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Targeting polo-like kinase 1 for cancer therapy

Nature Reviews Cancer volume 6, pages 321–330 (2006)Cite this article

Abstract

Human polo-like kinase 1 (PLK1) is essential during mitosis and in the maintenance of genomic stability. PLK1 is overexpressed in human tumours and has prognostic potential in cancer, indicating its involvement in carcinogenesis and its potential as a therapeutic target. The use of different PLK1 inhibitors has increased our knowledge of mitotic regulation and allowed us to assess their ability to suppress tumour growth in vivo. We address the structural features of the kinase domain and the unique polo-box domain of PLK1 that are most suited for drug development and discuss our current understanding of the therapeutic potential of PLK1.

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Figure 1: Polo-like kinases in human cells.
Figure 2: Structures of PLK1 domains.

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References

  1. Fenton, B. & Glover, D. M. A conserved mitotic kinase active at late anaphase–telophase in syncytial Drosophila embryos. Nature 363, 637–640 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Glover, D. M., Hagan, I. M. & Tavares, A. A. Polo-like kinases: a team that plays throughout mitosis. Genes Dev. 12, 3777–3787 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Clay, F. J., McEwen, S. J., Bertoncello, I., Wilks, A. F. & Dunn, A. R. Identification and cloning of a protein kinase-encoding mouse gene, Plk, related to the polo gene of Drosophila. Proc. Natl Acad. Sci. USA 90, 4882–4886 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lake, R. J. & Jelinek, W. R. Cell cycle- and terminal differentiation-associated regulation of the mouse mRNA encoding a conserved mitotic protein kinase. Mol. Cell. Biol. 13, 7793–7801 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Holtrich, U. et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc. Natl Acad. Sci. USA 91, 1736–1740 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hamanaka, R. et al. Cloning and characterization of human and murine homologues of the Drosophila polo serine-threonine kinase. Cell Growth Differ. 5, 249–257 (1994).

    CAS  PubMed  Google Scholar 

  7. Simmons, D. L., Neel, B. G., Stevens, R., Evett, G. & Erikson, R. L. Identification of an early-growth-response gene encoding a novel putative protein kinase. Mol. Cell. Biol. 12, 4164–4169 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ouyang, B. et al. Human Prk is a conserved protein serine/threonine kinase involved in regulating M phase functions. J. Biol. Chem. 272, 28646–28651 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Holtrich, U. et al. Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages. Oncogene 19, 4832–4839 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Fode, C., Motro, B., Yousefi, S., Heffernan, M. & Dennis, J. W. Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proc. Natl Acad. Sci. USA 91, 6388–6392 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Karn, T. et al. Human SAK related to the PLK/polo family of cell cycle kinases shows high mRNA expression in testis. Oncol. Reports 4, 505–510 (1997).

    CAS  Google Scholar 

  12. Mundt, K. E., Golsteyn, R. M., Lane, H. A. & Nigg, E. A. On the regulation and function of human polo-like kinase 1 (PLK1): effects of overexpression on cell cycle progression. Biochem. Biophys. Res. Commun. 239, 377–385 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Smith, M. R. et al. Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase. Biochem. Biophys. Res. Commun. 234, 397–405 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Eckerdt, F., Yuan, J. & Strebhardt, K. Polo-like kinases and oncogenesis. Oncogene 24, 267–276 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Stevenson, C. S. et al. Scytonemin-a marine natural product inhibitor of kinases key in hyperproliferative inflammatory diseases. Inflamm. Res. 51, 112–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Stevenson, C. S. et al. The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore. J. Pharmacol. Exp. Ther. 303, 858–866 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, Y. et al. Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase. Chem. Biol. 12, 99–107 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Steegmaier, M. et al. BI 2536, a potent and highly selective inhibitor of Polo-like kinase 1 (Plk1), induces mitotic arrest and apoptosis in a broad spectrum of tumor cell lines. Clin. Cancer Res. 11 (Suppl.), 9147 (2005).

    Google Scholar 

  19. Baum A et al. In vivo activity of BI 2536, a potent and selective inhibitor of the mitotic kinase Plk1, in a range of human cancer xenograft models. Clin. Cancer Res. 11 (Suppl.), 9146 (2005).

    Google Scholar 

  20. Mross K et al. A phase I single dose escalation study of the Polo-like kinase 1 (Plk1) inhibitor BI 2536 in patients with advanced solid tumors. Clin. Cancer Res. 11 (Suppl.), 9032 (2005).

    Google Scholar 

  21. Gumireddy, K. et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell 7, 275–286 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Xie, S., Xie, B., Lee, M. Y. & Dai, W. Regulation of cell cycle checkpoints by polo-like kinases. Oncogene 24, 277–286 (2005).

    Article  PubMed  CAS  Google Scholar 

  24. van Vugt, M. A. & Medema, R. H. Getting in and out of mitosis with Polo-like kinase-1. Oncogene 24, 2844–2859 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Golsteyn, R. M. et al. Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5. J. Cell Sci. 107, 1509–1517 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Golsteyn, R. M., Mundt, K. E., Fry, A. M. & Nigg, E. A. Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J. Cell Biol. 129, 1617–1628 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Lee, K. S., Yuan, Y. L., Kuriyama, R. & Erikson, R. L. Plk is an M-phase-specific protein kinase and interacts with a kinesin-like protein, CHO1/MKLP-1. Mol. Cell. Biol. 15, 7143–7151 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sunkel, C. E. & Glover, D. M. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89, 25–38 (1988).

    Article  PubMed  Google Scholar 

  29. Kitada, K., Johnson, A. L., Johnston, L. H. & Sugino, A. A multicopy suppressor gene of the Saccharomyces cerevisiae G1 cell cycle mutant gene dbf4 encodes a protein kinase and is identified as CDC5. Mol. Cell. Biol. 13, 4445–4457 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ohkura, H., Hagan, I. M. & Glover, D. M. The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring, and septum, can drive septum formation in G1 and G2 cells. Genes Dev. 9, 1059–1073 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. 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 

  32. Wianny, F., Tavares, A., Evans, M. J., Glover, D. M. & Zernicka-Goetz, M. Mouse polo-like kinase 1 associates with the acentriolar spindle poles, meiotic chromosomes and spindle midzone during oocyte maturation. Chromosoma 107, 430–439 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Lee, K. S. & Erikson, R. L. Plk is a functional homolog of Saccharomyces cerevisiae Cdc5, and elevated Plk activity induces multiple septation structures. Mol. Cell. Biol. 17, 3408–3417 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, X. & Erikson, R. L. Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk1 by siRNA. Proc. Natl Acad. Sci. USA 99, 8672–8676 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, X. & Erikson, R. L. Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc. Natl Acad. Sci. USA 100, 5789–5794 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jang, Y. J., Lin, C. Y., Ma, S. & Erikson, R. L. Functional studies on the role of the C-terminal domain of mammalian polo-like kinase. Proc. Natl Acad. Sci. USA 99, 1984–1989 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smits, V. A. et al. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nature Cell Biol. 2, 672–676 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. van Vugt, M. A., Bras, A. & Medema, R. H. Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells. Mol. Cell 15, 799–811 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. van Vugt, M. A., Bras, A. & Medema, R. H. Restarting the cell cycle when the checkpoint comes to a halt. Cancer Res. 65, 7037–7040 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Ando, K. et al. Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J. Biol. Chem. 279, 25549–25561 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Hanks, S. K., Quinn, A. M. & Hunter, T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42–52 (1988).

    Article  CAS  PubMed  Google Scholar 

  42. Hanks, S. K. & Quinn, A. M. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 200, 38–62 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Guex, N. & Peitsch, M. C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Bayliss, R., Sardon, T., Vernos, I. & Conti, E. Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol. Cell 12, 851–862 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Nowakowski, J. et al. Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography. Structure. (Camb.) 10, 1659–1667 (2002).

    Article  CAS  Google Scholar 

  46. Cheetham, G. M. et al. Crystal structure of aurora-2, an oncogenic serine/threonine kinase. J. Biol. Chem. 277, 42419–42422 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Yang, J. et al. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nature Struct. Biol. 9, 940–944 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Lowery, D. M., Lim, D. & Yaffe, M. B. Structure and function of Polo-like kinases. Oncogene 24, 248–259 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Hamanaka, R. et al. Polo-like kinase is a cell cycle-regulated kinase activated during mitosis. J. Biol. Chem. 270, 21086–21091 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Marshall, C. J. Signal transduction. Hot lips and phosphorylation of protein kinases. Nature 367, 686 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Knighton, D. R. et al. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253, 414–420 (1991).

    Article  CAS  PubMed  Google Scholar 

  52. Knighton, D. R. et al. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253, 407–414 (1991).

    Article  CAS  PubMed  Google Scholar 

  53. Ellinger-Ziegelbauer, H. et al. Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes Cells 5, 491–498 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Walter, S. A., Cutler, R. E. Jr, Martinez, R., Gishizky, M. & Hill, R. J. Stk10, a new member of the polo-like kinase kinase family highly expressed in hematopoietic tissue. J. Biol. Chem. 278, 18221–18228 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Kelm, O., Wind, M., Lehmann, W. D. & Nigg, E. A. Cell cycle-regulated phosphorylation of the Xenopus polo-like kinase Plx1. J. Biol. Chem. 277, 25247–25256 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Elia, A. E. et al. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell 115, 83–95 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Cheng, K. Y., Lowe, E. D., Sinclair, J., Nigg, E. A. & Johnson, L. N. The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex. EMBO J. 22, 5757–5768 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yaffe, M. B. & Cantley, L. C. Mapping specificity determinants for protein-protein association using protein fusions and random peptide libraries. Methods Enzymol. 328, 157–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Elia, A. E., Cantley, L. C. & Yaffe, M. B. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 299, 1228–1231 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Lee, K. S., Grenfell, T. Z., Yarm, F. R. & Erikson, R. L. Mutation of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk. Proc. Natl Acad. Sci. USA 95, 9301–9306 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Lin, C. Y. et al. Peripheral Golgi protein GRASP65 is a target of mitotic polo-like kinase (Plk) and Cdc2. Proc. Natl Acad. Sci. USA 97, 12589–12594 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yarm, F. R. Plk phosphorylation regulates the microtubule-stabilizing protein TCTP. Mol. Cell. Biol. 22, 6209–6221 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Preisinger, C. et al. Plk1 docking to GRASP65 phosphorylated by Cdk1 suggests a mechanism for Golgi checkpoint signalling. EMBO J. 24, 753–765 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lee, K. S., Song, S. & Erikson, R. L. The polo-box-dependent induction of ectopic septal structures by a mammalian polo kinase, plk, in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 96, 14360–14365 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Seong, Y. S. et al. A spindle checkpoint arrest and a cytokinesis failure by the dominant-negative polo-box domain of Plk1 in U-2 OS cells. J. Biol. Chem. 277, 32282–32293 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Yuan, J. et al. Polo-like kinase, a novel marker for cellular proliferation. Am. J. Pathol. 150, 1165–1172 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wolf, G. et al. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 14, 543–549 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Knecht, R. et al. Prognostic significance of polo-like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Cancer Res. 59, 2794–2797 (1999).

    CAS  PubMed  Google Scholar 

  70. Knecht, R., Oberhauser, C. & Strebhardt, K. PLK (polo-like kinase), a new prognostic marker for oropharyngeal carcinomas. Int. J. Cancer 89, 535–536 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Strebhardt, K., Kneisel, L., Linhart, C., Bernd, A. & Kaufmann, R. Prognostic value of pololike kinase expression in melanomas. JAMA 283, 479–480 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Kneisel, L. et al. Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease. J. Cutan. Pathol. 29, 354–358 (2002).

    Article  PubMed  Google Scholar 

  73. Takahashi, T. et al. Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. Cancer Sci. 94, 148–152 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Macmillan, J. C., Hudson, J. W., Bull, S., Dennis, J. W. & Swallow, C. J. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann. Surg. Oncol. 8, 729–740 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Weichert, W. et al. Polo-like kinase 1 expression is a prognostic factor in human colon cancer. World J. Gastroenterol. 11, 5644–5650 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yamada, S. et al. Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene 23, 5901–5911 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Ahr, A. et al. Identification of high risk breast-cancer patients by gene expression profiling. Lancet 359, 131–132 (2002).

    Article  PubMed  Google Scholar 

  78. Simizu, S. & Osada, H. Mutations in the Plk gene lead to instability of Plk protein in human tumour cell lines. Nature Cell Biol. 2, 852–854 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Llamazares, S. et al. polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev. 5, 2153–2165 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Sunkel, C. E. & Glover, D. M. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89, 25–38 (1988).

    Article  PubMed  Google Scholar 

  81. Lane, H. A. & Nigg, E. A. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J. Cell Biol. 135, 1701–1713 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Cogswell, J. P., Brown, C. E., Bisi, J. E. & Neill, S. D. Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function. Cell Growth Differ. 11, 615–623 (2000).

    CAS  PubMed  Google Scholar 

  83. Liu, X., Lei, M. & Erikson, R. L. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol. Cell. Biol. 26, 2073–2108 (2006).

    Google Scholar 

  84. Spankuch-Schmitt, B. et al. Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells. Oncogene 21, 3162–3171 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Gray, P. J. Jr et al. Identification of human polo-like kinase 1 as a potential therapeutic target in pancreatic cancer. Mol. Cancer Ther. 3, 641–646 (2004).

    CAS  PubMed  Google Scholar 

  86. Spankuch-Schmitt, B., Bereiter-Hahn, J., Kaufmann, M. & Strebhardt, K. Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J. Natl Cancer Inst. 94, 1863–1877 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Reagan-Shaw, S. & Ahmad, N. Silencing of polo-like kinase (Plk) 1 via siRNA causes induction of apoptosis and impairment of mitosis machinery in human prostate cancer cells: implications for the treatment of prostate cancer. FASEB J. 19, 611–613 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Nogawa, M. et al. Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer. J. Clin. Invest. 115, 978–985 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Spankuch, B. et al. Cancer inhibition in nude mice after systemic application of U6 promoter-driven short hairpin RNAs against PLK1. J. Natl Cancer Inst. 96, 862–872 (2004).

    Article  PubMed  CAS  Google Scholar 

  90. Jackson, A. L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nature Biotechnol. 21, 635–637 (2003).

    Article  CAS  Google Scholar 

  91. Daub, H., Specht, K. & Ullrich, A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nature Rev. Drug Discov. 3, 1001–1010 (2004).

    Article  CAS  Google Scholar 

  92. Shawver, L. K., Slamon, D. & Ullrich, A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1, 117–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. McInnes, C., Mezna, M. & Fischer, P. M. Progress in the discovery of polo-like kinase inhibitors. Curr. Top. Med. Chem. 5, 181–197 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Jessani, N. & Cravatt, B. F. The development and application of methods for activity-based protein profiling. Curr. Opin. Chem. Biol. 8, 54–59 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Walker, E. H. et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 6, 909–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Ihle, N. T. et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol. Cancer Ther. 3, 763–772 (2004).

    CAS  PubMed  Google Scholar 

  97. Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4, 927–936 (2004).

    Article  CAS  Google Scholar 

  98. Wu, S. Y. et al. Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop. Structure. (Camb.) 11, 399–410 (2003).

    Article  CAS  Google Scholar 

  99. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Sumara, I. et al. Roles of polo-like kinase 1 in the assembly of functional mitotic spindles. Curr. Biol. 14, 1712–1722 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Casenghi, M. et al. Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. Dev. Cell 5, 113–125 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Murray, A. W. Recycling the cell cycle: cyclins revisited. Cell 116, 221–234 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A. & Nishida, E. Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 410, 215–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Yuan, J. et al. Cooperative phosphorylation including the activity of polo-like kinase 1 regulates the subcellular localization of cyclin B1. Oncogene 21, 8282–8292 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Jackman, M., Lindon, C., Nigg, E. A. & Pines, J. Active cyclin B1–Cdk1 first appears on centrosomes in prophase. Nature Cell Biol. 5, 143–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Qian, Y. W., Erikson, E., Li, C. & Maller, J. L. Activated polo-like kinase Plx1 is required at multiple points during mitosis in Xenopus laevis. Mol. Cell. Biol. 18, 4262–4271 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Toyoshima-Morimoto, F., Taniguchi, E. & Nishida, E. Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep. 3, 341–348 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wasch, R. & Engelbert, D. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene 24, 1–10 (2005).

    Article  PubMed  CAS  Google Scholar 

  111. Castro, A., Bernis, C., Vigneron, S., Labbe, J. C. & Lorca, T. The anaphase-promoting complex: a key factor in the regulation of cell cycle. Oncogene 24, 314–325 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Moshe, Y., Boulaire, J., Pagano, M. & Hershko, A. Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. Proc. Natl Acad. Sci. USA 101, 7937–7942 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hansen, D. V., Loktev, A. V., Ban, K. H. & Jackson, P. K. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFβTrCP-dependent destruction of the APC inhibitor Emi1. Mol. Biol. Cell 15, 5623–5634 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ahonen, L. J. et al. Polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores. Curr. Biol. 15, 1078–1089 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Liu, X., Zhou, T., Kuriyama, R. & Erikson, R. L. Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like protein CHO1/MKLP-1. J. Cell Sci. 117, 3233–3246 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Neef, R. et al. Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. J. Cell Biol. 162, 863–875 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhou, T., Aumais, J. P., Liu, X., Yu-Lee, L. Y. & Erikson, R. L. A role for Plk1 phosphorylation of NudC in cytokinesis. Dev. Cell 5, 127–138 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, J. et al. Crystal structure of an activated Akt–protein kinase B ternary complex with GSK3–peptide and AMP–PNP. Nature Struct. Biol. 9, 940–944 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Tokumitsu, Y. et al. Prognostic significance of polo-like kinase expression in esophageal carcinoma. Int. J. Oncol. 15, 687–692 (1999).

    CAS  PubMed  Google Scholar 

  120. Wolf, G. et al. Polo-like kinase: a novel marker of proliferation: correlation with estrogen-receptor expression in human breast cancer. Pathol. Res. Pract. 196, 753–759 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Weichert, W. et al. Polo-like kinase isoforms in breast cancer: expression patterns and prognostic implications. Virchows Arch. 446, 442–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Takai, N. et al. Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage. Cancer Lett. 164, 41–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Takai, N. et al. Polo-like kinase (PLK) expression in endometrial carcinoma. Cancer Lett. 169, 41–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Dietzmann, K., Kirches, E., von, B., Jachau, K. & Mawrin, C. Increased human polo-like kinase-1 expression in gliomas. J. Neurooncol. 53, 1–11 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Ito, Y. et al. Polo-like kinase 1 overexpression is an early event in the progression of papillary carcinoma. Br. J. Cancer 90, 414–418 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Weichert, W. et al. Overexpression of Polo-like kinase 1 is a common and early event in pancreatic cancer. Pancreatology. 5, 259–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Weichert, W. et al. Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades. Prostate 60, 240–245 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Mito, K. et al. Expression of Polo-like kinase (PLK1) in non-Hodgkin's lymphomas. Leuk. Lymphoma 46, 225–231 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Wipf, P. & Halter, R. J. Chemistry and biology of wortmannin. Org. Biomol. Chem. 3, 2053–2061 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Yves Matthess and Sven Kappel for their assistance with the diagrams in this manuscript.

Author information

Authors and Affiliations

  1. the Department of Obstetrics and Gynecology, School of Medicine, J.W. Goethe-University, Theodore-Stern-Kai 7, Frankfurt, 60590, Germany

    Klaus Strebhardt

  2. Singapore Oncogenome Laboratory, Centre of Molecular Medicine, Institute of Molecular and Cell Biology, 61 Biopolis Drive, #03–14 Proteos, Singapore, 138673

    Axel Ullrich

  3. Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18A, Martinsried, 82152, Germany

    Axel Ullrich

Authors
  1. Klaus Strebhardt
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Correspondence to Klaus Strebhardt.

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DATABASES

National Cancer Institute

breast cancer

FURTHER INFORMATION

NCBI Protein Database

SWISS-MODEL server

University of Arizona Cell Cycle and Mitosis Tutorial

Glossary

ABPP

The chemical strategy that uses active site-directed probes to directly profile the functional state of enzyme families in complex proteomes.

Centromere region

A specialized segment of the chromosome that is typically observed as a primary constriction that functions in sister chromatid adhesion, kinteochore formation and pairing of homologous chromosomes, and is involved in the control of gene expression.

Centrosome

A highly organized organelle that acts as the cell microtubule-organizing center and includes two centrioles that are surrounded by an amorphous, proteinaceous matrix termed the pericentriolar material.

Chemical lead optimization programme

The purpose of this stage during the process of drug development is to optimize the molecules or compounds that demonstrate the potential to be transformed into drugs. The creation of hundreds, possibly thousands, of analogues, is aimed at, for example, improving the effectiveness, diminishing the toxicity or increasing the organism's absorption of the drug.

Degron

A degradation signal found in certain proteins.

EC50

The plasma concentration required for obtaining 50% of the maximum effect in vivo.

Equatorial spindle midzone

During metaphase the chromosomes congregate at the cell equator between the two ends to which the spindle tapers. This plane marks the point at which the whole cell will divide when nuclear division is completed.

GI50

The concentration of compound required for 50% inhibition of growth in vitro.

IC50

The concentration of compound required for 50% inhibition of an enzyme in vitro. Generally, nanomolar or even picomolar values rather than micromolar values are desirable.

Ki value

The value of Ki corresponds to the inhibitor concentration when half of the enzyme molecules bind an inhibitor molecule (half-saturation concentration).

Kinetochore

A protein structure in eukaryotes that assembles on the centromere and joins the chromosome to microtubule polymers from the mitotic spindle during mitosis.

Mitotic catastrophe

A specific type of apoptotic response that occurs during mitosis as a consequence of deregulated (or abnormal) mitotic processes, which is one of the principal antiproliferative effects of most anticancer agents.

Mitotic index

The mitotic index is the fraction of cells in a microscope field that contain condensed chromosomes.

Monoastral

A radial array of microtubules that are nucleated from duplicated but unseparated centrosomes surrounded by a ring of chromosomes.

Neutropaenia

A decrease in circulating neutrophils in the peripheral blood. The absolute neutrophil count (ANC) defines neutropaenia.

Oriented peptide libraries

The consensus sequence of optimal peptide substrates is determined by sequencing the mixture of products generated during a brief reaction with the kinase of interest Based on these results, a library of several million peptide substrates is generated and used for determining the substrate specificity of protein kinases.

Polo-boxes

The most obvious conserved structural features of PLKs, which regulate their subcellular localization and their catalytic activity.

Polo-cap

This region helps to hold both polo-boxes in the correct orientation.

Post-mitotic bridge

As a cleavage furrow forms in late anaphase and then ingresses, the microtubules of the central spindle are pushed in a bridge that tethers the two daughter cells, which is called the mid-body.

Septation

The separation between mother and daughter cell during cell division requires cytoplasmic division. This process is called cytokinesis in mammalian cells and septation in fungi.

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Strebhardt, K., Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 6, 321–330 (2006). https://doi.org/10.1038/nrc1841

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