<i>In vitro</i> biological activity of a novel small-molecule inhibitor of polo-like kinase 1

Lansing, Timothy J.; McConnell, Randy T.; Duckett, Derek R.; Spehar, Glenn; Knick, Victoria B.; Hassler, Daniel F.; Noro, Nobuhiro; Furuta, Masaaki; Emmitte, Kyle A.; Gilmer, Tona M.; Mook, Robert A.; Cheung, Mui

doi:10.1158/1535-7163.mct-06-0543

Cited by 135 publications

(111 citation statements)

References 33 publications

(28 reference statements)

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“…CIF1 is a highly phosphorylated protein, containing 29 in vivo phospho-serine and phospho-threonine sites (15). To test whether CIF1 is an in vivo substrate of TbPLK, we treated the cells with GW843682X, a small-molecule Polo-like kinase inhibitor (16,17). CIF1 was detected as a doublet on the Western blot, and treatment with GW843682X reduced the level of the upper band of CIF1, which was confirmed to be the phosphorylated form of CIF1, suggesting de-phosphorylation of CIF1 by TbPLK inhibition ( Fig.…”

Section: Cif1 Colocalizes With Tbplk At Early Cell Cycle Stages and Wmentioning

confidence: 99%

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Zhou¹,

Zhao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

160

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Cytokinesis in Trypanosoma brucei, an early branching protozoan, occurs along its longitudinal axis uni-directionally from the anterior tip of the new flagellum attachment zone filament toward the cell's posterior end. However, the underlying mechanisms remain elusive. Here we report that cytokinesis in T. brucei is regulated by a concerted action of Polo-like kinase, Aurora B kinase, and a trypanosome-specific protein CIF1. Phosphorylation of CIF1 by Polo-like kinase targets it to the anterior tip of the new flagellum attachment zone filament, where it subsequently recruits Aurora B kinase to initiate cytokinesis. Consistent with its role, CIF1 depletion inhibits cytokinesis initiation from the anterior end of the cell, but, surprisingly, triggers cytokinesis initiation from the posterior end of the cell, suggesting the activation of an alternative cytokinesis from the opposite cell end. Our results reveal the mechanistic roles of CIF1 and Polo-like kinase in cytokinesis initiation and elucidate the mechanism underlying the recruitment of Aurora B kinase to the cytokinesis initiation site at late anaphase. These findings also delineate a signaling cascade controlling cytokinesis initiation from the anterior end of the cell and uncover a backup cytokinesis that is initiated from the posterior end of the cell when the typical anterior-to-posterior cytokinesis is compromised.cytokinesis | Polo-like kinase | Aurora B kinase | backup cytokinesis |

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Section: Cif1 Colocalizes With Tbplk At Early Cell Cycle Stages and Wmentioning

confidence: 99%

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Zhou¹,

Zhao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

160

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“…In fact, multiple small-molecule inhibitors targeting the enzymatic kinase domain and the regulatory Polobox binding domain (PBD) have been recently developed and characterized. 1,[7][8][9][10][11][12][13][14][15][16][17][18][19] In particular, BI 2536 and BI 6727 are the most intensively investigated Plk1 inhibitors. [20][21][22][23][24][25] Poloxin, the first reported non-peptidic inhibitor of the PBD of Plk1, shows its specificity and anti-proliferative activity in vitro as well as in vivo.…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53

et al. 2013

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“…NEK2, Plk1, Cdk1, Aurora A and Aurora B, are critical regulators of entry into and progression through mitosis and inhibition of these kinases can provoke phenotypes similar to what we observed using BMS-345541, [43][44][45][46][47] As, in preliminary experiments, we had observed a mild inhibition of Cdk1, we carried out more extensive in vitro kinase assays, to examine whether BMS-345541 was capable of directly blocking the activity of any of these mitotic kinases. A range of different concentrations of BMS-345541 was tested using commercially available in vitro kinase assay kits, and the IC 50 of BMS-345541 determined for each of the kinases.…”

confidence: 60%

The IKK Inhibitor BMS-345541 Affects Multiple Mitotic Cell Cycle Transitions

Blažková

Schubert²,

Mikule³

et al. 2007

Cell Cycle

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The IκB kinase (IKK) complex controls processes such as inflammation, immune responses, cell survival and the proliferation of both normal and tumor cells. By activating NFκB, the IKK complex contributes to G 1 /S transition and first evidence has been presented that IKKα also regulates entry into mitosis. At what stage IKK is required and whether IKK also contributes to progression through mitosis and cytokinesis, however, has not yet been determined. In this study, we use BMS-345541, a potent allosteric small molecule inhibitor of IKK, to inhibit IKK specifically during G 2 and during mitosis. We show that BMS-345541 affects several mitotic cell cycle transitions, including mitotic entry, prometaphase to anaphase progression and cytokinesis. Adding BMS-345541 to the cells released from arrest in S-phase blocked the activation of Aurora A, B and C, Cdk1 activation and histone H3 phosphorylation. Additionally, treatment of the mitotic cells with BMS-345541 resulted in precocious cyclin B1 and securin degradation, defective chromosome separation and improper cytokinesis. BMS-345541 was also found to override the spindle checkpoint in nocodazole-arrested cells. In vitro kinase assays using BMS-345541 indicate that these effects are not primarily due to a direct inhibitory effect of BMS-345541 on mitotic kinases such as Cdk1, Aurora A or B, Plk1 or NEK2. This study points towards a new potential role of IKK in cell cycle progression. Since deregulation of the cell cycle is one of the hallmarks of tumor formation and progression, the newly discovered level of BMS-345541 function could be useful for cell cycle control studies and may provide valuable clues for the design of future therapeutics.

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In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1

Abstract: Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis.

Cited by 135 publications

References 33 publications

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53

The IKK Inhibitor BMS-345541 Affects Multiple Mitotic Cell Cycle Transitions

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