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GSK-3 inhibitors induce chromosome instability

Tighe, Anthony; Ray-Sinha, Arpita; Staples, Oliver D and Taylor, Stephen S (2007) GSK-3 inhibitors induce chromosome instability. BMC Cell Biology, 8 . Article Number: 34. ISSN 1471-2121

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Abstract

Background: Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC) may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results: To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/ S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain monooriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion: Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK- 3 inhibitors may induce unwanted side effects by inducing chromosome instability.

Item Type:Article
Additional Information:Published: 14 August 2007. 17 pages (page numbers not for citation purposes).
Uncontrolled Keywords:GLYCOGEN-SYNTHASE KINASE-3; ADENOMATOUS-POLYPOSIS-COLI; APC TUMOR-SUPPRESSOR; SPINDLE CHECKPOINT; KINETOCHORE LOCALIZATION; MITOTIC CHECKPOINT; AURORA-B; MICROTUBULE DYNAMICS; STRUCTURAL INSIGHTS; CELL-DIVISION
Subjects:R Medicine > R Medicine (General)
R Medicine > RD Surgery
Departments, Research Centres and Related Units:Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Cancer Studies
DOI:10.1186/1471-2121-8-34
Publisher's Statement:© 2007 Tighe et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Related URLs:
Refereed:Yes
Status:Published
ID Code:692
Deposited On:04 Jun 2008 17:03
Last Modified:20 May 2011 08:57

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