Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin
Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin
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DOI：
10.1073/pnas.1017935108
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发表时间：
2011-04-12
影响因子：
11.1
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
--
作者：
Avitabile, Daniele;Bailey, Brandi;Sussman, Mark A.
以核仁完整性丧失为特征的核仁应激，在心脏方面还没有被描述过。除了核糖体的生物发生外，核仁对细胞增殖和应激反应的控制也至关重要。我们的研究小组先前证明了核仁蛋白核干蛋白（NS）在心脏病理损伤反应中的诱导作用。NS与核磷蛋白（NPM）相互作用，核磷蛋白是具有细胞保护特性的核仁应激标志物。NS和NPM的动态行为表明，核仁破坏是与心脏细胞应激反应相关的早期事件。暴露于阿霉素或放线菌素d后，新生大鼠心肌细胞（NRCM）和心脏祖细胞（CPC）都会发生NS和NPM快速易位到核质中，并抑制新的核糖体前RNA合成。NS沉默可显著增加阿霉素治疗后CPC中NPM的细胞死亡，而NPM单独下调可诱导细胞死亡。NS或NPM过表达显著降低阿霉素刺激培养心肌细胞的caspase 8活性。小鼠心肌梗死引起的核仁结构改变支持了核仁应激作为病理性损伤的一般反应的模型。总的来说，这些发现作为心肌核仁应激的初步描述，并建立了核仁作为应激传感器，调节细胞对病理损伤的反应的假设。
Nucleolar stress, characterized by loss of nucleolar integrity, has not been described in the cardiac context. In addition to ribosome biogenesis, nucleoli are critical for control of cell proliferation and stress responses. Our group previously demonstrated induction of the nucleolar protein nucleostemin (NS) in response to cardiac pathological insult. NS interacts with nucleophosmin (NPM), a marker of nucleolar stress with cytoprotective properties. The dynamic behavior of NS and NPM reveal that nucleolar disruption is an early event associated with stress response in cardiac cells. Rapid translocation of NS and NPM to the nucleoplasm and suppression of new preribosomal RNA synthesis occurs in both neonatal rat cardiomyocytes (NRCM) and cardiac progenitor cells (CPC) upon exposure to doxorubicin or actinomycin D. Silencing of NS significantly increases cell death resulting from doxorubicin treatment in CPC, whereas NPM knockdown alone induces cell death. Overexpression of either NS or NPM significantly decreases caspase 8 activity in cultured cardiomyocytes challenged with doxorubicin. The presence of altered nucleolar structures resulting from myocardial infarction in mice supports the model of nucleolar stress as a general response to pathological injury. Collectively, these findings serve as the initial description of myocardial nucleolar stress and establish the postulate that nucleoli acts as sensors of stress, regulating the cellular response to pathological insults.