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  • Review Article
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Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy

Key Points

  • In recent years, the pharmaceutical industry has put in great efforts to study protein kinases as drug targets.

  • Multiple studies have provided stunning illustrations that polo-like kinase 1 (PLK1) acts together with cyclin-dependent kinase 1 (CDK1)-cyclin B1 and Aurora A or Aurora B to orchestrate a plethora of critical cell cycle events.

  • The development and application of new chemical entities targeting PLK1 provide a beacon for those wishing to explore its cellular functions. Moreover, the proliferative activity of cancer cells depends strongly on PLK1 reflecting its key regulatory influence on mitotic events.

  • As 'limitless proliferation' is one of the hallmarks of cancer, PLK1 inhibitors, which have recently entered the clinic, are hot candidates in the race to become blockbuster drugs for cancer.

  • Selectivity seems to be an important issue for PLK1 inhibitors because the jury is still out on the roles of PLK2, PLK3 and PLK4 in cancer.

  • Notably, haploinsufficient Plk4 mice and elderly Plk3 knockout mice develop tumours. In addition, PLK2 and PLK3 are considered as stress-response genes in certain types of cells and the function of both genes seems to contribute to the guarding of genomic integrity.

  • PLK1 represents a model protein kinase target for cancer drug development because in addition to its kinase domain, which is related to members of the superfamily of protein kinases, it also encompasses the unique, less conserved polo-box domain (PBD).

  • ATP-competitive PLK1 inhibitors are promiscuous by simultaneously inhibiting several PLK family members. It will therefore be essential to determine the impact that novel agents have on the enzymatic activity of all members of the PLK family.

  • The principal issue in preclinical and clinical trials will be to know whether PBD-specific or kinase domain-specific compounds differ in their efficacy to suppress tumour growth.

  • The development of highly specific small-molecules targeting PLK1 as magic bullets for the treatment of cancer will remain to be a sophisticated challenge in biological, medical and pharmacological research.

Abstract

The polo-like kinase 1 (PLK1) acts in concert with cyclin-dependent kinase 1–cyclin B1 and Aurora kinases to orchestrate a wide range of critical cell cycle events. Because PLK1 has been preclinically validated as a cancer target, small-molecule inhibitors of PLK1 have become attractive candidates for anticancer drug development. Although the roles of the closely related PLK2, PLK3 and PLK4 in cancer are less well understood, there is evidence showing that PLK2 and PLK3 act as tumour suppressors through their functions in the p53 signalling network, which guards the cell against various stress signals. In this article, recent insights into the biology of PLKs will be reviewed, with an emphasis on their role in malignant transformation, and progress in the development of small-molecule PLK1 inhibitors will be examined.

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Figure 1: Localization and selected functions of PLK1 during mitosis.
Figure 2: Model of the bora-mediated phosphorylation of PLK1 at Thr210 by Aurora A.
Figure 3: Chromosome congression defects and the mislocalization of PLK1 by polo box domain inhibition.

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References

  1. Sunkel, C. E. & Glover, D. M. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89 (Pt 1), 25–38 (1988). This paper describes the mitotic phenotype of cells homozygous for mutant alleles of the locus polo.

    PubMed  Google Scholar 

  2. 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 

  3. 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 

  4. 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 

  5. Andrysik, Z. et al. The novel mouse polo-like kinase 5 responds to DNA damage and localizes in the nucleolus. Nucleic Acids Res. 38, 2931–2943 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. van de Weerdt, B. C. & Medema, R. H. Polo-like kinases: a team in control of the division. Cell Cycle 5, 853–864 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Petronczki, M., Lenart, P. & Peters, J. M. Polo on the rise — from mitotic entry to cytokinesis with Plk1. Dev. Cell 14, 646–659 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Takaki, T., Trenz, K., Costanzo, V. & Petronczki, M. Polo-like kinase 1 reaches beyond mitosis — cytokinesis, DNA damage response, and development. Curr. Opin. Cell Biol. 20, 650–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Archambault, V. & Glover, D. M. Polo-like kinases: conservation and divergence in their functions and regulation. Nature Rev. Mol. Cell Biol. 10, 265–275 (2009).

    Article  CAS  Google Scholar 

  11. Barr, F. A. & Gruneberg, U. Cytokinesis: placing and making the final cut. Cell 131, 847–860 (2007). References 3, 4, 7–11 are excellent reviews on the multiple roles of PLK1 and its phylogenetic counterparts during mitosis.

    Article  CAS  PubMed  Google Scholar 

  12. 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). This report describes for the first time the elevated levels of PLK1 in human cancer and initiated many follow-on studies analysing the expression signature of PLK1 in a broad spectrum of human tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. Strebhardt, K. & Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nature Rev. Cancer 6, 321–330 (2006).

    Article  CAS  Google Scholar 

  19. Strebhardt, K. & Ullrich, A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nature Rev. Cancer 8, 473–480 (2008).

    Article  CAS  Google Scholar 

  20. Schoffski, P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 14, 559–570 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Xie, S. et al. Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase 3. J. Biol. Chem. 276, 36194–36199 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Xie, S. et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J. Biol. Chem. 276, 43305–43312 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Shimizu-Yoshida, Y. et al. Radiation-inducible hSNK gene is transcriptionally regulated by p53 binding homology element in human thyroid cells. Biochem. Biophys. Res. Commun. 289, 491–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Lowery, D. M. et al. Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO J. 26, 2262–2273 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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). This report describes the first example of a functional analysis of the polo-box showing that this unique module regulates the subcellular localization of PLK1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Song, S., Grenfell, T. Z., Garfield, S., Erikson, R. L. & Lee, K. S. Essential function of the polo box of Cdc5 in subcellular localization and induction of cytokinetic structures. Mol. Cell Biol. 20, 286–298 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. Reynolds, N. & Ohkura, H. Polo boxes form a single functional domain that mediates interactions with multiple proteins in fission yeast polo kinase. J. Cell Sci. 116, 1377–1387 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. 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). This excellent paper identifies the polo-box domain of Plk1 as a specific phosphoserine or phosphothreonine binding domain.

    Article  CAS  PubMed  Google Scholar 

  35. van de Weerdt, B. C. et al. Polo-box domains confer target specificity to the polo-like kinase family. Biochim. Biophys. Acta 1783, 1015–1022 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Kang, Y. H. et al. Self-regulated Plk1 recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation. Mol. Cell 24, 409–422 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Neef, R. et al. Choice of Plk1 docking partners during mitosis and cytokinesis is controlled by the activation state of Cdk1. Nat. Cell Biol. 9, 436–444 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. 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 

  41. 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 

  42. 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 

  43. Jang, Y. J., Ma, S., Terada, Y. & Erikson, R. L. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J. Biol. Chem. 277, 44115–44120 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Daub, H. et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell 31, 438–448 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Qian, Y. W., Erikson, E. & Maller, J. L. Purification and cloning of a protein kinase that phosphorylates and activates the polo-like kinase Plx1. Science 282, 1701–1704 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. 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 

  48. Chan, E. H., Santamaria, A., Sillje, H. H. & Nigg, E. A. Plk1 regulates mitotic Aurora A function through βTrCP-dependent degradation of hBora. Chromosoma 117, 457–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Seki, A., Coppinger, J. A., Jang, C. Y., Yates, J. R. & Fang, G. Bora and the kinase Aurora A cooperatively activate the kinase Plk1 and control mitotic entry. Science 320, 1655–1658 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Macurek, L. et al. Polo-like kinase-1 is activated by Aurora A to promote checkpoint recovery. Nature 455, 119–123 (2008). References 48–50 establish the role of bora for the activation of PLK1 by Aurora A.

    Article  CAS  PubMed  Google Scholar 

  51. Laoukili, J. et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat. Cell Biol. 7, 126–136 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Major, M. L., Lepe, R. & Costa, R. H. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol. Cell Biol. 24, 2649–2661 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, I. C. et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell Biol. 25, 10875–10894 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fu, Z. et al. Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat. Cell Biol. 10, 1076–1082 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Martin, B. T. & Strebhardt, K. Polo-like kinase 1: target and regulator of transcriptional control. Cell Cycle 5, 2881–2885 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. Whibley, C., Pharoah, P. D. & Hollstein, M. p53 polymorphisms: cancer implications. Nature Rev. Cancer 9, 95–107 (2009).

    Article  CAS  Google Scholar 

  58. Vazquez, A., Bond, E. E., Levine, A. J. & Bond, G. L. The genetics of the p53 pathway, apoptosis and cancer therapy. Nature Rev. Drug Discov. 7, 979–987 (2008).

    Article  CAS  Google Scholar 

  59. 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 

  60. Liu, X., Lei, M. & Erikson, R. L. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol. Cell Biol. 26, 2093–2108 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Guan, R. et al. Small interfering RNA-mediated polo-like kinase 1 depletion preferentially reduces the survival of p53-defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res. 65, 2698–2704 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Yang, X. et al. Plk1-mediated phosphorylation of topors regulates p53 stability. J. Biol. Chem. 284, 18588–18592 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Weger, S., Hammer, E. & Heilbronn, R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett. 579, 5007–5012 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Rajendra, R. et al. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J. Biol. Chem. 279, 36440–36444 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Momand, J., Wu, H. H. & Dasgupta, G. MDM2-master regulator of the p53 tumor suppressor protein. Gene 242, 15–29 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Kreis, N. N. et al. Long-term downregulation of polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21WAF1/CIP1. Cell Cycle 8, 460–472 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Koida, N. et al. Inhibitory role of Plk1 in the regulation of p73-dependent apoptosis through physical interaction and phosphorylation. J. Biol. Chem. 283, 8555–8563 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Soond, S. M. et al. p73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. Cell Cycle 7, 1214–1223 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Kaghad, M. et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809–819 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Sur, S. et al. A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc. Natl Acad. Sci. USA 106, 3964–3969 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  71. zur Hausen, H. Papillomaviruses and cancer: from basic studies to clinical application. Nature Rev. Cancer 2, 342–350 (2002).

    Article  CAS  Google Scholar 

  72. Patel, D., Incassati, A., Wang, N. & McCance, D. J. Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res. 64, 1299–1306 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Incassati, A., Patel, D. & McCance, D. J. Induction of tetraploidy through loss of p53 and upregulation of Plk1 by human papillomavirus type-16 E6. Oncogene 25, 2444–2451 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Meraldi, P., Honda, R. & Nigg, E. A. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J. 21, 483–492 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lin, H. R., Ting, N. S., Qin, J. & Lee, W. H. M phase-specific phosphorylation of BRCA2 by polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex. J. Biol. Chem. 278, 35979–35987 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Lee, M., Daniels, M. J. & Venkitaraman, A. R. Phosphorylation of BRCA2 by the polo-like kinase Plk1 is regulated by DNA damage and mitotic progression. Oncogene 23, 865–872 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Tsvetkov, L., Xu, X., Li, J. & Stern, D. F. Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. J. Biol. Chem. 278, 8468–8475 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. van Vugt, M. A., Smits, V. A., Klompmaker, R. & Medema, R. H. Inhibition of polo-like kinase-1 by DNA damage occurs in an ATM- or ATR-dependent fashion. J. Biol. Chem. 276, 41656–41660 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Ree, A. H., Bratland, A., Nome, R. V., Stokke, T. & Fodstad, O. Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1. Oncogene 22, 8952–8955 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Tang, J., Erikson, R. L. & Liu, X. Checkpoint kinase 1 (Chk1) is required for mitotic progression through negative regulation of polo-like kinase 1 (Plk1). Proc. Natl Acad. Sci USA 103, 11964–11969 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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 

  82. Smits, V. A. et al. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nature Cell Biol. 2, 672–676 (2000). This paper reports that PLK1 is an important target of the DNA damage checkpoint.

    Article  CAS  PubMed  Google Scholar 

  83. Syljuasen, R. G., Jensen, S., Bartek, J. & Lukas, J. Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and polo-like kinase 1 kinases. Cancer Res. 66, 10253–10257 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Yamaguchi, T. et al. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis. J. Cell Biol. 171, 431–436 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rizki, A., Mott, J. D. & Bissell, M. J. Polo-like kinase 1 is involved in invasion through extracellular matrix. Cancer Res. 67, 11106–11110 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Takai, N., Hamanaka, R., Yoshimatsu, J. & Miyakawa, I. Polo-like kinases (Plks) and cancer. Oncogene 24, 287–291 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. 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). References 88 and 89 both describe for the first time the clinical relevance of PLK1 overexpression for patients with tumours.

    CAS  PubMed  Google Scholar 

  90. Salvatore, G. et al. A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 67, 10148–10158 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Liu, L., Zhang, M. & Zou, P. Expression of PLK1 and survivin in diffuse large B-cell lymphoma. Leuk. Lymphoma 48, 2179–2183 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Yamamoto, Y. et al. Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer. Oncology 70, 231–237 (2006).

    Article  PubMed  Google Scholar 

  93. Liu, L., Zhang, M. & Zou, P. Polo-like kinase 1 as a new target for non-Hodgkin's lymphoma treatment. Oncology 74, 96–103 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Kanaji, S. et al. Expression of polo-like kinase 1 (PLK1) protein predicts the survival of patients with gastric carcinoma. Oncology 70, 126–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Jang, Y. J., Kim, Y. S. & Kim, W. H. Oncogenic effect of polo-like kinase 1 expression in human gastric carcinomas. Int. J. Oncol. 29, 589–594 (2006).

    CAS  PubMed  Google Scholar 

  96. Weichert, W. et al. Expression patterns of polo-like kinase 1 in human gastric cancer. Cancer Sci. 97, 271–276 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ma, S., Liu, M. A., Yuan, Y. L. & Erikson, R. L. The serum-inducible protein kinase Snk is a G1 phase polo-like kinase that is inhibited by the calcium- and integrin-binding protein CIB. Mol. Cancer Res. 1, 376–384 (2003).

    CAS  PubMed  Google Scholar 

  99. Anger, M. et al. Cell cycle dependent expression of Plk1 in synchronized porcine fetal fibroblasts. Mol. Reprod. Dev. 65, 245–253 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Warnke, S. et al. Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr. Biol. 14, 1200–1207 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Cizmecioglu, O., Warnke, S., Arnold, M., Duensing, S. & Hoffmann, I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle 7, 3548–3555 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Ma, S., Charron, J. & Erikson, R. L. Role of Plk2 (Snk) in mouse development and cell proliferation. Mol. Cell Biol. 23, 6936–6943 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Habedanck, R., Stierhof, Y. D., Wilkinson, C. J. & Nigg, E. A. The polo kinase Plk4 functions in centriole duplication. Nature Cell Biol. 7, 1140–1146 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Kauselmann, G. et al. The polo-like protein kinases Fnk and Snk associate with a Ca2+- and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J. 18, 5528–5539 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Burns, T. F., Fei, P., Scata, K. A., Dicker, D. T. & El-Deiry, W. S. Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells. Mol. Cell Biol. 23, 5556–5571 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tovar, C. et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc. Natl Acad. Sci. USA 103, 1888–1893 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Khan, S. H. & Wahl, G. M. p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest. Cancer Res. 58, 396–401 (1998).

    CAS  PubMed  Google Scholar 

  108. Lanni, J. S. & Jacks, T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell Biol. 18, 1055–1064 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Van den Berghe, H. & Michaux, L. 5q, twenty-five years later: a synopsis. Cancer Genet. Cytogenet. 94, 1–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Nimer, S. D. & Golde, D. W. The 5q– abnormality. Blood 70, 1705–1712 (1987).

    CAS  PubMed  Google Scholar 

  111. Syed, N. et al. Transcriptional silencing of polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies. Blood 107, 250–256 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Li, Z. et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc. Natl Acad. Sci. USA 105, 15535–15540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Esquela-Kerscher, A. & Slack, F. J. Oncomirs – microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006).

    Article  CAS  Google Scholar 

  114. Donohue, P. J., Alberts, G. F., Guo, Y. & Winkles, J. A. Identification by targeted differential display of an immediate early gene encoding a putative serine/threonine kinase. J. Biol. Chem. 270, 10351–10357 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Li, B. et al. Prk, a cytokine-inducible human protein serine/threonine kinase whose expression appears to be down-regulated in lung carcinomas. J. Biol. Chem. 271, 19402–19408 (1996).

    Article  CAS  PubMed  Google Scholar 

  116. 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 

  117. 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 

  118. Chase, D. et al. Expression and phosphorylation of fibroblast-growth-factor-inducible kinase (Fnk) during cell-cycle progression. Biochem. J. 333 (Pt 3), 655–660 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bahassi el, M. et al. Mammalian polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. Oncogene 21, 6633–6640 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Zimmerman, W. C. & Erikson, R. L. Polo-like kinase 3 is required for entry into S phase. Proc. Natl Acad. Sci. USA 104, 1847–1852 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang, Q. et al. Cell cycle arrest and apoptosis induced by human polo-like kinase 3 is mediated through perturbation of microtubule integrity. Mol. Cell Biol. 22, 3450–3459 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jiang, N., Wang, X., Jhanwar-Uniyal, M., Darzynkiewicz, Z. & Dai, W. Polo box domain of Plk3 functions as a centrosome localization signal, overexpression of which causes mitotic arrest, cytokinesis defects, and apoptosis. J. Biol. Chem. 281, 10577–10582 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Yang, F. et al. Identification of a novel mitotic phosphorylation motif associated with protein localization to the mitotic apparatus. J. Cell Sci. 120, 4060–4070 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Ruan, Q. et al. Polo-like kinase 3 is golgi localized and involved in regulating golgi fragmentation during the cell cycle. Exp. Cell Res. 294, 51–59 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Lopez-Sanchez, I., Sanz-Garcia, M. & Lazo, P. A. Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a downstream target in a pathway that induces golgi fragmentation. Mol. Cell Biol. 29, 1189–1201 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Sutterlin, C., Hsu, P., Mallabiabarrena, A. & Malhotra, V. Fragmentation and dispersal of the pericentriolar golgi complex is required for entry into mitosis in mammalian cells. Cell 109, 359–369 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Conn, C. W., Hennigan, R. F., Dai, W., Sanchez, Y. & Stambrook, P. J. Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase, Plk3. Cancer Res. 60, 6826–6831 (2000).

    CAS  PubMed  Google Scholar 

  128. Zhou, T. et al. Profiles of global gene expression in ionizing-radiation-damaged human diploid fibroblasts reveal synchronization behind the G1 checkpoint in a G0-like state of quiescence. Environ. Health Perspect. 114, 553–559 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Kis, E. et al. Microarray analysis of radiation response genes in primary human fibroblasts. Int. J. Radiat. Oncol. Biol. Phys. 66, 1506–1514 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Staib, F. et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res. 65, 10255–10264 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Han, E. S. et al. The in vivo gene expression signature of oxidative stress. Physiol. Genomics 34, 112–126 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Yang, Y. et al. Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1α under hypoxic conditions. Cancer Res. 68, 4077–4085 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wang, L., Gao, J., Dai, W. & Lu, L. Activation of polo-like kinase 3 by hypoxic stresses. J. Biol. Chem. 283, 25928–25935 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Dai, W. et al. PRK, a cell cycle gene localized to 8p21, is downregulated in head and neck cancer. Genes Chromosomes. Cancer 27, 332–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  135. 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 

  136. Weichert, W. et al. Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br. J. Cancer 90, 815–821 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 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 

  138. Fode, C., Binkert, C. & Dennis, J. W. Constitutive expression of murine Sak-a suppresses cell growth and induces multinucleation. Mol. Cell Biol. 16, 4665–4672 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hudson, J. W. et al. Late mitotic failure in mice lacking Sak, a polo-like kinase. Curr. Biol. 11, 441–446 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. Bettencourt-Dias, M. et al. SAK/PLK4 is required for centriole duplication and flagella development. Curr. Biol. 15, 2199–2207 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Li, J. et al. SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia. 7, 312–323 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Deloukas, P. et al. A physical map of 30,000 human genes. Science 282, 744–746 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Hammond, C., Jeffers, L., Carr, B. I. & Simon, D. Multiple genetic alterations, 4q28, a new suppressor region, and potential gender differences in human hepatocellular carcinoma. Hepatology 29, 1479–1485 (1999).

    Article  CAS  PubMed  Google Scholar 

  144. Hudson, J. W., Chen, L., Fode, C., Binkert, C. & Dennis, J. W. Sak kinase gene structure and transcriptional regulation. Gene 241, 65–73 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. 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 

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

    Article  CAS  Google Scholar 

  147. Pérez de Castro, I., de Cárcer, G., Montoya, G. & Malumbres, M. Emerging cancer therapeutic opportunities by inhibiting mitotic kinases. Curr. Opin. Pharmacol. 8, 375–383 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. McInnes, C. Progress in the evaluation of CDK inhibitors as anti-tumor agents. Drug Discov. Today 13, 875–881 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Lapenna, S. & Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nature Rev. Drug Discov. 8, 547–566 (2009).

    Article  CAS  Google Scholar 

  150. Yuan, J., Kramer, A., Eckerdt, F., Kaufmann, M. & Strebhardt, K. Efficient internalization of the polo-box of polo-like kinase 1 fused to an antennapedia peptide results in inhibition of cancer cell proliferation. Cancer Res. 62, 4186–4190 (2002).

    CAS  PubMed  Google Scholar 

  151. 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  CAS  PubMed  Google Scholar 

  152. Matthess, Y. et al. Conditional inhibition of cancer cell proliferation by tetracycline-responsive, H1 promoter-driven silencing of PLK1. Oncogene 24, 2973–2980 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Kappel, S., Matthess, Y., Zimmer, B., Kaufmann, M. & Strebhardt, K. Tumor inhibition by genomically integrated inducible RNAi-cassettes. Nucleic Acids Res. 34, 4527–4536 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Goldstein, D. M., Gray, N. S. & Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery. Nature Rev. Drug Discov. 7, 391–397 (2008).

    Article  CAS  Google Scholar 

  156. Johnson, E. F., Stewart, K. D., Woods, K. W., Giranda, V. L. & Luo, Y. Pharmacological and functional comparison of the polo-like kinase family: insight into inhibitor and substrate specificity. Biochemistry 46, 9551–9563 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Kothe, M. et al. Structure of the catalytic domain of human polo-like kinase 1. Biochemistry 46, 5960–5971 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Steegmaier, M. et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol. 17, 316–322 (2007). This report laid the foundation for the preclinical and clinical testing of the promising compound BI 2536.

    Article  CAS  PubMed  Google Scholar 

  159. Kothe, M. et al. Selectivity-determining residues in Plk1. Chem. Biol. Drug Des. 70, 540–546 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Wang, H. Y. et al. Pharmacophore modeling and virtual screening for designing potential PLK1 inhibitors. Bioorg. Med. Chem. Lett. 18, 4972–4977 (2008).

    Article  CAS  PubMed  Google Scholar 

  161. McInnes, C. et al. Inhibitors of polo-like kinase reveal roles in spindle-pole maintenance. Nature Chem. Biol. 2, 608–617 (2006).

    Article  CAS  Google Scholar 

  162. Peters, U., Cherian, J., Kim, J. H., Kwok, B. H. & Kapoor, T. M. Probing cell-division phenotype space and polo-like kinase function using small molecules. Nature Chem. Biol. 2, 618–626 (2006). References 161 and 162 are both excellent papers that describe the effects of novel small-molecule inhibitors targeting the kinase domain of PLK1.

    Article  CAS  Google Scholar 

  163. Santamaria, A. et al. Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis. Mol. Biol. Cell 18, 4024–4036 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lansing, T. J. et al. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol. Cancer Ther. 6, 450–459 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Baumann, C., Korner, R., Hofmann, K. & Nigg, E. A. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell 128, 101–114 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Sato, Y. et al. Imidazopyridine derivatives as potent and selective polo-like kinase (PLK) inhibitors. Bioorg. Med. Chem. Lett. 19, 4673–4678 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Mahajan, S. et al. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide]. J. Biol. Chem. 274, 9587–9599 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. Uckun, F. M. et al. Anti-breast cancer activity of LFM-A13, a potent inhibitor of polo-like kinase (PLK). Bioorg. Med. Chem. 15, 800–814 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Uckun, F. M. Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. Cell Cycle 6, 3021–3026 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Reindl, W., Yuan, J., Kramer, A., Strebhardt, K. & Berg, T. Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein–protein interactions. Chem. Biol. 15, 459–466 (2008). This paper describes the inhibition of the polo-box domain function by a small-molecule inhibitor.

    Article  CAS  PubMed  Google Scholar 

  171. Reindl, W., Strebhardt, K. & Berg, T. A high-throughput assay based on fluorescence polarization for inhibitors of the polo-box domain of polo-like kinase 1. Anal. Biochem. 383, 205–209 (2008).

    Article  CAS  PubMed  Google Scholar 

  172. Hanisch, A., Wehner, A., Nigg, E. A. & Sillje, H. H. Different Plk1 functions show distinct dependencies on polo-box domain-mediated targeting. Mol. Biol. Cell 17, 448–459 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Gali-Muhtasib, H., Roessner, A. & Schneider-Stock, R. Thymoquinone: a promising anti-cancer drug from natural sources. Int. J. Biochem. Cell Biol. 38, 1249–1253 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. Kaseb, A. O. et al. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res. 67, 7782–7788 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Reindl, W., Yuan, J., Kramer, A., Strebhardt, K. & Berg, T. A pan-specific inhibitor of the polo-box domains of polo-like kinases arrests cancer cells in mitosis. Chembiochem. 10, 1145–1148 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Watanabe, N. et al. Deficiency in chromosome congression by the inhibition of Plk1 polo box domain-dependent recognition. J. Biol. Chem. 284, 2344–2353 (2009).

    Article  CAS  PubMed  Google Scholar 

  177. Abou-Karam, M. & Shier, W. T. Inhibition of oncogene product enzyme activity as an approach to cancer chemoprevention. Tyrosine-specific protein kinase inhibition by purpurogallin from Quercus sp. nutgall. Phytother. Res. 13, 337–340 (1999).

    Article  CAS  PubMed  Google Scholar 

  178. Farnet, C. M. et al. Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism. Antimicrob. Agents Chemother. 42, 2245–2253 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Inamori, Y. et al. Biological activity of purpurogallin. Biosci. Biotechnol. Biochem. 61, 890–892 (1997).

    Article  CAS  PubMed  Google Scholar 

  180. Jackson, J. R., Patrick, D. R., Dar, M. M. & Huang, P. S. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nature Rev. Cancer 7, 107–117 (2007).

    Article  CAS  Google Scholar 

  181. 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 

  182. Lenart, P. et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr. Biol. 17, 304–315 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Jimeno, A. et al. Phase I study of ON 01910. Na, a novel modulator of the polo-like kinase 1 pathway, in adult patients with solid tumors. J. Clin. Oncol. 26, 5504–5510 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Jimeno, A. et al. Evaluation of the novel mitotic modulator ON 01910.Na in pancreatic cancer and preclinical development of an ex vivo predictive assay. Oncogene 28, 610–618 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Weinstein, J. et al. Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer. J. Clin. Oncol. 26, (2008).

  186. Ghalib, M. H. et al. ON01910.Na, a novel polo-like kinase pathway modulator as a treatment for patients with advanced cancer. AACR meeting website [online], (2008).

  187. Ohnuma, T. et al. Phase I study of ON 01910.Na by 3-day continuous infusion (CI) in patients (pts) with advanced cancer. J. Clin. Oncol. 24 (Suppl. 18), 13137 (2006).

    Google Scholar 

  188. Chapman, C. M., Perez-Galan, P. & Wiestner, A. ON 01910.Na, a novel clinical grade PLK-1 inhibitor, selectively induces apoptosis in human B-cell chronic lymphocytic leukemia (B-CLL). Onconova website [online], (2009).

  189. Tanaka, H. et al. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res. 63, 6942–6947 (2003).

    CAS  PubMed  Google Scholar 

  190. Garland, L. L., Taylor, C., Pilkington, D. L., Cohen, J. L. & Von Hoff, D. D. A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin. Cancer Res. 12, 5182–5189 (2006).

    Article  CAS  PubMed  Google Scholar 

  191. Von Hoff, D. D., Taylor, C., Rubin, S., Cohen, J. & Garland, L. A phase I and pharmacokinetic study of HMN-214, a novel oral polo-like kinase inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 22 (Suppl. 14), 3034 (2004).

    Article  Google Scholar 

  192. Patnaik, A. et al. HMN-214, a novel oral antimicrotubular agent and inhibitor of polo-like- and cyclin-dependent kinases: clinical, pharmacokinetic (PK) and pharmacodynamic (PD) relationships observed in a phase I trial of a daily x 5 schedule every 28 days. Proc. Am. Soc. Clin. Oncol. 22, 514 (2003).

    Google Scholar 

  193. Emmitte, K. A. et al. Discovery of thiophene inhibitors of polo-like kinase. Bioorg. Med. Chem. Lett. 19, 1018–1021 (2009).

    Article  CAS  PubMed  Google Scholar 

  194. Emmitte, K. A. et al. Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding. Bioorg. Med. Chem. Lett. 19, 1694–1697 (2009).

    Article  CAS  PubMed  Google Scholar 

  195. Erskine, S. et al. Biochemical characterization of GSK461364: a novel, potent, and selective inhibitor of polo-like kinase 1 (Plk1). Proc. Annu. Meet. Am. Assoc. Cancer Res. Abstr. 3257 (2007).

  196. Laquerre, S. et al. A potent and selective polo-like kinase 1 (Plk1) inhibitor (GSK461364) induces cell cycle arrest and growth inhibition of cancer cell. AACR meeting website [online], (2007).

  197. Erskine, S. et al. Biochemical characterization of GSK461364: a novel, potent, and selective inhibitor of polo-like kinase-1 (Plk1). AACR meeting website [online], http://www.aacrmeetingabstracts.org/cgi/gca?allch=&SEARCHID=1&AUTHOR1=Erskine&FULLTEXT=Plk1&FIRSTINDEX=0&hits=10&RESULTFORMAT=&gca=aacrmtg%3B2007%2F1_Annual_Meeting%2F3257 (2007).

  198. Sutton, D. et al. Efficacy of GSK461364, a selective Plk1 inhibitor, in human tumor xenograft models. AACR meeting website [online], (2007).

  199. Ikezoe, T. et al. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. Leukemia 23, 1564–1576 (2009).

    Article  CAS  PubMed  Google Scholar 

  200. Didier, C., Cavelier, C., Quaranta, M., Demur, C. & Ducommun, B. Evaluation of polo-like kinase 1 inhibition on the G2/M checkpoint in acute myelocytic leukaemia. Eur. J. Pharmacol. 591, 102–105 (2008).

    Article  CAS  PubMed  Google Scholar 

  201. Olmos, D. et al. Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors. J. Clin. Oncol. 27 (Suppl. 15) 3536 (2009).

    Google Scholar 

  202. Beria, I. et al. Identification of 4, 5-Dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective polo-like kinase 1 inhibitors. J. Med. Chem. 53 (Suppl. 9), 3532–3551 (2010).

    Article  CAS  PubMed  Google Scholar 

  203. Valsasina, B. et al. Pyrazoloquinazolines: from an unselective hit to a potent Plk1-specific inhibitor. AACR website [online], (2009).

  204. Mross, K. et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 26, 5511–5517 (2008).

    Article  CAS  PubMed  Google Scholar 

  205. Hofheinz, R. et al. A phase I repeated dose escalation study of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors. J. Clin. Oncol. 24 (Suppl 18), 2038 (2006).

    Google Scholar 

  206. Ellis, P. M. et al. A phase I dose escalation trial of BI 2536, a novel Plk1 inhibitor, with standard dose pemetrexed in previously treated advanced or metastatic non-small cell lung cancer (NSCLC). J. Clin. Oncol. 26, 8115 (2008).

    Article  Google Scholar 

  207. von Pawel, J. et al. Randomized phase II trial of two dosing schedules of BI 2536, a novel Plk-1 inhibitor, in patients with relapsed advanced or metastatic non-small-cell lung cancer (NSCLC). J. Clin. Oncol. 26, 8030 (2008).

    Article  Google Scholar 

  208. Pandha, H. S. et al. An open label phase II trial of BI 2536, a novel Plk1 inhibitor, in patients with metastatic hormone refractory prostate cancer (HRPC). J. Clin. Oncol. 26, 14547 (2008).

    Article  Google Scholar 

  209. Mross, K. et al. A randomized phase II trial of the novel polo-like kinase 1 inhibitor BI 2536 in chemonaïve patients with unresectable advanced pancreatic cancer: a study in cooperation with the CESAR network of investigators. Ann. Oncol. 19 (Suppl. 8), 493P (2008).

    Google Scholar 

  210. Rudolph, D. et al. BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin. Cancer Res. 15, 3094–3102 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. Schöffski, P. et al. A phase I single dose escalation study of the novel polo-like kinase I inhibitor BI 6727 in patients with advanced solid tumors. Eur. J. Cancer 6 (Suppl.), 14–15 (2008).

    Article  Google Scholar 

  212. Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Park, J. E. et al. Direct quantification of polo-like kinase 1 activity in cells and tissues using a highly sensitive and specific ELISA assay. Proc. Natl Acad. Sci. USA 106, 1725–1730 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Judge, A. D. et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J. Clin. Invest. 119, 661–673 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Spankuch, B. et al. Downregulation of Plk1 expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. Neoplasia. 10, 223–234 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Steinhauser, I. M., Langer, K., Strebhardt, K. M. & Spankuch, B. Effect of trastuzumab-modified antisense oligonucleotide-loaded human serum albumin nanoparticles prepared by heat denaturation. Biomaterials 29, 4022–4028 (2008).

    Article  CAS  PubMed  Google Scholar 

  217. Steinhauser, I., Langer, K., Strebhardt, K. & Spankuch, B. Uptake of plasmid-loaded nanoparticles in breast cancer cells and effect on Plk1 expression. J. Drug Target. 17, 627–637 (2009).

    Article  CAS  PubMed  Google Scholar 

  218. Bandeiras, T. M. et al. Structure of wild-type Plk-1 kinase domain in complex with a selective DARPin. Acta Crystallogr. D. Biol. Crystallogr. 64, 339–353 (2008).

    Article  CAS  PubMed  Google Scholar 

  219. Nolen, B., Taylor, S. & Ghosh, G. Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell 15, 661–675 (2004).

    Article  CAS  PubMed  Google Scholar 

  220. 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 

  221. García-Alvarez, B., de Cárcer, G., Ibañez, S., Bragado-Nilsson, E. & Montoya, G. Molecular and structural basis of polo-like kinase 1 substrate recognition: implications in centrosomal localization. Proc. Natl Acad. Sci. USA 104, 3107–3112 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Yun, S. M. et al. Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1. Nature Struct. Mol. Biol. 16, 876–882 (2009).

    Article  CAS  Google Scholar 

  223. Leung, G. C. et al. The Sak polo-box comprises a structural domain sufficient for mitotic subcellular localization. Nature Struct. Biol. 9, 719–724 (2002).

    Article  CAS  PubMed  Google Scholar 

  224. Lu, L. Y. et al. Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol. Cell Biol. 28, 6870–6876 (2008). This excellent report describes the structure and function of the PLK4 polo-box.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. 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 

  227. Liby, K. et al. Identification of the human homologue of the early-growth response gene Snk, encoding a serum-inducible kinase. DNA Seq. 11, 527–533 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  229. Nothias, J. Y., Majumder, S., Kaneko, K. J. & DePamphilis, M. L. Regulation of gene expression at the beginning of mammalian development. J. Biol. Chem. 270, 22077–22080 (1995).

    Article  CAS  PubMed  Google Scholar 

  230. Ko, M. A. et al. Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nature Genet. 37, 883–888 (2005).

    Article  CAS  PubMed  Google Scholar 

  231. 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 

  232. Casenghi, M., Barr, F. A. & Nigg, E. A. Phosphorylation of Nlp by Plk1 negatively regulates its dynein-dynactin-dependent targeting to the centrosome. J. Cell Sci. 118, 5101–5108 (2005).

    Article  CAS  PubMed  Google Scholar 

  233. Oshimori, N., Ohsugi, M. & Yamamoto, T. The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity. Nat. Cell Biol. 8, 1095–1101 (2006).

    Article  CAS  PubMed  Google Scholar 

  234. De Luca, M., Lavia, P. & Guarguaglini, G. A functional interplay between Aurora-A, Plk1 and TPX2 at spindle poles: Plk1 controls centrosomal localization of Aurora-A and TPX2 spindle association. Cell Cycle 5, 296–303 (2006).

    Article  CAS  PubMed  Google Scholar 

  235. Kumagai, A. & Dunphy, W. G. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science 273, 1377–1380 (1996).

    Article  CAS  PubMed  Google Scholar 

  236. Roshak, A. K. et al. The human polo-like kinase, PLK, regulates cdc2/cyclin B through phosphorylation and activation of the cdc25C phosphatase. Cell Signal 12, 405–411 (2000).

    Article  CAS  PubMed  Google Scholar 

  237. Watanabe, N. et al. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFβ-TrCP. Proc. Natl Acad. Sci. USA 101, 4419–4424 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Inoue, D. & Sagata, N. The polo-like kinase Plx1 interacts with and inhibits Myt1 after fertilization of Xenopus eggs. EMBO J. 24, 1057–1067 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. 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 

  240. 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 

  241. Yamashiro, S. et al. Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1. Dev. Cell 14, 787–797 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. 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 

  243. Elowe, S., Hummer, S., Uldschmid, A., Li, X. & Nigg, E. A. Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions. Genes Dev. 21, 2205–2219 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Goto, H. et al. Complex formation of Plk1 and INCENP required for metaphase–anaphase transition. Nat. Cell Biol. 8, 180–187 (2006).

    Article  CAS  PubMed  Google Scholar 

  245. Qi, W., Tang, Z. & Yu, H. Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Mol. Biol. Cell 17, 3705–3716 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. 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 

  247. Sumara, I. et al. The dissociation of cohesin from chromosomes in prophase is regulated by polo-like kinase. Mol. Cell 9, 515–525 (2002).

    Article  CAS  PubMed  Google Scholar 

  248. Riedel, C. G. et al. Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature 441, 53–61 (2006).

    Article  CAS  PubMed  Google Scholar 

  249. Kitajima, T. S. et al. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature 441, 46–52 (2006).

    Article  CAS  PubMed  Google Scholar 

  250. Tang, Z. et al. PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev. Cell 10, 575–585 (2006).

    Article  CAS  PubMed  Google Scholar 

  251. 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 

  252. 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 

  253. Eckerdt, F. & Strebhardt, K. Polo-like kinase 1: target and regulator of anaphase-promoting complex/cyclosome-dependent proteolysis. Cancer Res. 66, 6895–6898 (2006).

    Article  CAS  PubMed  Google Scholar 

  254. Golan, A., Yudkovsky, Y. & Hershko, A. The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and Plk. J. Biol. Chem. 277, 15552–15557 (2002).

    Article  CAS  PubMed  Google Scholar 

  255. Kraft, C. et al. Mitotic regulation of the human anaphase-promoting complex by phosphorylation. EMBO J. 22, 6598–6609 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Nasmyth, K. Segregating sister genomes: the molecular biology of chromosome separation. Science 297, 559–565 (2002).

    Article  CAS  PubMed  Google Scholar 

  257. Alexandru, G., Uhlmann, F., Mechtler, K., Poupart, M. A. & Nasmyth, K. Phosphorylation of the cohesin subunit Scc1 by Polo/Cdc5 kinase regulates sister chromatid separation in yeast. Cell 105, 459–472 (2001).

    Article  CAS  PubMed  Google Scholar 

  258. Hornig, N. C. & Uhlmann, F. Preferential cleavage of chromatin-bound cohesin after targeted phosphorylation by polo-like kinase. EMBO J. 23, 3144–3153 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Mishima, M., Kaitna, S. & Glotzer, M. Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity. Dev. Cell 2, 41–54 (2002).

    Article  CAS  PubMed  Google Scholar 

  260. Mishima, M., Pavicic, V., Gruneberg, U., Nigg, E. A. & Glotzer, M. Cell cycle regulation of central spindle assembly. Nature 430, 908–913 (2004).

    Article  CAS  PubMed  Google Scholar 

  261. Burkard, M. E. et al. Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells. PLoS. Biol. 7, e1000111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Brennan, I. M., Peters, U., Kapoor, T. M. & Straight, A. F. Polo-like kinase controls vertebrate spindle elongation and cytokinesis. PLoS. One. 2, e409 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Burkard, M. E. et al. Chemical genetics reveals the requirement for polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells. Proc. Natl Acad. Sci. USA 104, 4383–4388 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Petronczki, M., Glotzer, M., Kraut, N. & Peters, J. M. Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Dev. Cell 12, 713–725 (2007).

    Article  CAS  PubMed  Google Scholar 

  265. Hutterer, A. et al. Mitotic activation of the kinase Aurora-A requires its binding partner bora. Dev. Cell 11, 147–157 (2006).

    Article  CAS  PubMed  Google Scholar 

  266. Seki, A. et al. Plk1- and β-TrCP-dependent degradation of Bora controls mitotic progression. J. Cell Biol. 181, 65–78 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I regret that I am unable to cite numerous original and significant papers because of space constraints. I thank C. McInnes for the critical review of the manuscript. I thank T. Berg, S. Kappel, M. Sanhaji and Y. Matthess for assistance in the preparation of the list of references and figures. This work was supported by the Deutsche Krebshilfe, the Else–Kröner–Fresenius–Stiftung, the Carls–Stiftung and LOEWE Centre Frankfurt.

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Strebhardt, K. Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov 9, 643–660 (2010). https://doi.org/10.1038/nrd3184

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