| The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent. | |
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MedLine Citation:
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PMID: 22293494 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aurora kinases are mitotic serine/threonine protein kinases and are attractive novel targets for anticancer therapy. Many small-molecule inhibitors of Aurora kinases are currently undergoing clinical trials. Aurora A kinase is essential for successful mitotic transition. MK8745 is a novel and selective small-molecule inhibitor of Aurora A kinase. MK8745 induced apoptotic cell death in a p53-dependent manner when tested in vitro in cell lines of multiple lineages. Cells expressing wild-type p53 showed a short delay in mitosis followed by cytokinesis, resulting in 2N cells along with apoptosis. However, cells lacking or with mutant p53 resulted in a prolonged arrest in mitosis followed by endoreduplication and polyploidy. Cytokinesis was completely inhibited in p53-deficient cells, as observed by the absence of 2N cell population. The induction of apoptosis in p53-proficient cells was associated with activation of caspase 3 and release of cytochrome c but was independent of p21. Exposure of p53 wild-type cells to MK8745 resulted in the induction of p53 phosphorylation (ser15) and an increase in p53 protein expression. p53-dependent apoptosis by MK8745 was further confirmed in HCT 116 p53(-/-) cells transfected with wild-type p53. Transient knockdown of Aurora A by specific siRNA recapitulated these p53- dependent effects, with greater percent induction of apoptosis in p53 wild-type cells. In conclusion, our studies show p53 as a determining factor for induction of apoptosis vs. polyploidy upon inhibition of Aurora A. |
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Authors:
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Jayasree S Nair; Alan L Ho; Gary K Schwartz |
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Publication Detail:
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Type: Journal Article Date: 2012-02-15 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 11 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-02-29 Completed Date: 2012-09-14 Revised Date: 2013-05-20 |
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: 807-17 Citation Subset: IM |
Affiliation:
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Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. nairj@mskcc.org |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Cell Cycle / drug effects, genetics Cell Proliferation / drug effects Flow Cytometry Fluorescent Antibody Technique HCT116 Cells Humans Microscopy, Fluorescence Polyploidy* Protein Kinase Inhibitors / pharmacology* Protein-Serine-Threonine Kinases / antagonists & inhibitors* Tumor Suppressor Protein p53 / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Protein Kinase Inhibitors; 0/Tumor Suppressor Protein p53; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase |
| Comments/Corrections | |
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