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| Status |
Public on Aug 13, 2015 |
| Title |
Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signalling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here we show that multinucleate OIS cells originated mostly from failed mitosis. Prior to senescence, mutant RasV12 activation in primary human fibroblasts compromised mitosis, associated with abnormal expression of mitotic genes that enter M-phase. Simultaneously, RasV12 activation enhanced survival of damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional up-regulation of Mcl1 was responsible for enhanced slippage of cells with mitotic defects and subsequent cell survival. Importantly, mitotic slippage and oncogene signalling synergistically induced senescence and key senescence regulators p21 and p16. We propose that activated Ras induces transcriptional changes that predispose cells undergoing OIS to mitotic stress and multinucleation.
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| Overall design |
We used RNA-seq of IMR90 cells with inducible expression of oncogenic RasV12 that were synchronised in mitosis, to characterise the nature of mitotic defects that lead to multinucleation of oncogene-induced senescent cells
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| Contributor(s) |
Dikovskaya D, Cole JJ, Adams PD |
| Citation(s) |
26299965 |
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| Submission date |
Jul 09, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Peter Adams |
| Organization name |
University of Glasgow, Beatson Institute for Cancer Research
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| Street address |
Switchback Rd, Bearsden
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| City |
Glasgow |
| ZIP/Postal code |
G61 1BD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA289328 |
| SRA |
SRP060598 |
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