The Small-Molecule Inhibitor BI 2536 Reveals Novel Insights into Mitotic Roles of Polo-like Kinase 1

Lénárt, Péter; Petronczki, Mark; Steegmaier, Martin; Fiore, Barbara; Lipp, Jesse J.; Hoffmann, M.; Rettig, Wolfgang; Kraut, Norbert; Peters, Jan‐Michael

doi:10.1016/j.cub.2006.12.046

Cited by 619 publications

(471 citation statements)

References 47 publications

(83 reference statements)

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“…BI 4834 treatment for 15 min did not cause a detectable reduction in H3 phosphorylation or of the CDC27 mobility shift or an increase of inhibitory CDK1 phosphorylation, indicating that the phosphorylation states of Aurora B and CDK1 substrates were not or not to the same degree affected as the phosphorylation of PLK1 substrates. These data are consistent with the previous observation that inhibition of PLK1 causes activation of the spindle assembly checkpoint and an arrest in prometaphase, which depends on Aurora B and CDK1 activity (8,34).…”

Section: Identification Of Plk1-dependent Phosphorylation Sites-supporting

confidence: 93%

“…1A. We used the compound BI 4834 to inhibit PLK1 in this study because this compound inhibits PLK1 with similar efficacy (IC 50 7.6 nM) but with higher selectivity over the related enzyme PLK3 (IC 50 198.4 nM) as the previously characterized compound BI 2536 (8). Treatment of cells with increasing amounts of BI 4834 showed that at 250 nM BI 4834 caused a cellular phenotype indistinguishable from BI 2536 treatment, e.g.…”

Section: Identification Of Plk1-dependent Phosphorylation Sites-mentioning

confidence: 99%

“…During mitotic entry, PLK1 amplifies cyclin-dependent kinase 1 (CDK1) activation, enabling efficient onset of mitosis (4) and mediates centrosome maturation, the accumulation of ␥-tubulin complexes on centrosomes (5,6). In prometaphase, PLK1 is required for the generation of stable kinetochoremicrotubule attachments (7)(8)(9)(10). PLK1 also promotes dissociation of cohesin from chromosome arms in prophase and prometaphase by phosphorylating cohesin's STAG2 subunit (11)(12)(13)(14), as well as multiple aspects of cytokinesis by phosphorylating activators and effectors of RhoA (1,15).…”

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confidence: 99%

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Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome

Grosstessner-Hain

Hegemann

Novatchkova

et al. 2011

Molecular & Cellular Proteomics

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Polo-like kinase 1 (PLK1) is a key regulator of mitotic progression and cell division, and small molecule inhibitors of PLK1 are undergoing clinical trials to evaluate their utility in cancer therapy. Despite this importance, current knowledge about the identity of PLK1 substrates is limited. Here we present the results of a proteome-wide analysis of PLK1-regulated phosphorylation sites in mitotic human cells. We compared phosphorylation sites in HeLa cells that were or were not treated with the PLK1-inhibitor BI 4834, by labeling peptides via methyl esterification, fractionation of peptides by strong cation exchange chromatography, and phosphopeptide enrichment via immobilized metal affinity chromatography. Analysis by quantitative mass spectrometry identified 4070 unique mitotic phosphorylation sites on 2069 proteins. Of these, 401 proteins contained one or multiple phosphorylation sites whose abundance was decreased by PLK1 inhibition. These include proteins implicated in PLK1-regulated processes such as DNA damage, mitotic spindle formation, spindle assembly checkpoint signaling, and chromosome segregation, but also numerous proteins that were not suspected to be regulated by

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Section: Identification Of Plk1-dependent Phosphorylation Sites-supporting

confidence: 93%

Section: Identification Of Plk1-dependent Phosphorylation Sites-mentioning

confidence: 99%

mentioning

confidence: 99%

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Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome

Grosstessner-Hain

Hegemann

Novatchkova

et al. 2011

Molecular & Cellular Proteomics

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“…Consistently, the Aurora A inhibitor MLN8054 also appears to exhibit an inhibitory effect on Aurora A stability at the centrosome in human cells, 19 and a specific small molecule inhibitor of Polo kinases, termed BI 2536, has recently been reported to block the targeting of Plk1 to the centrosome by a similar inactivation mechanism. 38 This positive correlation between activity status and targeted subcellular localisation might therefore be a conserved feature of mitotic protein kinase biology.…”

Section: Discussionmentioning

confidence: 95%

VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

Tyler¹,

Shpiro²,

Marquez³

et al. 2007

Cell Cycle

108

100

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“…1 The use of small molecule inhibitors has revealed roles of PLK1 in cell cycle regulation, mainly during mitosis. 2 Consistent with these functions, PLK1 localization is also dynamic during cell cycle progression, moving from centrosomes to spindle poles, kinetochores and midbodies. 3 Elevated PLK1 activity, often observed in cancer cells, supports increased proliferation, compromising genomic integrity which could be due to altered transcriptional programs.…”

Section: Introductionmentioning

confidence: 82%

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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The Small-Molecule Inhibitor BI 2536 Reveals Novel Insights into Mitotic Roles of Polo-like Kinase 1

Cited by 619 publications

References 47 publications

Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome

Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome

VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

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

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