title: Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest.
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.
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: ddikovskaya@gmail.com.
authors: Dina
authors: D
authors: Dikovskaya
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK.
authors: John J
authors: JJ
authors: Cole
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Susan M
authors: SM
authors: Mason
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Colin
authors: C
authors: Nixon
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Saadia A
authors: SA
authors: Karim
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Lynn
authors: L
authors: McGarry
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: William
authors: W
authors: Clark
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK.
authors: Rachael N
authors: RN
authors: Hewitt
authors: Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6058, USA.
authors: Morgan A
authors: MA
authors: Sammons
authors: Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6058, USA.
authors: Jiajun
authors: J
authors: Zhu
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Dimitris
authors: D
authors: Athineos
authors: School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors: Joshua D G
authors: JD
authors: Leach
authors: School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors: Francesco
authors: F
authors: Marchesi
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK.
authors: John
authors: J
authors: van Tuyn
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK.
authors: Stephen W
authors: SW
authors: Tait
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK.
authors: Claire
authors: C
authors: Brock
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Jennifer P
authors: JP
authors: Morton
authors: Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
authors: Hong
authors: H
authors: Wu
authors: Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6058, USA.
authors: Shelley L
authors: SL
authors: Berger
authors: Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Karen
authors: K
authors: Blyth
authors: Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: p.adams@beatson.gla.ac.uk.
authors: Peter D
authors: PD
authors: Adams
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence; D015726:Giant Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008938:Mitosis; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018631:ras Proteins