible with small molecules has been particularly valuable in dissecting biological mechanisms.

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Figure 1: Overview of mitosis.
Figure 2: Screening strategy used to identify genes required for feedback control of anaphase onset in budding yeast21.
Figure 3: Manipulation of chromosome-microtubule attachments with small molecules.
Figure 4: Correction of improper chromosome attachments by activation of Aurora kinase45.
Figure 5: Force production by the contractile ring in cytokinesis.
Figure 6: Assay to examine cytokinesis in the presence of a monopolar spindle25.

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References

  1. Kops, G.J., Weaver, B.A. & Cleveland, D.W. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer 5, 773–785 (2005).

    CAS  PubMed  Google Scholar 

  2. Inoue, S. Polarization optical studies of the mitotic spindle. I. The demonstration of spindle fibers in living cells. Chromosoma 5, 487–500 (1953).

    CAS  PubMed  Google Scholar 

  3. Inoue, S. The effect of colchicine on the microscopic and submicroscopic structure of the mitotic spindle. Exp. Cell Res. Suppl. 2, 305 (1952).

    Google Scholar 

  4. Inoue, S. & Sato, H. Cell motility by labile association of molecules. The nature of mitotic spindle fibers and their role in chromosome movement. J. Gen. Physiol. 50 (Suppl.) 259–292 (1967).

    CAS  PubMed Central  Google Scholar 

  5. Inoue, S. in Primitive Motile Systems in Cell Biology (eds. Allen, R.D. & Kamiya, K.) 549–598 (Academic, New York, 1964).

    Google Scholar 

  6. Inoue, S. Cell division and the mitotic spindle. J. Cell Biol. 91, 131s–147s (1981).

    CAS  PubMed  Google Scholar 

  7. Taylor, E.W. The mechanism of colchicine inhibition of mitosis. I. Kinetics of inhibition and the binding of H3-colchicine. J. Cell Biol. 25 (Suppl.), 145–160 (1965).

    CAS  PubMed Central  Google Scholar 

  8. Borisy, G.G. & Taylor, E.W. The mechanism of action of colchicine. Binding of colchincine-3H to cellular protein. J. Cell Biol. 34, 525–533 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Borisy, G.G. & Taylor, E.W. The mechanism of action of colchicine. Colchicine binding to sea urchin eggs and the mitotic apparatus. J. Cell Biol. 34, 535–548 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shelanski, M.L. & Taylor, E.W. Isolation of a protein subunit from microtubules. J. Cell Biol. 34, 549–554 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Weisenberg, R.C., Borisy, G.G. & Taylor, E.W. The colchicine-binding protein of mammalian brain and its relation to microtubules. Biochemistry 7, 4466–4479 (1968).

    CAS  PubMed  Google Scholar 

  12. Mohri, H. Amino-acid composition of 'Tubulin' constituting microtubules of sperm flagella. Nature 217, 1053–1054 (1968).

    CAS  PubMed  Google Scholar 

  13. Mitchison, T.J. & Salmon, E.D. Mitosis: a history of division. Nat. Cell Biol. 3, E17–E21 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Jordan, M.A. et al. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 56, 816–825 (1996).

    CAS  PubMed  Google Scholar 

  16. Weaver, B.A. & Cleveland, D.W. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell 8, 7–12 (2005).

    CAS  PubMed  Google Scholar 

  17. Tao, W. et al. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 8, 49–59 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Weinert, T.A. & Hartwell, L.H. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241, 317–322 (1988).

    CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  24. Mayer, T.U. et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971–974 (1999).

    CAS  PubMed  Google Scholar 

  25. Canman, J.C. et al. Determining the position of the cell division plane. Nature 424, 1074–1078 (2003).

    CAS  PubMed  Google Scholar 

  26. Sudo, T., Nitta, M., Saya, H. & Ueno, N.T. Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res. 64, 2502–2508 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Li, X. & Nicklas, R.B. Mitotic forces control a cell-cycle checkpoint. Nature 373, 630–632 (1995).

    CAS  PubMed  Google Scholar 

  29. Waters, J.C., Chen, R.H., Murray, A.W. & Salmon, E.D. Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J. Cell Biol. 141, 1181–1191 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen, R.H., Waters, J.C., Salmon, E.D. & Murray, A.W. Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores. Science 274, 242–246 (1996).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. King, J.M. & Nicklas, R.B. Tension on chromosomes increases the number of kinetochore microtubules but only within limits. J. Cell Sci. 113, 3815–3823 (2000).

    CAS  PubMed  Google Scholar 

  33. Biggins, S. & Murray, A.W. The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the spindle checkpoint. Genes Dev. 15, 3118–3129 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Meraldi, P., Honda, R. & Nigg, E.A. Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr. Opin. Genet. Dev. 14, 29–36 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Biggins, S. et al. The conserved protein kinase Ipl1 regulates microtubule binding to kinetochores in budding yeast. Genes Dev. 13, 532–544 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cheeseman, I.M. et al. Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p. Cell 111, 163–172 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Nicklas, R.B. & Ward, S.C. Elements of error correction in mitosis: microtubule capture, release, and tension. J. Cell Biol. 126, 1241–1253 (1994).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Ault, J.G. & Rieder, C.L. Chromosome mal-orientation and reorientation during mitosis. Cell Motil. Cytoskeleton 22, 155–159 (1992).

    CAS  PubMed  Google Scholar 

  44. Carmena, M. & Earnshaw, W.C. The cellular geography of aurora kinases. Nat. Rev. Mol. Cell Biol. 4, 842–854 (2003).

    CAS  PubMed  Google Scholar 

  45. Lampson, M.A., Renduchitala, K., Khodjakov, A. & Kapoor, T.M. Correcting improper chromosome-spindle attachments during cell division. Nat. Cell Biol. 6, 232–237 (2004).

    CAS  PubMed  Google Scholar 

  46. Kapoor, T.M., Mayer, T.U., Coughlin, M.L. & Mitchison, T.J. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J. Cell Biol. 150, 975–988 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Peterson, J.R. & Mitchison, T.J. Small molecules, big impact: a history of chemical inhibitors and the cytoskeleton. Chem. Biol. 9, 1275–1285 (2002).

    CAS  PubMed  Google Scholar 

  48. Carter, S.B. Effects of cytochalasins on mammalian cells. Nature 213, 261–264 (1967).

    CAS  PubMed  Google Scholar 

  49. Wessells, N.K. et al. Microfilaments in cellular and developmental processes. Science 171, 135–143 (1971).

    CAS  PubMed  Google Scholar 

  50. Spudich, J.A. & Lin, S. Cytochalasin B, its interaction with actin and actomyosin from muscle (cell movement-microfilaments-rabbit striated muscle). Proc. Natl. Acad. Sci. USA 69, 442–446 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Straight, A.F. et al. Dissecting temporal and spatial control of cytokinesis with a myosin II Inhibitor. Science 299, 1743–1747 (2003).

    CAS  PubMed  Google Scholar 

  52. Martineau, S.N., Andreassen, P.R. & Margolis, R.L. Delay of HeLa cell cleavage into interphase using dihydrocytochalasin B: retention of a postmitotic spindle and telophase disc correlates with synchronous cleavage recovery. J. Cell Biol. 131, 191–205 (1995).

    PubMed  Google Scholar 

  53. Canman, J.C., Hoffman, D.B. & Salmon, E.D. The role of pre- and post-anaphase microtubules in the cytokinesis phase of the cell cycle. Curr. Biol. 10, 611–614 (2000).

    CAS  PubMed  Google Scholar 

  54. Barr, F.A., Sillje, H.H. & Nigg, E.A. Polo-like kinases and the orchestration of cell division. Nat. Rev. Mol. Cell Biol. 5, 429–440 (2004).

    CAS  PubMed  Google Scholar 

  55. Zhang, J., Campbell, R.E., Ting, A.Y. & Tsien, R.Y. Creating new fluorescent probes for cell biology. Nat. Rev. Mol. Cell Biol. 3, 906–918 (2002).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge support from US National Institutes of Health grant GM71772 (T.M.K.) M.A.L. is a Francis Goulet fellow.

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Correspondence to Tarun M Kapoor.

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Lampson, M., Kapoor, T. Unraveling cell division mechanisms with small-molecule inhibitors. Nat Chem Biol 2, 19–27 (2006). https://doi.org/10.1038/nchembio757

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