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Updated: Apr 5, 2026
Generation and Isolation of Cell Cycle-arrested Cells with Complex Karyotypes
Published on: April 13, 2018
Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell
Dina Dikovskaya1, John J Cole1, Susan M Mason2
1Institute of Cancer Sciences, CR-UK Beatson Laboratories, University of Glasgow, Glasgow G61 1BD, 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.
Insights
Oncogene-induced senescence (OIS) causes multinucleation through failed mitosis. Activated Ras signaling disrupts cell division and promotes survival of damaged cells, leading to multinucleate senescent cells.
Area of Science:
- Cell Biology
- Cancer Biology
- Molecular Biology
Background:
- Oncogene-induced senescence (OIS) is a crucial tumor suppression mechanism.
- Multinucleation is a common feature of OIS, but its origin remains unclear.
Purpose of the Study:
- To investigate the origin of multinucleation during OIS.
- To elucidate the molecular mechanisms linking oncogene activation, mitosis, and senescence.
Main Methods:
- Utilized primary human fibroblasts expressing mutant H-RasV12.
- Analyzed mitotic progression, gene expression, and cell survival pathways.
- Investigated the roles of ERK signaling and Mcl1 in mitotic defects and senescence.
Main Results:
- Mutant H-RasV12 activation in fibroblasts disrupted mitosis, causing spindle and chromatin defects.
- H-RasV12 enhanced survival of cells with mitotic damage, promoting mitotic slippage.
- ERK-dependent Mcl1 upregulation contributed to mitotic slippage.
- Mitotic slippage and oncogene signaling cooperatively induced senescence, upregulating p21 and p16.
Conclusions:
- Multinucleate OIS cells primarily arise from failed mitosis.
- Activated Ras signaling coordinates mitotic disruption and enhanced cell survival to drive multinucleation in senescence.
