Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation
Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation
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DOI：
10.1038/emboj.2011.492
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发表时间：
2012-03-07
期刊：
影响因子：
11.4
通讯作者：
Bertrand, Pascale
中科院分区：
文献类型：
--
作者：
Barascu, Aurelia;Le Chalony, Catherine;Bertrand, Pascale
我们报告了三种衰老诱导条件、DNA 损伤反应 (DDR) 缺陷、氧化应激 (OS) 和核形状改变之间的串扰。隐性常染色体遗传病毛细血管扩张共济失调 (A-T) 与 DDR 缺陷、内源性 OS 和过早衰老有关。在这里，我们发现 A-T 细胞中频繁的核形状改变，以及关键核结构成分核纤层蛋白 B1 的积累。核纤层蛋白 B1 过度表达足以诱导野生型细胞的核形状改变和衰老，而 A-T 细胞中核纤层蛋白 B1 水平的正常化会反过来减少核形状改变和衰老。我们进一步表明，OS 通过 p38 丝裂原激活蛋白激酶激活来增加核纤层蛋白 B1 水平。核纤层蛋白 B1 积累和核形状改变也会发生在应激诱导的衰老和癌基因诱导的衰老 (OIS) 这两种典型的衰老情况下。这些数据揭示核纤层蛋白 B1 作为控制 OS 诱导的衰老的通用分子介质，与 OIS 中已确定的共济失调毛细血管扩张突变 (ATM) 作用无关。 EMBO 杂志 (2012) 31, 1080-1094。 doi：10.1038/emboj.2011.492；在线发表 2012 年 1 月 13 日 主题类别：基因组稳定性与动态；疾病分子生物学
We report crosstalk between three senescence-inducing conditions, DNA damage response (DDR) defects, oxidative stress (OS) and nuclear shape alterations. The recessive autosomal genetic disorder Ataxia telangiectasia (A-T) is associated with DDR defects, endogenous OS and premature ageing. Here, we find frequent nuclear shape alterations in A-T cells, as well as accumulation of the key nuclear architecture component lamin B1. Lamin B1 overexpression is sufficient to induce nuclear shape alterations and senescence in wild-type cells, and normalizing lamin B1 levels in A-T cells reciprocally reduces both nuclear shape alterations and senescence. We further show that OS increases lamin B1 levels through p38 Mitogen Activated Protein kinase activation. Lamin B1 accumulation and nuclear shape alterations also occur during stress-induced senescence and oncogene-induced senescence (OIS), two canonical senescence situations. These data reveal lamin B1 as a general molecular mediator that controls OS-induced senescence, independent of established Ataxia Telangiectasia Mutated (ATM) roles in OIS. The EMBO Journal (2012) 31, 1080-1094. doi: 10.1038/emboj.2011.492; Published online 13 January 2012 Subject Categories: genome stability & dynamics; molecular biology of disease