Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest
Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest
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DOI：
10.1016/j.celrep.2015.07.055
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发表时间：
2015-09-01
期刊：
影响因子：
8.8
通讯作者：
Adams, Peter D.
中科院分区：
文献类型：
--
作者：
Dikovskaya, Dina;Cole, John J.;Adams, Peter D.
癌基因诱导的衰老（OIS）是一种肿瘤抑制机制，阻断细胞增殖的致癌信号。OIS常伴有多核化;然而，其起源尚不清楚。在这里，我们表明，多核OIS细胞主要来自失败的有丝分裂。在衰老之前，原代人成纤维细胞中的突变体H-RasV 12激活损害了有丝分裂，这与功能上与所观察到的有丝分裂纺锤体和染色质缺陷相关的有丝分裂基因的异常表达一致。同时，H-RasV 12激活增强了有丝分裂受损细胞的存活，最终导致延长的有丝分裂停滞和通过有丝分裂滑移异常退出有丝分裂。ERK依赖的转录上调的Mcl 1是，至少在一定程度上，负责增强有丝分裂缺陷的细胞的存活和滑移。重要的是，有丝分裂滑移和癌基因信号协同诱导衰老和关键衰老效应子p21和p16。总之，激活的Ras协同触发有丝分裂破坏和增强的细胞存活以促进多核衰老细胞的形成。
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.