Lamin B1 loss is a senescence-associated biomarker.
Lamin B1 loss is a senescence-associated biomarker.
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DOI：
10.1091/mbc.e11-10-0884
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发表时间：
2012-06
影响因子：
3.3
通讯作者：
Campisi J
中科院分区：
文献类型：
--
作者：
Freund A;Laberge RM;Demaria M;Campisi J
这项研究严格定义核纤层蛋白B1损失作为衰老的标志，响应于所有经典的衰老信号，包括DNA损伤，癌基因激活和复制衰竭。这种下降是由p53或pRb通路的激活诱导的，并且在体内响应于衰老诱导剂量的辐射而发生。细胞衰老是一种有效的肿瘤抑制机制，可以阻止细胞增殖，并与衰老有关。然而，衰老的研究一直受到缺乏简单的，唯一的衰老状态的生物标志物。衰老细胞发生特征性的形态学变化，包括核增大和不规则以及染色质重组。由于核纤层的改变可以影响核形态和基因表达，我们研究了衰老细胞的核纤层。我们在这里表明，当原代人类和小鼠细胞株被DNA损伤、复制衰竭或癌基因表达诱导衰老时，核纤层蛋白B1丢失。核纤层蛋白B1的丢失不依赖于p38丝裂原活化蛋白激酶、核因子-κB、共济失调毛细血管扩张突变激酶或活性氧信号通路，这些都是衰老表型的正调节因子。然而，激活p53或pRB肿瘤抑制通路足以诱导核纤层蛋白B1损失。核纤层蛋白B1通过mRNA稳定性的降低而不是通过凋亡过程中观察到的半胱天冬酶介导的降解在mRNA水平下降。辐射诱导衰老后，小鼠组织中核纤层蛋白B1的蛋白和mRNA表达均下降。我们的研究结果表明，核纤层蛋白B1的损失可以作为在培养和体内衰老的生物标志物。
This study rigorously defines lamin B1 loss as a marker of senescence in response to all classic signals of senescence, including DNA damage, oncogene activation, and replicative exhaustion. This decline is induced by activation of either the p53 or the pRb pathway and occurs in vivo in response to a senescence-inducing dose of radiation. Cellular senescence is a potent tumor-suppressive mechanism that arrests cell proliferation and has been linked to aging. However, studies of senescence have been impeded by the lack of simple, exclusive biomarkers of the senescent state. Senescent cells develop characteristic morphological changes, which include enlarged and often irregular nuclei and chromatin reorganization. Because alterations to the nuclear lamina can affect both nuclear morphology and gene expression, we examined the nuclear lamina of senescent cells. We show here than lamin B1 is lost from primary human and murine cell strains when they are induced to senesce by DNA damage, replicative exhaustion, or oncogene expression. Lamin B1 loss did not depend on the p38 mitogen-activated protein kinase, nuclear factor-κB, ataxia telangiectasia–mutated kinase, or reactive oxygen species signaling pathways, which are positive regulators of senescent phenotypes. However, activation of either the p53 or pRB tumor suppressor pathway was sufficient to induce lamin B1 loss. Lamin B1 declined at the mRNA level via a decrease in mRNA stability rather than by the caspase-mediated degradation seen during apoptosis. Last, lamin B1 protein and mRNA declined in mouse tissue after senescence was induced by irradiation. Our findings suggest that lamin B1 loss can serve as biomarker of senescence both in culture and in vivo.