The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions

Blazkova, Hana; von Schubert, Conrad; Mikule, Keith; Schwab, Rebekka; Angliker, Nico; Schmuckli-Maurer, Jacqueline; Fernandez, Paula C; Doxsey, Stephen; Dobbelaere, Dirk, (2007). The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions. Cell cycle, 6(20), pp. 2531-40. Georgetown, Tex.: Landes Bioscience 10.4161/cc.6.20.4807

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The IkappaB kinase (IKK) complex controls processes such as inflammation, immune responses, cell survival and the proliferation of both normal and tumor cells. By activating NFkappaB, the IKK complex contributes to G1/S transition and first evidence has been presented that IKKalpha 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 G2 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Molecular Pathobiology

UniBE Contributor:

Von Schubert, Conrad; Schmuckli, Jacqueline and Dobbelaere, Dirk,

ISSN:

1538-4101

Publisher:

Landes Bioscience

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:53

Last Modified:

30 Jul 2014 08:10

Publisher DOI:

10.4161/cc.6.20.4807

PubMed ID:

17704647

Web of Science ID:

000251085800016

URI:

https://boris.unibe.ch/id/eprint/22726 (FactScience: 36316)

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