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)

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 > School 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
62558	1	Senescence-associated chromatin changes a barrier to tumor progression.	Peter Adams	Cancer Research UK (CAN-RES-UK)	16566	ICS - EPIGENETICS