BY: MORGAN ATKINSON
During the cell cycle (both mitosis and meiosis), there are many proteins involved, but Polo-like Kinases have been shown to be regulators of the different stages of the cell cycle, ensuring that it occurs correctly. There are five total Polo-like kinases (PLK’s), each of which has a unique role in regulating cell division (de Cárcer, Guillermo et al. 2011). It is incredibly important that cell division occurs without error, as errors in DNA or other cell structures have critical, and possible fatal consequences, and because of this the proper function of PLK’s 1-5 is vital.
Overall, the structure of all five PLK’s are very similar with key structures being the polo-box domain (PBD), which activates the properties of the PLK and also is the site of localization (de Cárcer, Guillermo et al. 2011). In addition, PLK’s also have a serine/threonine kinase domain. Both of these domains are sites of binding, and modification by proteins, which is important to understanding how they regulate the cell cycle (de Cárcer, Guillermo et al. 2011). However, there are some significant differences among all five of the PLKS, both in structure and function.
Firstly, PLK1 is involved in several key parts of the cell cycle, including chromosome regulation, the beginning of mitosis, bi-polar spindle formation and cytokinesis (Barr, Siljie & Nigg 2004). PLK2 has been studied and been found to regulate the G1 phase of cell division and it has important roles in centrosome and centriole replication. There have also been shown to be interactions between PLK2 and PLK4, but not much is known (Barr, Siljie & Nigg 2004). PLK3 is involved with the S phase of cell division, specifically DNA replication and mitotic entry via golgi apparatus. PLK4 is involved in centriole replication, similar to PLK2. Finally, PLK5 so far has not been identified as regulating the cell cycle, but instead has an incomplete PDB and is involved in neuron differentiation (de Cárcer, Guillermo et al. 2011).
While PLK regulation is key to having a proper cell cycle and division, PLK’s, specifically PLK1 has been linked to tumorigenesis and cancer outcome. PLK1 has been found to be overexpressed in samples of many different types of cancer (Lee et al 2014). One of the theories is that since PLK1 is involved in centrosome maturation and chromosome maturation, if it does not function properly, abnormal chromosome separation can occur, causing cancer cells, which is due to the loss of oncogenes (Lee et al 2014). PLK1 has also been shown to bind to, and inhibit the anti-tumor gene, P53. In addition, PLK1 is also involved with apoptosis, since it interacts with FAAD (which controls apoptosis), and inhibits it, preventing proper apoptosis and leading to cancer cells (Lee et al 2014). The combination of the inhibition of apoptosis, inhibition of P53 and abnormal chromosome division creates the perfect conditions for cancer cells (Lee et al 2014). However, other PLK’s are also implicated in cancer cells, as PLK2 is silenced in several types of cancer, and mice studies have shown that decreased levels of PLK3 and PLK4 make mice more susceptible to tumors (PMC3230524). Finally, PLK5 has been shown to be silenced in brain tumors, but not much more is known about its role (Lee et al 2014).
The role of PLK1 in cancer has also been shown through several successful inhibitors, as it is a key target in anti-cancer therapies (Lee et al 2014). Some of these inhibitors include BI2536, Volasertib, Poloxin and others (Gutteridge et al 2016). All of these are effective inhibitors as BI2536 was shown to inhibit and prevent tumor growth, Volasertib was shown to be a competitive ATP-inhibitor and work on preventing cancer, and finally, Poloxin was shown to be a competitive inhibitor by binding to the Polo Box Domain and interfering with the structure and function of PLK1 (Gutteridge et al 2016). Currently, there are also other PLK inhibitors being studied, with the goal to have cancer treatments that are targeted and have significantly less side effects than chemotherapy Gutteridge et al 2016).
Overall, the PLK group has incredibly important roles in cell division; however, they also have the potential to go awry and cause both tumors and cancers of many types. While PLK1 has been shown to have the clearest link between elevated levels and cancer, other PLK’s have been implicated in cancer growth (Lee et al 2014). Finally, PLK’s offer a specific drug target that allow for cancer therapies without as many side effects as chemotherapy (Gutteridge et al 2016). More research needs to be, and is being, conducted regarding the role of PLK’s in cancer and the potential for targeted drug therapies.
Barr, F., Silljé, H. & Nigg, E. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5, 429–441 (2004). https://doi.org/10.1038/nrm1401
de Cárcer, Guillermo et al. “From Plk1 to Plk5: functional evolution of polo-like kinases.” Cell cycle (Georgetown, Tex.) vol. 10,14 (2011): 2255-62. doi:10.4161/cc.10.14.16494
Gutteridge, Rosie Elizabeth Ann et al. “Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics.” Molecular cancer therapeutics vol. 15,7 (2016): 1427-35. doi:10.1158/1535-7163.MCT-15-0897
Lee, Su-Yeon et al. “Polo-like kinases (plks), a key regulator of cell cycle and new potential target for cancer therapy.” Development & reproduction vol. 18,1 (2014): 65-71. doi:10.12717/DR.2014.18.1.065