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Cell Rep. 2015 Sep 1;12(9):1483-96. doi: 10.1016/j.celrep.2015.07.055. Epub 2015 Aug 20.

Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest.

Author information

1
Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: ddikovskaya@gmail.com.
2
Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK.
3
Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
4
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6058, USA.
5
School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.
6
Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
7
Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: p.adams@beatson.gla.ac.uk.

Abstract

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells.

PMID:
26299965
PMCID:
PMC4562906
DOI:
10.1016/j.celrep.2015.07.055
[Indexed for MEDLINE]
Free PMC Article

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