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Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition.

Sadaie, M; Dillon, C; Narita, M; Young, ARJ; Cairney, CJ; Godwin, LS; Torrance, CJ; Bennett, DC; Keith, WN; Narita, M (2015) Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition. Molecular Biology of the Cell, 26 (17). pp. 2971-2985. ISSN 1939-4586
SGUL Authors: Bennett, Dorothy Catherine

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Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.

Item Type: Article
Additional Information: © 2015 Sadaie et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (
Keywords: Aurora Kinase B, Cell Aging, Cell Division, Cell Line, Cell Nucleus, Chromosome Segregation, Cytokinesis, HeLa Cells, High-Throughput Screening Assays, Humans, Mitosis, Phenotype, Polyploidy, Protein Kinase Inhibitors, Small Molecule Libraries, Cell Line, Hela Cells, Cell Nucleus, Humans, Protein Kinase Inhibitors, Cell Aging, Cell Division, Chromosome Segregation, Cytokinesis, Mitosis, Phenotype, Polyploidy, Small Molecule Libraries, High-Throughput Screening Assays, Aurora Kinase B, Developmental Biology, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Molecular Biology of the Cell
ISSN: 1939-4586
Language: ENG
1 September 2015Published
23 June 2015Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-Share Alike 3.0
Project IDFunderFunder ID
A6691Cancer Research UK
A9892Cancer Research UK
PubMed ID: 26133385
Web of Science ID: WOS:000360133800003
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