Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/74433
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Type: | Journal article |
Title: | A Screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect |
Author: | Shaukat, Z. Wong, H. Nicolson, S. Saint, R. Gregory, S. |
Citation: | PLoS One, 2012; 7(10):1-10 |
Publisher: | Public Library of Science |
Issue Date: | 2012 |
ISSN: | 1932-6203 1932-6203 |
Editor: | Jennings, B. |
Statement of Responsibility: | Zeeshan Shaukat, Heidi W.S. Wong, Shannon Nicolson, Robert B. Saint and Stephen L. Gregory |
Abstract: | BACKGROUND: The spindle assembly checkpoint is crucial for the maintenance of a stable chromosome number. Defects in the checkpoint lead to Chromosomal INstability (CIN), which is linked to the progression of tumors with poor clinical outcomes such as drug resistance and metastasis. As CIN is not found in normal cells, it offers a cancer-specific target for therapy, which may be particularly valuable because CIN is common in advanced tumours that are resistant to conventional therapy. PRINCIPAL FINDINGS: Here we identify genes that are required for the viability of cells with a CIN phenotype. We have used RNAi knockdown of the spindle assembly checkpoint to induce CIN in Drosophila and then screened the set of kinase and phosphatase genes by RNAi knockdown to identify those that induce apoptosis only in the CIN cells. Genes identified include those involved in JNK signaling pathways and mitotic cytoskeletal regulation. CONCLUSIONS/SIGNIFICANCE: The screen demonstrates that it is feasible to selectively kill cells with CIN induced by spindle checkpoint defects. It has identified candidates that are currently being pursued as cancer therapy targets (e.g. Nek2: NIMA related kinase 2), confirming that the screen is able to identify promising drug targets of clinical significance. In addition, several other candidates were identified that have no previous connection with mitosis or apoptosis. Further screening and detailed characterization of the candidates could potentially lead to the therapies that specifically target advanced cancers that exhibit CIN. |
Keywords: | Cytoskeleton Animals Humans Drosophila Chromosomal Instability Phosphoric Monoester Hydrolases Phosphotransferases Cell Cycle Proteins Apoptosis Cell Survival MAP Kinase Signaling System Gene Knockdown Techniques Molecular Targeted Therapy M Phase Cell Cycle Checkpoints NIMA-Related Kinase 1 Protein Serine-Threonine Kinases |
Rights: | Copyright: © 2012 Shaukat et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
DOI: | 10.1371/journal.pone.0047447 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/525477 http://purl.org/au-research/grants/nhmrc/1027878 |
Published version: | http://dx.doi.org/10.1371/journal.pone.0047447 |
Appears in Collections: | Aurora harvest 4 Molecular and Biomedical Science publications |
Files in This Item:
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hdl_74433.pdf | Published version | 1.47 MB | Adobe PDF | View/Open |
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