Phosphorylation of Plk1 at Ser326 regulates its functions during mitotic progression

Department of Biochemistry, Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
Oncogene (Impact Factor: 8.46). 09/2008; 27(52):6635-45. DOI: 10.1038/onc.2008.262
Source: PubMed


Polo-like kinase 1 (Plk1), the best characterized member of the mammalian polo-like kinase family, is well regulated throughout the cell cycle at the protein expression level. Moreover, it is known that Plk1 kinase activity is also regulated at the post-translational level through phosphorylation. However, the upstream kinases of Plk1 have not been identified. Although the involvement of the p38 MAP kinase pathway in cellular responses to stress has been well documented, the role of this pathway in normal cell cycle progression is unclear. Here, we show that phosphorylated p38 and MAP kinase-activated protein kinase 2 (MK2) are colocalized with Plk1 to the spindle poles during prophase and metaphase. Specific depletion of various members of the p38 MAP kinase pathway by the use of RNA interference revealed that the pathway is required for mitotic progression under normal growth conditions. Furthermore, MK2 directly phosphorylates Ser326 of Plk1. Ectopic expression of Plk1-S326A completely blocked cells at mitosis, likely due to the defect of bipolar spindle formation and subsequent activation of the spindle checkpoint. Only Plk1-S326E, but not the Plk1-S326A, efficiently rescued the p38 or MK2-depletion-induced mitotic defects, further solidifying the requirement of S326 phosphorylation during mitotic progression.

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    • "Thus, in controlling well differentiated HCC cells development, PLK1 may be important, while, in moderate or poor differentiated HCC cells, PLK1 maybe need to collaborate with other factors. Also, given that the distinct sites of phosphorylation in PLK1 will influence different stage of cell growth [19, 20], further studies are still needed to investigate whether the different sites of phosphorylation in PLK1 will affect the differentiation of HCC stem cells. In addition, the similar elevated levels of PLK1 expression in HCCs and surrounding cirrhosis suggested that PLK1 can serve as the prognostic standard to judge the possibility of canceration of cirrhosis tissue. "
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    ABSTRACT: Polo-like kinase 1 (PLK1), one of serine/threonine-protein kinase, has been demonstrated to play pivotal roles in malignant transformation. Here we illustrated the clinicopathological significance of PLK1 expression in hepatocellular carcinoma (HCC) in more detail. Immunohistochemistry was performed to detect the expression of PLK1 in 67 HCC patients as well as corresponding noncancerous liver tissues. In addition, the correlation of PLK1 expression with clinicopathological factors or prognosis of HCC was analyzed. Results showed that the expression of PLK1 was increased significantly in HCC tissues than that of corresponding normal liver tissues. The correlation between PLK1 and HCC cell differentiation or capsule invasion was also revealed. We found that PLK1 inhibition promoted cell arrest in G2/M phase of cell cycle and cell apoptosis. Our results also indicated that the potential mechanisms of PLK1 inhibition regulating cell growth involved enhancing expression of caspase3, caspase8, and Bax and decreasing expression of Bcl-2. Furthermore, we also found that PLK1 downregulation inducing inhibition of cell growth was associated with enhancing expression of p53. Thus, we presume that the status of PLK1 expression might be an independent prognostic factor for HCC and targeting PLK1 might be a useful strategy for diagnosis and treatment of human HCC.
    International Journal of Plant Genomics 06/2014; 2014:312130. DOI:10.1155/2014/312130
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    • "Thus, p53 null cells are unable to downregulate PLK1 in response to chemotherapy, leading to chemoresistance [25] [26]. Indeed, PLK1 colocalizes with p38 and MK2 at the spindle during mitosis and is phosphorylated by MK2, linking their activities and suggesting pathway crosstalk [27]. We recently made the important discovery that endometrial cancer cells with inactivated p53 rely on the p38 pathway to maintain the G2/M checkpoint [28]. "
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    ABSTRACT: Serous uterine endometrial carcinomas are aggressive type II cancers with poor outcomes for which new treatment strategies are urgently needed, in particular, strategies that augment sensitivity to established chemotherapy regimens. The tumor suppressor gene TP53 is dysregulated in more than 90% of serous tumors, altering master regulators of the G2/M cell cycle checkpoint in unique and predictable ways and desensitizing cells to chemotherapy. We hypothesized that synthetic lethality can be achieved in endometrial cancer cells with mutant p53 by combining paclitaxel with agents to overcome G2/M arrest and induce mitotic catastrophe. The combination of BIBF1120, an investigational VEGFR, PDGFR, and FGFR multityrosine kinase inhibitor with established anti-angiogenic activity, with paclitaxel abrogated the G2/M checkpoint in p53-null endometrial cancer cells via modulation of G2/M checkpoint regulators followed by induction of mitotic cell death. In endometrial cancer cells harboring an oncogenic gain-of-function p53 mutation, synthetic lethality was created by combining paclitaxel with BIBF1120 and a histone deacetylase inhibitor, which serves to destabilize mutant p53. These cells were also sensitive to an inhibitor of the G2/M kinase Wee1 in combination with paclitaxel. These findings reveal that, in addition to antiangiogenic activity, the angiokinase inhibitor BIBF1120 can be used to restore sensitivity to paclitaxel and induce mitotic cell death in endometrial cancer cells with non-functional p53. These preclinical data serve as a critical platform for the creative design of future clinical trials utilizing molecularly enhanced chemotherapy to achieve synthetic lethality based on the mutational landscape.
    Obstetrics and Gynecology International 12/2013; 2013(17):828165. DOI:10.1155/2013/828165
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    • "The expression of a mutant Plk1 or depletion of Plk1 caused spindle pole defects, accumulation of cells at the M phase, and massive cell death (Guan et al., 2005; Reagan-Shaw and Ahmad, 2005; Bu et al., 2008). Tang et al. (2008) described how MK2 colocalizes with activated p38 MAPK and Plk1 at spindle poles where it phosphorylates Plk1 at Ser326 to promote normal mitotic progression (Fig. 2D). Importantly, the same study reported that MK2 acts as a Plk1 kinase and that MK2 knockdown resulted in mitotic arrest. "
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    ABSTRACT: Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK-2 or MK2) is a downstream substrate of the p38 MAPK responsible for the signaling events influencing inflammation, cell division and differentiation, apoptosis as well as cell motility in response to a wide range of extracellular stimuli. Because of the failure of p38 MAPK inhibitors in clinical trials, MK2 unveiled as a potential target to regulate inflammatory cytokines mRNA stability and translation. Recent work suggests that this mechanism may underlie pathophysiology of brain disorders associated with inflammation. In addition, MK2 is a prominent kinase that phosphorylates heat shock protein 27, an intensively investigated biomarker of cancer progression. This phosphorylation decreases its chaperone properties, making MK2 an endogenous inhibitor of Hsp27. MK2 is also one of the major players in the signal transduction pathways activated in response to DNA damage. Experimental evidence highlights the role of MK2 in G2/M and the mitotic spindle checkpoints, two mechanisms by which MK2 contributes to the maintenance of genomic stability. Thus, MK2 is considered a good molecular target to increase, in combination with chemotherapeutic agents, the sensitivity of treatment especially in p53-mutated tumors. This review looks at the functions of MK2 in inflammation, Hsp27 regulation and cell cycle checkpoint control with focus on brain pathologies. Analysis of MK2 signaling in various disease models and summary of the data on MK2 inhibitors suggest novel indications for MK2 inhibitors in addition to their mainstream use against peripheral inflammatory disorders.
    Molecular pharmacology 12/2013; DOI:10.1124/mol.113.090365 · 4.13 Impact Factor
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