Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition
| Autor: | Mahito Sadaie, Christian Dillon, Masashi Narita, Andrew R. J. Young, Claire J. Cairney, Lauren S. Godwin, Christopher J. Torrance, Dorothy C. Bennett, W. Nicol Keith |
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| Přispěvatelé: | Narita, Masashi [0000-0001-7764-577X], Narita, Masako [0000-0002-9774-4908], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Senescence
Population Mitosis Biology Cell Line Chromosome segregation Polyploidy Small Molecule Libraries Chromosome Segregation Aurora Kinase B Humans education Molecular Biology Protein Kinase Inhibitors Cellular Senescence Cytokinesis Genetics Cell Nucleus education.field_of_study Cell Cycle Articles Cell Biology Cell biology High-Throughput Screening Assays Spindle checkpoint Phenotype Chromosome passenger complex Cell Division HeLa Cells |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1059-1524 1939-4586 |
| Popis: | Compound screening for altered nuclear phenotypes identifies several promiscuous kinase inhibitors that trigger progression of senescence during a polyploid G1. Their common target is AURKB. More-specific inhibition of AURKB phenocopies these compounds, demonstrating a causative role for AURKB defects in a unique mode of senescence development. 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. |
| Databáze: | OpenAIRE |
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