Cell death during crisis is mediated by mitotic telomere deprotection.
Cell death during crisis is mediated by mitotic telomere deprotection.
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危机期间的细胞死亡是由有丝分裂端粒脱保护介导的。
DOI：
10.1038/nature14513
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发表时间：
2015-06-25
期刊：
影响因子：
64.8
通讯作者：
Karlseder, Jan
中科院分区：
文献类型：
--
作者：
Hayashi, Makoto T.;Cesare, Anthony J.;Rivera, Teresa;Karlseder, Jan
肿瘤的形成受到两个障碍的阻碍，即复制性衰老和危机。衰老是由短端粒引发的，并通过肿瘤抑制途径的破坏而绕过。在衰老旁路之后，细胞经历危机，在此期间，群体中几乎所有的细胞都死亡。逃避危机的细胞具有不稳定的基因组和其他转化参数。危机期间细胞死亡的机制仍然难以捉摸。我们发现，危机中的细胞进行自发的有丝分裂停滞，导致在有丝分裂过程中或在以下的细胞周期死亡。该表型由p53功能丧失诱导，并被端粒酶过表达抑制。端粒融合触发有丝分裂停滞在p53受损的非危机细胞，表明这种融合的根本原因。通过部分TRF2敲低而加重的有丝分裂端粒去保护增加了在有丝分裂停滞期间死亡的细胞的比率，并且使癌细胞对有丝分裂毒物敏感。我们提出了一个危机途径，其中染色体融合诱导有丝分裂停滞，导致有丝分裂端粒脱保护和细胞死亡，从而消除癌前细胞的人口。
Tumour formation is blocked by two barriers, replicative senescence and crisis. Senescence is triggered by short telomeres and is bypassed by disruption of tumour suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbor unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remained elusive. We show that cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. The phenotype was induced by loss of p53 function, and suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating such fusions as the underlying cause. Exacerbation of mitotic telomere deprotection by partial TRF2 knockdown increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.
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DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F
影响因子：
3.3
作者：
Dalton, W. Brian;Yang, Vincent W.
通讯作者：
Yang, Vincent W.
影响因子：
3.7
作者：
Stevens D;Gassmann R;Oegema K;Desai A
通讯作者：
Desai A
影响因子：
9.2
作者：
Smogorzewska, A;Karlseder, J;de Lange, T
通讯作者：
de Lange, T