Polo-like kinases and oncogenesis

Eckerdt, Frank; Yuan, Juping; Strebhardt, Klaus

doi:10.1038/sj.onc.1208273

Cited by 337 publications

(293 citation statements)

References 107 publications

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“…Polo-like kinase 1 is proposed to play a role in tumorigenesis and oncogenic transformation (Eckerdt et al, 2005;Takai et al, 2005). Plk1 overexpression is positively correlated with aggressiveness in a variety of human tumors, including melanomas, gliomas, nonsmall-cell lung, head and neck, esophageal, gastric, breast, ovarian, endometrial, colorectal and thyroid cancers (Wolf et al, 1997;Knecht et al, 1999Knecht et al, , 2000Strebhardt et al, 2000;Eckerdt et al, 2005;Takai et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Plk1 overexpression is positively correlated with aggressiveness in a variety of human tumors, including melanomas, gliomas, nonsmall-cell lung, head and neck, esophageal, gastric, breast, ovarian, endometrial, colorectal and thyroid cancers (Wolf et al, 1997;Knecht et al, 1999Knecht et al, , 2000Strebhardt et al, 2000;Eckerdt et al, 2005;Takai et al, 2005). Patients with a moderate Plk1 expression level usually survive longer than those with a high Plk1 level.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with a moderate Plk1 expression level usually survive longer than those with a high Plk1 level. Thus, Plk1 has been proposed as a new prognostic marker for many types of malignancies (Eckerdt et al, 2005;Takai et al, 2005). Moreover, inhibition of Plk1 with various techniques, such as RNA interference (RNAi) and small-molecule inhibitor, results in growth arrest or apoptosis in cancer cells and inhibits xenograft tumor growth in nude mice (Liu and Erikson, 2003;Spankuch et al, 2004;Gumireddy et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Lei

Erikson

2008

Oncogene

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We previously reported that polo-like kinase 1 (Plk1) depletion by lentivirus-based RNA interference led to mitotic arrest and apoptosis in cancer cells, whereas normal diploid cell lines, hTERT-RPE1 and MCF10A, survived a similar level of depletion. To study homogeneous cell lines, we generated several Plk1-depleted hTERT-RPE1 and MCF10A clones that were derived from single cells depleted of Plk1. We found that in the long term, Plk1 depletion slowed proliferation of hTERT-RPE1 cells, apparently due to attenuated progression through S phase. These cells had altered morphology and were elongated compared with control. In contrast, MCF10A clones with mild levels of depletion showed no obvious phenotype. They appeared to have normal proliferation rates with no cell-cycle arrest. However, one MCF10A clone, which was severely depleted of Plk1, although viable, showed sporadic G2/M arrest and apoptosis. This MCF10A clone and all the hTERT-RPE1 clones displayed evidence of DNA-damage checkpoint activation. These data further support the interpretation that cancer cell lines have a much greater requirement for Plk1 than normal nontransformed diploid cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Lei

Erikson

2008

Oncogene

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“…PLKs studied in yeasts (Cdc5, and Plo1), fruit flies (Plo1), worms (Plc1), and mice (Plk1) also regulate the specialized cell division that gives rise to gametes, known as meiosis [10,11]. In humans, deregulated PLKs are strongly implicated in tumorigenesis and therefore, represent an ideal protein kinase target for cancer drug development [12]. However, our understanding of its downstream targets for phosphorylation is still at infancy.…”

Section: * Corresponding Author Email: Asourirajan@gmailcom Phone: mentioning

confidence: 99%

Cloning, expression and purification of functionally active Saccharomyces cerevisiae Polo-like Kinase, Cdc5 in E. coli

2015

J App Biol Biotech

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Polo-like Kinases (PLKs) belong to the serine/threonine family of protein kinases. They govern cell cycle progression in concert with CDKs and other cell cycle kinases in most eukaryotes studied. Polo-box domain, the signature motif of PLKs, functions to recruit the kinase to its substrates. However, the substrate specificity, and the complete repertoire of its substrates is not fully known, and their mode of action is still under investigation. The present study was undertaken to clone and express the budding yeast PLK, Cdc5 in E. coli. The recombinant Cdc5 was successfully expressed as a GST-Cdc5 fusion protein of ~ 107 kDa. GST-Cdc5 was purified to ~ 95% homogeneity. Interestingly, the recombinant GST-Cdc5 exhibited kinase activity in vitro. GST-Cdc5, but not GST-tag alone phosphorylated the generic substrate casein as well as showed autophosphorylation of the kinase itself. Thus, the recombinant GST-Cdc5 protein is functionally active in vitro and mimics its characteristics in vivo. The availability of the recombinant and active Cdc5 protein would facilitate structure-function investigations as well as the generation of appropriate truncated and site-directed mutant proteins, respectively for further insight into the cell cycle regulation mechanisms of PLKs.

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“…4 The importance of PLK1 in cell proliferation and its overexpression in various human cancers appear to be sufficient to override cellular checkpoints and induce genetic instability, promoting tumorigenesis. [5][6][7] Also the level of PLK1 positively correlates with aggressiveness of tumor progression, and patients with high PLK1 expression in their tumors exhibit a significantly poorer rate of survival than those with low PLK1 expression. [8][9][10][11] Induction of apoptosis occurs in most tumor cells but not in normal cells upon interfering with PLK1 function, [12][13][14] and tumor regressions in mouse xenograft models has also been observed.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Nair

Schwartz

2015

Cell Cycle

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Sarcomas are rare cancers and the current treatments in inoperable or metastatic disease have not been shown to prolong survival. In order to develop novel targeted therapies, we tested the efficacy of polo-like kinase 1 (PLK-1) inhibitor (TAK-960) in sarcoma. All the sarcoma cell lines were sensitive to TAK-960 with IC50s in the low nanomolar range. We chose MPNST, CHP100 and LS141 for our studies and of which MPNST cells exclusively underwent polyploidy after a delay in mitosis for about 18 hours; CHP100 cells, after a 24h mitotic delay, died of apoptosis; LS141, after a delay in mitosis stayed at 4N with mild apoptosis. Apoptosis induced by TAK-960 in CHP100 was associated with downregulation of Mcl-1 and the effect was recapitulated by down-regulating PLK1 by siRNA, confirming that the effect of TAK-960 on Mcl-1 expression is target specific. With suppression of Mcl-1 by siRNA, TAK-960 induced apoptosis in MPNST cells as well. These effects were confirmed in vivo, such that TAK-960 more effectively inhibited CHP100 than MPNST xenografts. In the setting of PLK-1 inhibition, Mcl-1 down regulation is shown to be an important determinant of apoptosis. Collectively, the net effect of this is to drive cells to apoptosis, resulting in a greater anti-tumor effect in vivo. Therefore, targeting PLK-1 should have a greater impact in treating sarcomas provided there is concomitant suppression of Mcl-1. These results further indicate that Mcl-1 could be an important biomarker to predict sensitivity to the induction of apoptosis by PLK-1 targeted therapy in sarcoma.

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Polo-like kinases and oncogenesis

Cited by 337 publications

References 107 publications

Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Cloning, expression and purification of functionally active Saccharomyces cerevisiae Polo-like Kinase, Cdc5 in E. coli

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

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