| Autor: |
Dina Dikovskaya, John J. Cole, Susan M. Mason, Colin Nixon, Saadia A. Karim, Lynn McGarry, William Clark, Rachael N. Hewitt, Morgan A. Sammons, Jiajun Zhu, Dimitris Athineos, Joshua D.G. Leach, Francesco Marchesi, John van Tuyn, Stephen W. Tait, Claire Brock, Jennifer P. Morton, Hong Wu, Shelley L. Berger, Karen Blyth, Peter D. Adams |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 12, Iss 9, Pp 1483-1496 (2015) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2015.07.055 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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