| The IKK inhibitor BMS-345541 affects multiple mitotic cell cycle transitions. | |
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MedLine Citation:
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PMID: 17704647 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Hana Blazkova; Conrad von Schubert; Keith Mikule; Rebekka Schwab; Nico Angliker; Jacqueline Schmuckli-Maurer; Paula C Fernandez; Stephen Doxsey; Dirk A Dobbelaere |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2007-07-30 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 6 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-10-24 Completed Date: 2007-11-13 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 2531-40 Citation Subset: IM |
Affiliation:
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Division of Molecular Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cercopithecus aethiops Chromosomes, Mammalian / genetics Cyclin A / metabolism Cyclin B / metabolism Cyclin B1 Humans I-kappa B Kinase / metabolism* Imidazoles / pharmacology* Mitosis / drug effects* Mitotic Spindle Apparatus / metabolism Quinoxalines / pharmacology* Telomerase / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA82834/CA/NCI NIH HHS; GM051994/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; 0/CCNB1 protein, human; 0/Cyclin A; 0/Cyclin B; 0/Cyclin B1; 0/Imidazoles; 0/Quinoxalines; EC 2.7.11.10/I-kappa B Kinase; EC 2.7.7.49/TERT protein, human; EC 2.7.7.49/Telomerase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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