A screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect
| Autor: | Shannon Nicolson, Heidi W. S. Wong, Zeeshan Shaukat, Stephen L. Gregory, Robert Saint |
|---|---|
| Přispěvatelé: | Shaukat, Zeeshan, Wong, Heidi WS, Nicolson, Shannon, Saint, Robert B, Gregory, Stephen L |
| Rok vydání: | 2012 |
| Předmět: |
Genome instability
Genetic Screens Mad2 lcsh:Medicine Apoptosis Cell Cycle Proteins 0302 clinical medicine RNA interference Chromosome instability Molecular Cell Biology Basic Cancer Research NIMA-Related Kinase 1 Molecular Targeted Therapy lcsh:Science Cytoskeleton 0303 health sciences Gene knockdown Multidisciplinary Drosophila Melanogaster Chromosomal INstability (CIN) Animal Models female genital diseases and pregnancy complications 3. Good health Cell biology Spindle checkpoint Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques Medicine Drosophila Cell Division Research Article Cell Survival MAP Kinase Signaling System Mitosis Biology Protein Serine-Threonine Kinases 03 medical and health sciences Model Organisms Chromosomal Instability Genetics Cancer Genetics cancer Animals Humans neoplasms 030304 developmental biology lcsh:R Phosphotransferases Phosphoric Monoester Hydrolases M Phase Cell Cycle Checkpoints lcsh:Q |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 10, p e47447 (2012) |
| ISSN: | 1932-6203 |
| Popis: | 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 Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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