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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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.
Llamazares, S. et al. polo encodes a protein kinase homolog required for mitosis in Drosophila. Genes Dev. 5, 2153–2165 (1991).
Glover, D. M., Hagan, I. M. & Tavares, A. A. Polo-like kinases: a team that plays throughout mitosis. Genes Dev. 12, 3777–3787 (1998).
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).
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).
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).
van de Weerdt, B. C. & Medema, R. H. Polo-like kinases: a team in control of the division. Cell Cycle 5, 853–864 (2006).
Petronczki, M., Lenart, P. & Peters, J. M. Polo on the rise — from mitotic entry to cytokinesis with Plk1. Dev. Cell 14, 646–659 (2008).
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).
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).
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.
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.
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).
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).
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).
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).
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).
Strebhardt, K. & Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nature Rev. Cancer 6, 321–330 (2006).
Strebhardt, K. & Ullrich, A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nature Rev. Cancer 8, 473–480 (2008).
Schoffski, P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist 14, 559–570 (2009).
McInnes, C., Mezna, M. & Fischer, P. M. Progress in the discovery of polo-like kinase inhibitors. Curr. Top. Med. Chem. 5, 181–197 (2005).
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).
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).
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).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).
Yuan, J. et al. Polo-like kinase, a novel marker for cellular proliferation. Am. J. Pathol. 150, 1165–1172 (1997).
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).
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.
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Daub, H. et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell 31, 438–448 (2008).
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).
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).
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).
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).
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.
Laoukili, J. et al. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat. Cell Biol. 7, 126–136 (2005).
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).
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).
Fu, Z. et al. Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat. Cell Biol. 10, 1076–1082 (2008).
Martin, B. T. & Strebhardt, K. Polo-like kinase 1: target and regulator of transcriptional control. Cell Cycle 5, 2881–2885 (2006).
Ando, K. et al. Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation. J. Biol. Chem. 279, 25549–25561 (2004).
Whibley, C., Pharoah, P. D. & Hollstein, M. p53 polymorphisms: cancer implications. Nature Rev. Cancer 9, 95–107 (2009).
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).
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).
Liu, X., Lei, M. & Erikson, R. L. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol. Cell Biol. 26, 2093–2108 (2006).
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).
Yang, X. et al. Plk1-mediated phosphorylation of topors regulates p53 stability. J. Biol. Chem. 284, 18588–18592 (2009).
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).
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).
Momand, J., Wu, H. H. & Dasgupta, G. MDM2-master regulator of the p53 tumor suppressor protein. Gene 242, 15–29 (2000).
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).
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).
Soond, S. M. et al. p73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. Cell Cycle 7, 1214–1223 (2008).
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).
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).
zur Hausen, H. Papillomaviruses and cancer: from basic studies to clinical application. Nature Rev. Cancer 2, 342–350 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
Yamaguchi, T. et al. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis. J. Cell Biol. 171, 431–436 (2005).
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).
Eckerdt, F., Yuan, J. & Strebhardt, K. Polo-like kinases and oncogenesis. Oncogene 24, 267–276 (2005).
Takai, N., Hamanaka, R., Yoshimatsu, J. & Miyakawa, I. Polo-like kinases (Plks) and cancer. Oncogene 24, 287–291 (2005).
Wolf, G. et al. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 14, 543–549 (1997).
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.
Salvatore, G. et al. A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 67, 10148–10158 (2007).
Liu, L., Zhang, M. & Zou, P. Expression of PLK1 and survivin in diffuse large B-cell lymphoma. Leuk. Lymphoma 48, 2179–2183 (2007).
Yamamoto, Y. et al. Overexpression of polo-like kinase 1 (PLK1) and chromosomal instability in bladder cancer. Oncology 70, 231–237 (2006).
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).
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).
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).
Weichert, W. et al. Expression patterns of polo-like kinase 1 in human gastric cancer. Cancer Sci. 97, 271–276 (2006).
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).
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).
Anger, M. et al. Cell cycle dependent expression of Plk1 in synchronized porcine fetal fibroblasts. Mol. Reprod. Dev. 65, 245–253 (2003).
Warnke, S. et al. Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr. Biol. 14, 1200–1207 (2004).
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).
Ma, S., Charron, J. & Erikson, R. L. Role of Plk2 (Snk) in mouse development and cell proliferation. Mol. Cell Biol. 23, 6936–6943 (2003).
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).
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).
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).
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).
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).
Lanni, J. S. & Jacks, T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell Biol. 18, 1055–1064 (1998).
Van den Berghe, H. & Michaux, L. 5q, twenty-five years later: a synopsis. Cancer Genet. Cytogenet. 94, 1–7 (1997).
Nimer, S. D. & Golde, D. W. The 5q– abnormality. Blood 70, 1705–1712 (1987).
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).
Li, Z. et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc. Natl Acad. Sci. USA 105, 15535–15540 (2008).
Esquela-Kerscher, A. & Slack, F. J. Oncomirs – microRNAs with a role in cancer. Nature Rev. Cancer 6, 259–269 (2006).
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).
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).
Holtrich, U. et al. Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages. Oncogene 19, 4832–4839 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Kis, E. et al. Microarray analysis of radiation response genes in primary human fibroblasts. Int. J. Radiat. Oncol. Biol. Phys. 66, 1506–1514 (2006).
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).
Han, E. S. et al. The in vivo gene expression signature of oxidative stress. Physiol. Genomics 34, 112–126 (2008).
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).
Wang, L., Gao, J., Dai, W. & Lu, L. Activation of polo-like kinase 3 by hypoxic stresses. J. Biol. Chem. 283, 25928–25935 (2008).
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).
Weichert, W. et al. Polo-like kinase isoforms in breast cancer: expression patterns and prognostic implications. Virchows Arch. 446, 442–450 (2005).
Weichert, W. et al. Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br. J. Cancer 90, 815–821 (2004).
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).
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).
Hudson, J. W. et al. Late mitotic failure in mice lacking Sak, a polo-like kinase. Curr. Biol. 11, 441–446 (2001).
Bettencourt-Dias, M. et al. SAK/PLK4 is required for centriole duplication and flagella development. Curr. Biol. 15, 2199–2207 (2005).
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).
Deloukas, P. et al. A physical map of 30,000 human genes. Science 282, 744–746 (1998).
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).
Hudson, J. W., Chen, L., Fode, C., Binkert, C. & Dennis, J. W. Sak kinase gene structure and transcriptional regulation. Gene 241, 65–73 (2000).
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).
Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4, 927–936 (2004).
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).
McInnes, C. Progress in the evaluation of CDK inhibitors as anti-tumor agents. Drug Discov. Today 13, 875–881 (2008).
Lapenna, S. & Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nature Rev. Drug Discov. 8, 547–566 (2009).
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).
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).
Matthess, Y. et al. Conditional inhibition of cancer cell proliferation by tetracycline-responsive, H1 promoter-driven silencing of PLK1. Oncogene 24, 2973–2980 (2005).
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).
Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).
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).
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).
Kothe, M. et al. Structure of the catalytic domain of human polo-like kinase 1. Biochemistry 46, 5960–5971 (2007).
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.
Kothe, M. et al. Selectivity-determining residues in Plk1. Chem. Biol. Drug Des. 70, 540–546 (2007).
Wang, H. Y. et al. Pharmacophore modeling and virtual screening for designing potential PLK1 inhibitors. Bioorg. Med. Chem. Lett. 18, 4972–4977 (2008).
McInnes, C. et al. Inhibitors of polo-like kinase reveal roles in spindle-pole maintenance. Nature Chem. Biol. 2, 608–617 (2006).
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.
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).
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).
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).
Sato, Y. et al. Imidazopyridine derivatives as potent and selective polo-like kinase (PLK) inhibitors. Bioorg. Med. Chem. Lett. 19, 4673–4678 (2009).
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).
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).
Uckun, F. M. Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. Cell Cycle 6, 3021–3026 (2007).
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.
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).
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).
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).
Kaseb, A. O. et al. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res. 67, 7782–7788 (2007).
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).
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).
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).
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).
Inamori, Y. et al. Biological activity of purpurogallin. Biosci. Biotechnol. Biochem. 61, 890–892 (1997).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Emmitte, K. A. et al. Discovery of thiophene inhibitors of polo-like kinase. Bioorg. Med. Chem. Lett. 19, 1018–1021 (2009).
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).
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).
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).
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).
Sutton, D. et al. Efficacy of GSK461364, a selective Plk1 inhibitor, in human tumor xenograft models. AACR meeting website [online], (2007).
Ikezoe, T. et al. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. Leukemia 23, 1564–1576 (2009).
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).
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).
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).
Valsasina, B. et al. Pyrazoloquinazolines: from an unselective hit to a potent Plk1-specific inhibitor. AACR website [online], (2009).
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).
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).
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).
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).
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).
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).
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).
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).
Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009).
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).
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).
Spankuch, B. et al. Downregulation of Plk1 expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. Neoplasia. 10, 223–234 (2008).
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).
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).
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).
Nolen, B., Taylor, S. & Ghosh, G. Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell 15, 661–675 (2004).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
Ko, M. A. et al. Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nature Genet. 37, 883–888 (2005).
Casenghi, M. et al. Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. Dev. Cell 5, 113–125 (2003).
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).
Oshimori, N., Ohsugi, M. & Yamamoto, T. The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity. Nat. Cell Biol. 8, 1095–1101 (2006).
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).
Kumagai, A. & Dunphy, W. G. Purification and molecular cloning of Plx1, a Cdc25-regulatory kinase from Xenopus egg extracts. Science 273, 1377–1380 (1996).
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).
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).
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).
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).
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).
Yamashiro, S. et al. Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1. Dev. Cell 14, 787–797 (2008).
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).
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).
Goto, H. et al. Complex formation of Plk1 and INCENP required for metaphase–anaphase transition. Nat. Cell Biol. 8, 180–187 (2006).
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).
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).
Sumara, I. et al. The dissociation of cohesin from chromosomes in prophase is regulated by polo-like kinase. Mol. Cell 9, 515–525 (2002).
Riedel, C. G. et al. Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature 441, 53–61 (2006).
Kitajima, T. S. et al. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature 441, 46–52 (2006).
Tang, Z. et al. PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev. Cell 10, 575–585 (2006).
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).
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).
Eckerdt, F. & Strebhardt, K. Polo-like kinase 1: target and regulator of anaphase-promoting complex/cyclosome-dependent proteolysis. Cancer Res. 66, 6895–6898 (2006).
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).
Kraft, C. et al. Mitotic regulation of the human anaphase-promoting complex by phosphorylation. EMBO J. 22, 6598–6609 (2003).
Nasmyth, K. Segregating sister genomes: the molecular biology of chromosome separation. Science 297, 559–565 (2002).
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).
Hornig, N. C. & Uhlmann, F. Preferential cleavage of chromatin-bound cohesin after targeted phosphorylation by polo-like kinase. EMBO J. 23, 3144–3153 (2004).
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).
Mishima, M., Pavicic, V., Gruneberg, U., Nigg, E. A. & Glotzer, M. Cell cycle regulation of central spindle assembly. Nature 430, 908–913 (2004).
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).
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).
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).
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).
Hutterer, A. et al. Mitotic activation of the kinase Aurora-A requires its binding partner bora. Dev. Cell 11, 147–157 (2006).
Seki, A. et al. Plk1- and β-TrCP-dependent degradation of Bora controls mitotic progression. J. Cell Biol. 181, 65–78 (2008).
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.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1038/nrd3184
This article is cited by
-
Phospho PTEN mediated dephosphorylation of mitotic kinase PLK1 and Aurora Kinase A prevents aneuploidy and preserves genomic stability
Medical Oncology (2023)
-
CircCASC15-miR-100-mTOR may influence the cervical cancer radioresistance
Cancer Cell International (2022)
-
A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1
Oncogene (2022)
-
The phosphorylation and dephosphorylation switch of VCP/p97 regulates the architecture of centrosome and spindle
Cell Death & Differentiation (2022)
-
Genetic variations in AURORA cell cycle kinases are associated with glioblastoma multiforme
Scientific Reports (2021)