Disease relevance of PLK1

• Our results suggest that the phosphorylation of HSF1 by PLK1 is an essential step for HSF1 nuclear translocation by heat stress [1].
• Furthermore, this study suggests that PLK1 is a novel independent prognostic marker in ovarian carcinomas [2].
• When PLK1 function was blocked through adenovirus delivery of a dominant-negative gene, we observed tumor-selective apoptosis in most tumor cell lines [3].
• In this study, the expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimen of normal ovaries (n=9), cystadenomas (n=17), borderline tumours (n=13) and ovarian carcinomas (n=77) [2].
• In this study, expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimens of 135 breast carcinomas, and expression was correlated with clinicopathological parameters and patient prognosis [4].

High impact information on PLK1

• Following phosphorylation of PICH on the Cdk1 site T1063, Plk1 is recruited to PICH and controls its localization [5].
• We propose that the balance of Evi5 and Polo-like kinase activities determines the timely accumulation of Emi1 and cyclin, ensuring mitotic fidelity [6].
• Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase [7].
• During cell-cycle progression in HeLa cells, a change in the kinase activity of endogenous Plk1 toward S147 and/or S133 correlates with a kinase activity in the cell extracts [7].
• An anti-Plk1 antibody depletes the M-phase extracts of the kinase activity toward S147 and/or S133 [7].

Chemical compound and disease context of PLK1

• AIM: Polo-like kinase 1 (PLK1) serine/threonine kinase plays a vital role in multiple phases of mitosis in gastric cancer cells [8].
• In order to define the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells [9].
• Moreover, selective targeting of plk1 or chk1 in tumor xenografts of mice by oncolytic adenovirus mutants demonstrated potent anti-tumoral efficacy in the presence of low dose cisplatin [10].
• We used phosphorothioate antisense oligonucleotides (ASO) targeted against Plk1, together with paclitaxel, carboplatin, and Herceptin, for the treatment of breast cancer cells to identify conditions for enhanced drug sensitivity [11].
• Therefore, we suggest that the over-expression of PLK in the CA1 pyramidal cells at 12 h after ischemia may induce increase of GAD in the CA1 pyramidal cells, which plays an important role in delayed neuronal death via the increase of GABA or enhancement of GABA shunt pathway [12].

Biological context of PLK1

• This interaction results in the phosphorylation of HSF1 on serine 419 by PLK1 [1].
• Polo-like kinase 1 (PLK1) is an evolutionarily conserved serine/threonine kinase essential for cell mitosis [13].
• Nuclear run-on assays and mRNA stability studies demonstrated that the effect of NO. on PLK1 expression was associated with decreased transcription without changes in transcript stability [13].
• Reporter gene experiments showed that NO. decreased activity of the PLK1 proximal promoter, an effect that was blocked by p38 MAPK inhibitor [13].
• RESULTS: PLK1 gene knockdown was associated with increased cyclin B expression, increased cdc2 activity (but not with the expression levels), accumulation of gastric cancer cells at G2/M, improper mitotic spindle formation, delayed chromosome separation and delayed or arrested cytokinesis [8].

Anatomical context of PLK1

• Also, loss of PLK1 function has been shown to induce mitotic catastrophe in a HeLa cervical carcinoma cell line but not in normal Hs68 fibroblasts [3].
• In some lines, dominant-negative PLK1 induced a mitotic catastrophe similar to that published in HeLa cells (K. E. Mundt et al., Biochem. Biophys Res. Commun., 239: 377-385, 1997) [3].
• Mitotic phosphorylation of cdc25C and activation of cdk1 was blocked by dominant-negative PLK1 in human mammary epithelial cells as well as in the tumor lines regardless of whether they underwent mitotic catastrophe [3].
• Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies [14].
• Another kinase implicated in regulating progression through mitosis is Plk1 (polo-like kinase 1), the human homologue of the Drosophila gene product "polo." By antibody microinjection we have found that Plk1 is required for the functional maturation of centrosomes and hence for entry into mitosis [15].

Associations of PLK1 with chemical compounds

• Nitric oxide (NO.) has been shown to down-regulate PLK1 and up-regulate p21/Waf1 independent of cGMP [13].
• Here, we show that treatment of mitotic cells with doxorubicin and gamma-irradiation inhibits Plk1 activity through dephosphorylation of Plk1, and cells were arrested in G(2) phase [16].
• Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region [13].
• These results suggest that suppression of the activity of PLK1 via inhibition of tyrosine kinase activity by beta-HIVS might play a critical role in the induction of apoptosis [17].
• Here, we report that wortmannin, which was previously thought to be a highly selective inhibitor of phosphoinositide (PI) 3-kinases, is a potent inhibitor of mammalian PLK1 [18].
• Kif2a is regulated positively by Plk1 and negatively by Aurora A [19].

Physical interactions of PLK1

• Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA [20].
• Mitotic phosphorylation of the peripheral Golgi protein Nir2 by Cdk1 provides a docking mechanism for Plk1 and affects cytokinesis completion [21].
• Endogenous Plk1 co-immunoprecipitates with basal forms of Mcm7 as well as with slower migrating forms of Mcm7, induced in response to DNA damage [22].
• In a search for interactions between Chk2 and proteins with similar subcellular localization patterns, we found that Chk2 coimmunoprecipitates with Polo-like kinase 1, a regulator of chromosome segregation, mitotic entry, and mitotic exit [23].
• Phosphorylation of Claspin is mediated by Plk1 and is essential for binding to betaTrCP [24].

Enzymatic interactions of PLK1

• These results suggest that Plk1 phosphorylates Myt1 during M phase [25].
• We found that Plk1 can phosphorylate Nek2 in vitro and interacts with Nek2 in vivo [26].
• Plk1 phosphorylates recombinant Chk2 in vitro [23].

Regulatory relationships of PLK1

• Co-expression of constitutively active Plk1 stimulates nuclear entry of cyclin B1 [7].
• In response to DNA damage, ATM/ATR-dependent checkpoint pathways inhibit Plk1 activity [27].
• Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1 [28].
• Depletion of Plk1 by RNA interference suppresses BRCA2 modification [29].
• Interestingly, the Polo box domain of Plk3 is more potent in inhibiting cell proliferation and inducing apoptosis than that of Plk1, suggesting that this domain can provide an additional structural basis for discovery of new anticancer drugs given the current emphasis on Plk1 as a therapeutic target [30].
• Plk1 self-regulates the Plk1-PBIP1 interaction to timely localize to the kinetochores and promote proper chromosome segregation [31].
• Activation of Plk1 inhibited TNF-induced expression of cyclin D1 [32].

Co-localisations of PLK1

• We go on to characterize the mitosis-specific interaction of the Plk1-PBD with the cytokinesis effector kinase Rho-associated coiled-coil domain-containing protein kinase 2 (Rock2), demonstrate that Rock2 is a Plk1 substrate, and show that Rock2 colocalizes with Plk1 during cytokinesis [33].

Other interactions of PLK1

• APC phosphorylation by Cdk1, but not by Plk1, is sufficient for increased Cdc20 binding and APC activation [34].
• Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome [35].
• Endogenous ECT2 in mitotic cells strongly associated with Plk1 PBD, and this binding was inhibited by phosphatase treatment [20].
• Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1 [36].
• Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like protein CHO1/MKLP-1 [37].
• Mutation of these Cdk1-sites results in a form of PRC1 that prematurely recruits Plk1 to the spindle during prometaphase and blocks mitotic progression [38].

Analytical, diagnostic and therapeutic context of PLK1

• METHODS: PLK1 expression was determined in 160 gastric carcinoma patients by immunohistochemistry and compared with p53 expression and the proliferating cell nuclear antigen-labeling index (PCNA-LI) to evaluate the effect of PLK1 on tumor progression [39].
• The expression levels of PLK1, cdc2, cyclin B and caspase 3 were detected by Western blotting [8].
• In addition, expression of PLK1 was evaluated by immunoblot and PCR in colon carcinoma cell lines, and coexpression of PLK1 with the proliferation marker Ki-67 was investigated [40].
• METHODS: Expression of PLK1 was investigated by immunohistochemistry (158 cases) and immunoblotting in tissue of colon adenomas and adenocarcinomas [40].
• The physical interaction of Plk1 and B23 was further demonstrated by their co-immunoprecipitation and glutathione S-transferase fusion protein pull-down assays [41].

References