Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Dikovskaya, D. et al. (2015) Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest. Cell Reports, 12(9), pp. 1483-1496. (doi:10.1016/j.celrep.2015.07.055) (PMID:26299965) (PMCID:PMC4562906)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cole, Mr John and Blyth, Professor Karen and Hewitt, Miss Rachael and Nixon, Mr Colin and Reid, Mrs Claire and Marchesi, Dr Francesco and Clark, Mr William and Adams, Professor Peter and McGarry, Ms Lynn and van Tuyn, Dr John and Athineos, Mr Dimitris and Morton, Professor Jen and Tait, Professor Stephen and Mason, Miss Susan and Dikovskaya, Dr Dina and Karim, Ms Saadia
Authors: Dikovskaya, D., Cole, J. J., Mason, S. M., Nixon, C., Karim, S. A., McGarry, L., Clark, W., Hewitt, R. N., Sammons, M. A., Zhu, J., Athineos, D., Leach, J. D. G., Marchesi, F., van Tuyn, J., Tait, S. W., Brock, C., Morton, J. P., Wu, H., Berger, S. L., Blyth, K., and Adams, P. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier
ISSN:2211-1247
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Cell Reports 12(9):1483-1496
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
625581Senescence-associated chromatin changes a barrier to tumor progression.Peter AdamsCancer Research UK (CAN-RES-UK)16566ICS - EPIGENETICS