Thus, therapeutic approaches aimed at inactivating PLK1 and/or reactivating PLK2-4 might be highly useful in the treatment of human liver cancer. (HEPATOLOGY 2010.) Polo-like kinase (PLKs) proteins play pivotal roles in cell cycle progression and response to DNA damage.1 Four members of this family of serine/threonine kinases were identified: PLK1, PLK2 (also known as SNK), PLK3 (also known as FNK or PRK), and PLK4 (or SAK).1 PLKs are characterized by a highly conserved N-terminal serine/threonine kinase domain and one or two polo boxes in the C-terminal region,

which are crucial for subcellular localization and binding of specific phosphopeptides.2 Expression of PLKs is tightly regulated during the cell cycle.1 PLK1 Inhibitor Library solubility dmso is inhibited by numerous checkpoint genes, whereas PLK2-4 genes are activated by spindle checkpoints and DNA damage.1, 3 Despite the high sequence homology among the four members of the PLK family, their functions seem to diverge. PLK1 is involved mainly in the control of the G2/M phase, by promoting CDC25C phosphatase activity with subsequent activation of CyclinB1/CdK1 find more complex, and the degradation of early mitotic inhibitor-1 (EMI1), which inhibits the activated Anaphase-Promoting Complex/Cyclosome.1 PLK2 and PLK3 were identified as serum-inducible

growth responsive genes and are implicated in the stress-response.4 Analysis of PLK2 knockout mice indicated that PLK2 is implicated in embryonic development and cell cycle regulation, as confirmed by recent findings showing an involvement of PLK2 in promotion of S-phase entry and centriole duplication.5 Previously, levels of PLK3 have been described as either unchanged throughout the cell cycle6 or increased in mitosis.7 However, more recent evidence indicates that PLK3 expression peaks in G1 phase and is required for S phase entry through the regulation of cyclin E levels.8 Moreover, PLK3 is implicated in the regulation of Golgi apparatus fragmentation during cell cycle progression, and deregulated expression of PLK3 in vitro promotes cell cycle arrest and apoptosis, mainly due to microtubule disfunctions.9, 10 Like all other PLKs, PLK4 is

implicated in cell cycle regulation, because constitutive PLK4 expression leads to decreased cell growth and multinucleation in vitro.11, 12 Indeed, PLK4 is involved in the 上海皓元医药股份有限公司 proper reproduction of centrosomes,13 and it is required for the APC-dependent destruction of cyclin B1, with the consequent exit from mitosis.11 Due to the critical role of PLKs in controlling cell cycle progression, their involvement in oncogenesis might be envisaged. An oncogenic role for PLK1 has been hypothesized, because its constitutive expression in NIH3T3 fibroblasts causes oncogenic foci formation and is tumorigenic in nude mice.14 Furthermore, PLK1 is overexpressed in a variety of human tumors,3 including human hepatocellular carcinoma (HCC).